Daily Papers

Multimodal Large Language Models (MLLMs) have seen growing adoption across various scientific disciplines. These advancements encourage the investigation of molecule-text modeling within synthetic chemistry, a field dedicated to designing and conducting chemical reactions to synthesize new compounds with desired properties and applications. Current approaches, however, often neglect the critical role of multiple molecule graph interaction in understanding chemical reactions, leading to suboptimal performance in synthetic chemistry tasks. This study introduces PRESTO(Progressive Pretraining Enhances Synthetic Chemistry Outcomes), a new framework that bridges the molecule-text modality gap by integrating a comprehensive benchmark of pretraining strategies and dataset configurations. It progressively improves multimodal LLMs through cross-modal alignment and multi-graph understanding. Our extensive experiments demonstrate that PRESTO offers competitive results in downstream synthetic chemistry tasks. The code can be found at https://github.com/IDEA-XL/PRESTO.

In this paper we present SynKB, an open-source, automatically extracted knowledge base of chemical synthesis protocols. Similar to proprietary chemistry databases such as Reaxsys, SynKB allows chemists to retrieve structured knowledge about synthetic procedures. By taking advantage of recent advances in natural language processing for procedural texts, SynKB supports more flexible queries about reaction conditions, and thus has the potential to help chemists search the literature for conditions used in relevant reactions as they design new synthetic routes. Using customized Transformer models to automatically extract information from 6 million synthesis procedures described in U.S. and EU patents, we show that for many queries, SynKB has higher recall than Reaxsys, while maintaining high precision. We plan to make SynKB available as an open-source tool; in contrast, proprietary chemistry databases require costly subscriptions.

Recent advances in Large Language Models (LLMs) have shown that their reasoning capabilities can be significantly improved through Reinforcement Learning with Verifiable Reward (RLVR), particularly in domains like mathematics and programming, where ground-truth correctness can be automatically evaluated. However, extending this success to other reasoning-intensive domains remains challenging due to the scarcity of high-quality, verifiable datasets and the high cost of human supervision. In this work, we introduce the Loong Project: an open-source framework for scalable synthetic data generation and verification across a diverse range of reasoning-intensive domains. The framework consists of two key components: (1) LoongBench, a curated seed dataset containing 8,729 human-vetted examples across 12 domains (e.g., Advanced Mathematics, Chemistry, Logic), each paired with executable code and rich metadata; and (2) LoongEnv, a modular synthetic data generation environment that supports multiple prompting strategies to produce new question-answer-code triples. Together, these components form an agent-environment loop that enables reinforcement learning, where an LLM-based agent is rewarded for generating Chain-of-Thought (CoT) solutions that align with code-executed answers. Empirically, we benchmark LoongBench on a broad suite of both open-source and proprietary LLMs to evaluate domain coverage and reveal performance bottlenecks. In addition, we conduct a comprehensive analysis of synthetic data generated by LoongEnv, examining correctness, difficulty, and diversity. Code and documentation are available at https://github.com/camel-ai/loong.

Organic reaction mechanisms are the stepwise elementary reactions by which reactants form intermediates and products, and are fundamental to understanding chemical reactivity and designing new molecules and reactions. Although large language models (LLMs) have shown promise in understanding chemical tasks such as synthesis design, it is unclear to what extent this reflects genuine chemical reasoning capabilities, i.e., the ability to generate valid intermediates, maintain chemical consistency, and follow logically coherent multi-step pathways. We address this by introducing oMeBench, the first large-scale, expert-curated benchmark for organic mechanism reasoning in organic chemistry. It comprises over 10,000 annotated mechanistic steps with intermediates, type labels, and difficulty ratings. Furthermore, to evaluate LLM capability more precisely and enable fine-grained scoring, we propose oMeS, a dynamic evaluation framework that combines step-level logic and chemical similarity. We analyze the performance of state-of-the-art LLMs, and our results show that although current models display promising chemical intuition, they struggle with correct and consistent multi-step reasoning. Notably, we find that using prompting strategy and fine-tuning a specialist model on our proposed dataset increases performance by 50% over the leading closed-source model. We hope that oMeBench will serve as a rigorous foundation for advancing AI systems toward genuine chemical reasoning.

The automatic analysis of chemical literature has immense potential to accelerate the discovery of new materials and drugs. Much of the critical information in patent documents and scientific articles is contained in figures, depicting the molecule structures. However, automatically parsing the exact chemical structure is a formidable challenge, due to the amount of detailed information, the diversity of drawing styles, and the need for training data. In this work, we introduce MolGrapher to recognize chemical structures visually. First, a deep keypoint detector detects the atoms. Second, we treat all candidate atoms and bonds as nodes and put them in a graph. This construct allows a natural graph representation of the molecule. Last, we classify atom and bond nodes in the graph with a Graph Neural Network. To address the lack of real training data, we propose a synthetic data generation pipeline producing diverse and realistic results. In addition, we introduce a large-scale benchmark of annotated real molecule images, USPTO-30K, to spur research on this critical topic. Extensive experiments on five datasets show that our approach significantly outperforms classical and learning-based methods in most settings. Code, models, and datasets are available.

We introduce SynFormer, a generative modeling framework designed to efficiently explore and navigate synthesizable chemical space. Unlike traditional molecular generation approaches, we generate synthetic pathways for molecules to ensure that designs are synthetically tractable. By incorporating a scalable transformer architecture and a diffusion module for building block selection, SynFormer surpasses existing models in synthesizable molecular design. We demonstrate SynFormer's effectiveness in two key applications: (1) local chemical space exploration, where the model generates synthesizable analogs of a reference molecule, and (2) global chemical space exploration, where the model aims to identify optimal molecules according to a black-box property prediction oracle. Additionally, we demonstrate the scalability of our approach via the improvement in performance as more computational resources become available. With our code and trained models openly available, we hope that SynFormer will find use across applications in drug discovery and materials science.

Over the last decades, excellent computational chemistry tools have been developed. Their full potential has not yet been reached as most are challenging to learn and exist in isolation. Recently, large-language models (LLMs) have shown strong performance in tasks across domains, but struggle with chemistry-related problems. Moreover, these models lack access to external knowledge sources, limiting their usefulness in scientific applications. In this study, we introduce ChemCrow, an LLM chemistry agent designed to accomplish tasks across organic synthesis, drug discovery, and materials design. By integrating 17 expert-designed tools, ChemCrow augments the LLM performance in chemistry, and new capabilities emerge. Our agent autonomously planned the syntheses of an insect repellent, three organocatalysts, as well as other relevant molecules. Our evaluation, including both LLM and expert assessments, demonstrates ChemCrow's effectiveness in automating a diverse set of chemical tasks. Surprisingly, we find that GPT-4 as an evaluator cannot distinguish between clearly wrong GPT-4 completions and Chemcrow's performance. There is a significant risk of misuse of tools like ChemCrow, and we discuss their potential harms. Employed responsibly, our work not only aids expert chemists and lowers barriers for non-experts, but also fosters scientific advancement by bridging the gap between experimental and computational chemistry. A subset of the code is publicly available at https://github.com/ur-whitelab/chemcrow-public.

The efficient exploration of chemical space to design molecules with intended properties enables the accelerated discovery of drugs, materials, and catalysts, and is one of the most important outstanding challenges in chemistry. Encouraged by the recent surge in computer power and artificial intelligence development, many algorithms have been developed to tackle this problem. However, despite the emergence of many new approaches in recent years, comparatively little progress has been made in developing realistic benchmarks that reflect the complexity of molecular design for real-world applications. In this work, we develop a set of practical benchmark tasks relying on physical simulation of molecular systems mimicking real-life molecular design problems for materials, drugs, and chemical reactions. Additionally, we demonstrate the utility and ease of use of our new benchmark set by demonstrating how to compare the performance of several well-established families of algorithms. Surprisingly, we find that model performance can strongly depend on the benchmark domain. We believe that our benchmark suite will help move the field towards more realistic molecular design benchmarks, and move the development of inverse molecular design algorithms closer to designing molecules that solve existing problems in both academia and industry alike.

Methods for designing organic materials with desired properties have high potential impact across fields such as medicine, renewable energy, petrochemical engineering, and agriculture. However, using generative modeling to design substances with desired properties is difficult because candidate compounds must satisfy multiple constraints, including synthetic accessibility and other metrics that are intuitive to domain experts but challenging to quantify. We propose C5T5, a novel self-supervised pretraining method that enables transformers to make zero-shot select-and-replace edits, altering organic substances towards desired property values. C5T5 operates on IUPAC names -- a standardized molecular representation that intuitively encodes rich structural information for organic chemists but that has been largely ignored by the ML community. Our technique requires no edited molecule pairs to train and only a rough estimate of molecular properties, and it has the potential to model long-range dependencies and symmetric molecular structures more easily than graph-based methods. C5T5 also provides a powerful interface to domain experts: it grants users fine-grained control over the generative process by selecting and replacing IUPAC name fragments, which enables experts to leverage their intuitions about structure-activity relationships. We demonstrate C5T5's effectiveness on four physical properties relevant for drug discovery, showing that it learns successful and chemically intuitive strategies for altering molecules towards desired property values.

While large language models (LLMs) with Chain-of-Thought (CoT) reasoning excel in mathematics and coding, their potential for systematic reasoning in chemistry, a domain demanding rigorous structural analysis for real-world tasks like drug design and reaction engineering, remains untapped. Current benchmarks focus on simple knowledge retrieval, neglecting step-by-step reasoning required for complex tasks such as molecular optimization and reaction prediction. To address this, we introduce ChemCoTBench, a reasoning framework that bridges molecular structure understanding with arithmetic-inspired operations, including addition, deletion, and substitution, to formalize chemical problem-solving into transparent, step-by-step workflows. By treating molecular transformations as modular "chemical operations", the framework enables slow-thinking reasoning, mirroring the logic of mathematical proofs while grounding solutions in real-world chemical constraints. We evaluate models on two high-impact tasks: Molecular Property Optimization and Chemical Reaction Prediction. These tasks mirror real-world challenges while providing structured evaluability. By providing annotated datasets, a reasoning taxonomy, and baseline evaluations, ChemCoTBench bridges the gap between abstract reasoning methods and practical chemical discovery, establishing a foundation for advancing LLMs as tools for AI-driven scientific innovation.

Large Language Models(LLMs) have demonstrated remarkable performance across various domains, yet their capabilities in molecular reasoning remain insufficiently explored. Current approaches tend to rely heavily on general-purpose prompting, which lacks domain-specific molecular semantics, while those that use fine-tuning strategies often face challenges with interpretability and reasoning depth. To address these issues, we introduce MolReasoner, a two-stage framework designed to transition LLMs from memorization towards chemical reasoning. First, we propose Mol-SFT, which initializes the model's reasoning abilities via synthetic Chain-of-Thought(CoT) samples generated by GPT-4o and verified for chemical accuracy. Subsequently, Mol-RL applies reinforcement learning with specialized reward functions designed explicitly to align chemical structures with linguistic descriptions, thereby enhancing molecular reasoning capabilities. Our approach notably enhances interpretability, improving the model 's molecular understanding and enabling better generalization. Extensive experiments demonstrate that MolReasoner outperforms existing methods, and marking a significant shift from memorization-based outputs to robust chemical reasoning.

Retrosynthetic planning aims to devise a complete multi-step synthetic route from starting materials to a target molecule. Current strategies use a decoupled approach of single-step retrosynthesis models and search algorithms, taking only the product as the input to predict the reactants for each planning step and ignoring valuable context information along the synthetic route. In this work, we propose a novel framework that utilizes context information for improved retrosynthetic planning. We view synthetic routes as reaction graphs and propose to incorporate context through three principled steps: encode molecules into embeddings, aggregate information over routes, and readout to predict reactants. Our approach is the first attempt to utilize in-context learning for retrosynthesis prediction in retrosynthetic planning. The entire framework can be efficiently optimized in an end-to-end fashion and produce more practical and accurate predictions. Comprehensive experiments demonstrate that by fusing in the context information over routes, our model significantly improves the performance of retrosynthetic planning over baselines that are not context-aware, especially for long synthetic routes. Code is available at https://github.com/SongtaoLiu0823/FusionRetro.

Large language models (LLMs) have gained widespread interest due to their ability to process human language and perform tasks on which they have not been explicitly trained. This is relevant for the chemical sciences, which face the problem of small and diverse datasets that are frequently in the form of text. LLMs have shown promise in addressing these issues and are increasingly being harnessed to predict chemical properties, optimize reactions, and even design and conduct experiments autonomously. However, we still have only a very limited systematic understanding of the chemical reasoning capabilities of LLMs, which would be required to improve models and mitigate potential harms. Here, we introduce "ChemBench," an automated framework designed to rigorously evaluate the chemical knowledge and reasoning abilities of state-of-the-art LLMs against the expertise of human chemists. We curated more than 7,000 question-answer pairs for a wide array of subfields of the chemical sciences, evaluated leading open and closed-source LLMs, and found that the best models outperformed the best human chemists in our study on average. The models, however, struggle with some chemical reasoning tasks that are easy for human experts and provide overconfident, misleading predictions, such as about chemicals' safety profiles. These findings underscore the dual reality that, although LLMs demonstrate remarkable proficiency in chemical tasks, further research is critical to enhancing their safety and utility in chemical sciences. Our findings also indicate a need for adaptations to chemistry curricula and highlight the importance of continuing to develop evaluation frameworks to improve safe and useful LLMs.

Transformer-based deep neural networks have revolutionized the field of molecular-related prediction tasks by treating molecules as symbolic sequences. These models have been successfully applied in various organic chemical applications by pretraining them with extensive compound libraries and subsequently fine-tuning them with smaller in-house datasets for specific tasks. However, many conventional methods primarily focus on single molecules, with limited exploration of pretraining for reactions involving multiple molecules. In this paper, we propose ReactionT5, a novel model that leverages pretraining on the Open Reaction Database (ORD), a publicly available large-scale resource. We further fine-tune this model for yield prediction and product prediction tasks, demonstrating its impressive performance even with limited fine-tuning data compared to traditional models. The pre-trained ReactionT5 model is publicly accessible on the Hugging Face platform.

High-throughput reaction condition (RC) screening is fundamental to chemical synthesis. However, current RC screening suffers from laborious and costly trial-and-error workflows. Traditional computer-aided synthesis planning (CASP) tools fail to find suitable RCs due to data sparsity and inadequate reaction representations. Nowadays, large language models (LLMs) are capable of tackling chemistry-related problems, such as molecule design, and chemical logic Q\&A tasks. However, LLMs have not yet achieved accurate predictions of chemical reaction conditions. Here, we present MM-RCR, a text-augmented multimodal LLM that learns a unified reaction representation from SMILES, reaction graphs, and textual corpus for chemical reaction recommendation (RCR). To train MM-RCR, we construct 1.2 million pair-wised Q\&A instruction datasets. Our experimental results demonstrate that MM-RCR achieves state-of-the-art performance on two open benchmark datasets and exhibits strong generalization capabilities on out-of-domain (OOD) and High-Throughput Experimentation (HTE) datasets. MM-RCR has the potential to accelerate high-throughput condition screening in chemical synthesis.

Despite their ability to understand chemical knowledge, large language models (LLMs) remain limited in their capacity to propose novel molecules with desired functions (e.g., drug-like properties). In addition, the molecules that LLMs propose can often be challenging to make, and are almost never compatible with automated synthesis approaches. To better enable the discovery of functional small molecules, LLMs need to learn a new molecular language that is more effective in predicting properties and inherently synced with automated synthesis technology. Current molecule LLMs are limited by representing molecules based on atoms. In this paper, we argue that just like tokenizing texts into meaning-bearing (sub-)word tokens instead of characters, molecules should be tokenized at the level of functional building blocks, i.e., parts of molecules that bring unique functions and serve as effective building blocks for real-world automated laboratory synthesis. This motivates us to propose mCLM, a modular Chemical-Language Model that comprises a bilingual language model that understands both natural language descriptions of functions and molecular blocks. mCLM front-loads synthesizability considerations while improving the predicted functions of molecules in a principled manner. mCLM, with only 3B parameters, achieves improvements in synthetic accessibility relative to 7 other leading generative AI methods including GPT-5. When tested on 122 out-of-distribution medicines using only building blocks/tokens that are compatible with automated modular synthesis, mCLM outperforms all baselines in property scores and synthetic accessibility. mCLM can also reason on multiple functions and iteratively self-improve to rescue drug candidates that failed late in clinical trials ("fallen angels").

Designing de-novo molecules with desired property profiles requires efficient exploration of the vast chemical space ranging from 10^{23} to 10^{60} possible synthesizable candidates. While various deep generative models have been developed to design small molecules using diverse input representations, Molecular Large Language Models (Mol-LLMs) based on string representations have emerged as a scalable approach capable of exploring billions of molecules. However, there remains limited understanding regarding how standard language modeling practices such as textual representations, tokenization strategies, model size, and dataset scale impact molecular generation performance. In this work, we systematically investigate these critical aspects by introducing NovoMolGen, a family of transformer-based foundation models pretrained on 1.5 billion molecules for de-novo molecule generation. Through extensive empirical analyses, we identify a weak correlation between performance metrics measured during pretraining and actual downstream performance, revealing important distinctions between molecular and general NLP training dynamics. NovoMolGen establishes new state-of-the-art results, substantially outperforming prior Mol-LLMs and specialized generative models in both unconstrained and goal-directed molecular generation tasks, thus providing a robust foundation for advancing efficient and effective molecular modeling strategies.

Materials synthesis is vital for innovations such as energy storage, catalysis, electronics, and biomedical devices. Yet, the process relies heavily on empirical, trial-and-error methods guided by expert intuition. Our work aims to support the materials science community by providing a practical, data-driven resource. We have curated a comprehensive dataset of 17K expert-verified synthesis recipes from open-access literature, which forms the basis of our newly developed benchmark, AlchemyBench. AlchemyBench offers an end-to-end framework that supports research in large language models applied to synthesis prediction. It encompasses key tasks, including raw materials and equipment prediction, synthesis procedure generation, and characterization outcome forecasting. We propose an LLM-as-a-Judge framework that leverages large language models for automated evaluation, demonstrating strong statistical agreement with expert assessments. Overall, our contributions offer a supportive foundation for exploring the capabilities of LLMs in predicting and guiding materials synthesis, ultimately paving the way for more efficient experimental design and accelerated innovation in materials science.

Generative models have demonstrated substantial promise in Natural Language Processing (NLP) and have found application in designing molecules, as seen in General Pretrained Transformer (GPT) models. In our efforts to develop such a tool for exploring the organic chemical space in search of potentially electro-active compounds, we present "LLamol", a single novel generative transformer model based on the LLama 2 architecture, which was trained on a 13M superset of organic compounds drawn from diverse public sources. To allow for a maximum flexibility in usage and robustness in view of potentially incomplete data, we introduce "Stochastic Context Learning" as a new training procedure. We demonstrate that the resulting model adeptly handles single- and multi-conditional organic molecule generation with up to four conditions, yet more are possible. The model generates valid molecular structures in SMILES notation while flexibly incorporating three numerical and/or one token sequence into the generative process, just as requested. The generated compounds are very satisfactory in all scenarios tested. In detail, we showcase the model's capability to utilize token sequences for conditioning, either individually or in combination with numerical properties, making LLamol a potent tool for de novo molecule design, easily expandable with new properties.

Chemical reasoning usually involves complex, multi-step processes that demand precise calculations, where even minor errors can lead to cascading failures. Furthermore, large language models (LLMs) encounter difficulties handling domain-specific formulas, executing reasoning steps accurately, and integrating code effectively when tackling chemical reasoning tasks. To address these challenges, we present ChemAgent, a novel framework designed to improve the performance of LLMs through a dynamic, self-updating library. This library is developed by decomposing chemical tasks into sub-tasks and compiling these sub-tasks into a structured collection that can be referenced for future queries. Then, when presented with a new problem, ChemAgent retrieves and refines pertinent information from the library, which we call memory, facilitating effective task decomposition and the generation of solutions. Our method designs three types of memory and a library-enhanced reasoning component, enabling LLMs to improve over time through experience. Experimental results on four chemical reasoning datasets from SciBench demonstrate that ChemAgent achieves performance gains of up to 46% (GPT-4), significantly outperforming existing methods. Our findings suggest substantial potential for future applications, including tasks such as drug discovery and materials science. Our code can be found at https://github.com/gersteinlab/chemagent

Molecule generation with desired properties has grown immensely in popularity by disruptively changing the way scientists design molecular structures and providing support for chemical and materials design. However, despite the promising outcome, previous machine learning-based deep generative models suffer from a reliance on complex, task-specific fine-tuning, limited dimensional latent spaces, or the quality of expert rules. In this work, we propose MolGen, a pre-trained molecular language model that effectively learns and shares knowledge across multiple generation tasks and domains. Specifically, we pre-train MolGen with the chemical language SELFIES on more than 100 million unlabelled molecules. We further propose multi-task molecular prefix tuning across several molecular generation tasks and different molecular domains (synthetic & natural products) with a self-feedback mechanism. Extensive experiments show that MolGen can obtain superior performances on well-known molecular generation benchmark datasets. The further analysis illustrates that MolGen can accurately capture the distribution of molecules, implicitly learn their structural characteristics, and efficiently explore the chemical space with the guidance of multi-task molecular prefix tuning. Codes, datasets, and the pre-trained model will be available in https://github.com/zjunlp/MolGen.

Although large language models (LLMs) have significant potential to advance chemical discovery, current LLMs lack core chemical knowledge, produce unreliable reasoning trajectories, and exhibit suboptimal performance across diverse chemical tasks. To address these challenges, we propose Chem-R, a generalizable Chemical Reasoning model designed to emulate the deliberative processes of chemists. Chem-R is trained through a three-phase framework that progressively builds advanced reasoning capabilities, including: 1) Chemical Foundation Training, which establishes core chemical knowledge. 2) Chemical Reasoning Protocol Distillation, incorporating structured, expert-like reasoning traces to guide systematic and reliable problem solving. 3) Multi-task Group Relative Policy Optimization that optimizes the model for balanced performance across diverse molecular- and reaction-level tasks. This structured pipeline enables Chem-R to achieve state-of-the-art performance on comprehensive benchmarks, surpassing leading large language models, including Gemini-2.5-Pro and DeepSeek-R1, by up to 46% on molecular tasks and 66% on reaction tasks. Meanwhile, Chem-R also consistently outperforms the existing chemical foundation models across both molecular and reaction level tasks. These results highlight Chem-R's robust generalization, interpretability, and potential as a foundation for next-generation AI-driven chemical discovery.

Machine learning has promised to change the landscape of laboratory chemistry, with impressive results in molecular property prediction and reaction retro-synthesis. However, chemical datasets are often inaccessible to the machine learning community as they tend to require cleaning, thorough understanding of the chemistry, or are simply not available. In this paper, we introduce a novel dataset for yield prediction, providing the first-ever transient flow dataset for machine learning benchmarking, covering over 1200 process conditions. While previous datasets focus on discrete parameters, our experimental set-up allow us to sample a large number of continuous process conditions, generating new challenges for machine learning models. We focus on solvent selection, a task that is particularly difficult to model theoretically and therefore ripe for machine learning applications. We showcase benchmarking for regression algorithms, transfer-learning approaches, feature engineering, and active learning, with important applications towards solvent replacement and sustainable manufacturing.

The study demonstrates the capabilities of a vector-based approach for calculating stoichiometric coefficients in chemical equations, using black powder as an illustrative example. A method is proposed for selecting and constraining intermediate interactions between reactants, as well as for identifying final products. It is shown that even a small number of components can lead to a large number of final and intermediate products. Through concrete calculations, a correlation is established between the number of possible chemical equations and the number of reactants. A methodology is proposed for computing all possible chemical equations within a reaction system for arbitrary component ratios, enabling the derivation of all feasible chemical reactions. Additionally, a method is developed for calculating the chemical composition for a fixed set of reactants, allowing for the evaluation of the set of products resulting from all possible chemical interactions given a specified initial composition.

This paper studies the problem of solving complex chemistry problems with large language models (LLMs). Despite the extensive general knowledge in LLMs (such as GPT-4), they struggle with chemistry reasoning that requires faithful grounded reasoning with diverse chemical knowledge and an integrative understanding of chemical interactions. We propose InstructChem, a new structured reasoning approach that substantially boosts the LLMs' chemical reasoning capabilities. InstructChem explicitly decomposes the reasoning into three critical phrases, including chemical formulae generation by LLMs that offers the basis for subsequent grounded reasoning, step-by-step reasoning that makes multi-step derivations with the identified formulae for a preliminary answer, and iterative review-and-refinement that steers LLMs to progressively revise the previous phases for increasing confidence, leading to the final high-confidence answer. We conduct extensive experiments on four different chemistry challenges, including quantum chemistry, quantum mechanics, physical chemistry, and chemistry kinetics. Our approach significantly enhances GPT-4 on chemistry reasoning, yielding an 8% average absolute improvement and a 30% peak improvement. We further use the generated reasoning by GPT-4 to fine-tune smaller LMs (e.g., Vicuna) and observe strong improvement of the smaller LMs. This validates our approach and enables LLMs to generate high-quality reasoning.

The automated analysis of chemical literature holds promise to accelerate discovery in fields such as material science and drug development. In particular, search capabilities for chemical structures and Markush structures (chemical structure templates) within patent documents are valuable, e.g., for prior-art search. Advancements have been made in the automatic extraction of chemical structures from text and images, yet the Markush structures remain largely unexplored due to their complex multi-modal nature. In this work, we present MarkushGrapher, a multi-modal approach for recognizing Markush structures in documents. Our method jointly encodes text, image, and layout information through a Vision-Text-Layout encoder and an Optical Chemical Structure Recognition vision encoder. These representations are merged and used to auto-regressively generate a sequential graph representation of the Markush structure along with a table defining its variable groups. To overcome the lack of real-world training data, we propose a synthetic data generation pipeline that produces a wide range of realistic Markush structures. Additionally, we present M2S, the first annotated benchmark of real-world Markush structures, to advance research on this challenging task. Extensive experiments demonstrate that our approach outperforms state-of-the-art chemistry-specific and general-purpose vision-language models in most evaluation settings. Code, models, and datasets will be available.

Molecular structure recognition is the task of translating a molecular image into its graph structure. Significant variation in drawing styles and conventions exhibited in chemical literature poses a significant challenge for automating this task. In this paper, we propose MolScribe, a novel image-to-graph generation model that explicitly predicts atoms and bonds, along with their geometric layouts, to construct the molecular structure. Our model flexibly incorporates symbolic chemistry constraints to recognize chirality and expand abbreviated structures. We further develop data augmentation strategies to enhance the model robustness against domain shifts. In experiments on both synthetic and realistic molecular images, MolScribe significantly outperforms previous models, achieving 76-93% accuracy on public benchmarks. Chemists can also easily verify MolScribe's prediction, informed by its confidence estimation and atom-level alignment with the input image. MolScribe is publicly available through Python and web interfaces: https://github.com/thomas0809/MolScribe.

The success of AI models relies on the availability of large, diverse, and high-quality datasets, which can be challenging to obtain due to data scarcity, privacy concerns, and high costs. Synthetic data has emerged as a promising solution by generating artificial data that mimics real-world patterns. This paper provides an overview of synthetic data research, discussing its applications, challenges, and future directions. We present empirical evidence from prior art to demonstrate its effectiveness and highlight the importance of ensuring its factuality, fidelity, and unbiasedness. We emphasize the need for responsible use of synthetic data to build more powerful, inclusive, and trustworthy language models.

Machine learning (ML) models hold the promise of transforming atomic simulations by delivering quantum chemical accuracy at a fraction of the computational cost. Realization of this potential would enable high-throughout, high-accuracy molecular screening campaigns to explore vast regions of chemical space and facilitate ab initio simulations at sizes and time scales that were previously inaccessible. However, a fundamental challenge to creating ML models that perform well across molecular chemistry is the lack of comprehensive data for training. Despite substantial efforts in data generation, no large-scale molecular dataset exists that combines broad chemical diversity with a high level of accuracy. To address this gap, Meta FAIR introduces Open Molecules 2025 (OMol25), a large-scale dataset composed of more than 100 million density functional theory (DFT) calculations at the omegaB97M-V/def2-TZVPD level of theory, representing billions of CPU core-hours of compute. OMol25 uniquely blends elemental, chemical, and structural diversity including: 83 elements, a wide-range of intra- and intermolecular interactions, explicit solvation, variable charge/spin, conformers, and reactive structures. There are ~83M unique molecular systems in OMol25 covering small molecules, biomolecules, metal complexes, and electrolytes, including structures obtained from existing datasets. OMol25 also greatly expands on the size of systems typically included in DFT datasets, with systems of up to 350 atoms. In addition to the public release of the data, we provide baseline models and a comprehensive set of model evaluations to encourage community engagement in developing the next-generation ML models for molecular chemistry.

Large language models (LLMs) have recently demonstrated promising capabilities in chemistry tasks while still facing challenges due to outdated pretraining knowledge and the difficulty of incorporating specialized chemical expertise. To address these issues, we propose an LLM-based agent that synergistically integrates 137 external chemical tools created ranging from basic information retrieval to complex reaction predictions, and a dataset curation pipeline to generate the dataset ChemToolBench that facilitates both effective tool selection and precise parameter filling during fine-tuning and evaluation. We introduce a Hierarchical Evolutionary Monte Carlo Tree Search (HE-MCTS) framework, enabling independent optimization of tool planning and execution. By leveraging self-generated data, our approach supports step-level fine-tuning (FT) of the policy model and training task-adaptive PRM and ORM that surpass GPT-4o. Experimental evaluations demonstrate that our approach significantly improves performance in Chemistry QA and discovery tasks, offering a robust solution to integrate specialized tools with LLMs for advanced chemical applications. All datasets and code are available at https://github.com/AI4Chem/ChemistryAgent .

In molecular research, simulation \& design of molecules are key areas with significant implications for drug development, material science, and other fields. Current classical computational power falls inadequate to simulate any more than small molecules, let alone protein chains on hundreds of peptide. Therefore these experiment are done physically in wet-lab, but it takes a lot of time \& not possible to examine every molecule due to the size of the search area, tens of billions of dollars are spent every year in these research experiments. Molecule simulation \& design has lately advanced significantly by machine learning models, A fresh perspective on the issue of chemical synthesis is provided by deep generative models for graph-structured data. By optimising differentiable models that produce molecular graphs directly, it is feasible to avoid costly search techniques in the discrete and huge space of chemical structures. But these models also suffer from computational limitations when dimensions become huge and consume huge amount of resources. Quantum Generative machine learning in recent years have shown some empirical results promising significant advantages over classical counterparts.

To enhance large language models (LLMs) for chemistry problem solving, several LLM-based agents augmented with tools have been proposed, such as ChemCrow and Coscientist. However, their evaluations are narrow in scope, leaving a large gap in understanding the benefits of tools across diverse chemistry tasks. To bridge this gap, we develop ChemAgent, an enhanced chemistry agent over ChemCrow, and conduct a comprehensive evaluation of its performance on both specialized chemistry tasks and general chemistry questions. Surprisingly, ChemAgent does not consistently outperform its base LLMs without tools. Our error analysis with a chemistry expert suggests that: For specialized chemistry tasks, such as synthesis prediction, we should augment agents with specialized tools; however, for general chemistry questions like those in exams, agents' ability to reason correctly with chemistry knowledge matters more, and tool augmentation does not always help.

Identifying reliable synthesis pathways in materials chemistry is a complex task, particularly in polymer science, due to the intricate and often non-unique nomenclature of macromolecules. To address this challenge, we propose an agent system that integrates large language models (LLMs) and knowledge graphs (KGs). By leveraging LLMs' powerful capabilities for extracting and recognizing chemical substance names, and storing the extracted data in a structured knowledge graph, our system fully automates the retrieval of relevant literatures, extraction of reaction data, database querying, construction of retrosynthetic pathway trees, further expansion through the retrieval of additional literature and recommendation of optimal reaction pathways. A novel Multi-branched Reaction Pathway Search (MBRPS) algorithm enables the exploration of all pathways, with a particular focus on multi-branched ones, helping LLMs overcome weak reasoning in multi-branched paths. This work represents the first attempt to develop a fully automated retrosynthesis planning agent tailored specially for macromolecules powered by LLMs. Applied to polyimide synthesis, our new approach constructs a retrosynthetic pathway tree with hundreds of pathways and recommends optimized routes, including both known and novel pathways, demonstrating its effectiveness and potential for broader applications.

The recent success of large foundation models in artificial intelligence has prompted the emergence of chemical pre-trained models. Despite the growing interest in large molecular pre-trained models that provide informative representations for downstream tasks, attempts for multimodal pre-training approaches on the molecule domain were limited. To address this, we present a novel multimodal molecular pre-trained model that incorporates the modalities of structure and biochemical properties, drawing inspiration from recent advances in multimodal learning techniques. Our proposed model pipeline of data handling and training objectives aligns the structure/property features in a common embedding space, which enables the model to regard bidirectional information between the molecules' structure and properties. These contributions emerge synergistic knowledge, allowing us to tackle both multimodal and unimodal downstream tasks through a single model. Through extensive experiments, we demonstrate that our model shows remarkable capabilities in solving various meaningful chemical challenges, including conditional molecule generation, property prediction, molecule classification, and reaction prediction.

De novo design seeks to generate molecules with required property profiles by virtual design-make-test cycles. With the emergence of deep learning and neural generative models in many application areas, models for molecular design based on neural networks appeared recently and show promising results. However, the new models have not been profiled on consistent tasks, and comparative studies to well-established algorithms have only seldom been performed. To standardize the assessment of both classical and neural models for de novo molecular design, we propose an evaluation framework, GuacaMol, based on a suite of standardized benchmarks. The benchmark tasks encompass measuring the fidelity of the models to reproduce the property distribution of the training sets, the ability to generate novel molecules, the exploration and exploitation of chemical space, and a variety of single and multi-objective optimization tasks. The benchmarking open-source Python code, and a leaderboard can be found on https://benevolent.ai/guacamol

Quantitative chemistry is central to modern chemical research, yet the ability of large language models (LLMs) to perform its rigorous, step-by-step calculations remains underexplored. To fill this blank, we propose QCBench, a Quantitative Chemistry oriented benchmark comprising 350 computational chemistry problems across 7 chemistry subfields, which contains analytical chemistry, bio/organic chemistry, general chemistry, inorganic chemistry, physical chemistry, polymer chemistry and quantum chemistry. To systematically evaluate the mathematical reasoning abilities of large language models (LLMs), they are categorized into three tiers: easy, medium, and difficult. Each problem, rooted in realistic chemical scenarios, is structured to prevent heuristic shortcuts and demand explicit numerical reasoning. QCBench enables fine-grained diagnosis of computational weaknesses, reveals model-specific limitations across difficulty levels, and lays the groundwork for future improvements such as domain-adaptive fine-tuning or multi-modal integration. Evaluations on 24 LLMs demonstrate a consistent performance degradation with increasing task complexity, highlighting the current gap between language fluency and scientific computation accuracy. Code for QCBench is available at https://github.com/jiaqingxie/QCBench.

Molecule-text modeling, which aims to facilitate molecule-relevant tasks with a textual interface and textual knowledge, is an emerging research direction. Beyond single molecules, studying reaction-text modeling holds promise for helping the synthesis of new materials and drugs. However, previous works mostly neglect reaction-text modeling: they primarily focus on modeling individual molecule-text pairs or learning chemical reactions without texts in context. Additionally, one key task of reaction-text modeling -- experimental procedure prediction -- is less explored due to the absence of an open-source dataset. The task is to predict step-by-step actions of conducting chemical experiments and is crucial to automating chemical synthesis. To resolve the challenges above, we propose a new pretraining method, ReactXT, for reaction-text modeling, and a new dataset, OpenExp, for experimental procedure prediction. Specifically, ReactXT features three types of input contexts to incrementally pretrain LMs. Each of the three input contexts corresponds to a pretraining task to improve the text-based understanding of either reactions or single molecules. ReactXT demonstrates consistent improvements in experimental procedure prediction and molecule captioning and offers competitive results in retrosynthesis. Our code is available at https://github.com/syr-cn/ReactXT.

Retrosynthesis planning, essential in organic synthesis and drug discovery, has greatly benefited from recent AI-driven advancements. Nevertheless, existing methods frequently face limitations in both applicability and explainability. Traditional graph-based and sequence-to-sequence models often lack generalized chemical knowledge, leading to predictions that are neither consistently accurate nor easily explainable. To address these challenges, we introduce RetroDFM-R, a reasoning-based large language model (LLM) designed specifically for chemical retrosynthesis. Leveraging large-scale reinforcement learning guided by chemically verifiable rewards, RetroDFM-R significantly enhances prediction accuracy and explainability. Comprehensive evaluations demonstrate that RetroDFM-R significantly outperforms state-of-the-art methods, achieving a top-1 accuracy of 65.0% on the USPTO-50K benchmark. Double-blind human assessments further validate the chemical plausibility and practical utility of RetroDFM-R's predictions. RetroDFM-R also accurately predicts multistep retrosynthetic routes reported in the literature for both real-world drug molecules and perovskite materials. Crucially, the model's explicit reasoning process provides human-interpretable insights, thereby enhancing trust and practical value in real-world retrosynthesis applications.

Generative models for molecules have shown considerable promise for use in computational chemistry, but remain difficult to use for non-experts. For this reason, we introduce open-source infrastructure for easily building generative molecular models into the widely used DeepChem [Ramsundar et al., 2019] library with the aim of creating a robust and reusable molecular generation pipeline. In particular, we add high quality PyTorch [Paszke et al., 2019] implementations of the Molecular Generative Adversarial Networks (MolGAN) [Cao and Kipf, 2022] and Normalizing Flows [Papamakarios et al., 2021]. Our implementations show strong performance comparable with past work [Kuznetsov and Polykovskiy, 2021, Cao and Kipf, 2022].

Central to our understanding of chemical reactivity is the principle of mass conservation, which is fundamental for ensuring physical consistency, balancing equations, and guiding reaction design. However, data-driven computational models for tasks such as reaction product prediction rarely abide by this most basic constraint. In this work, we recast the problem of reaction prediction as a problem of electron redistribution using the modern deep generative framework of flow matching. Our model, FlowER, overcomes limitations inherent in previous approaches by enforcing exact mass conservation, thereby resolving hallucinatory failure modes, recovering mechanistic reaction sequences for unseen substrate scaffolds, and generalizing effectively to out-of-domain reaction classes with extremely data-efficient fine-tuning. FlowER additionally enables estimation of thermodynamic or kinetic feasibility and manifests a degree of chemical intuition in reaction prediction tasks. This inherently interpretable framework represents a significant step in bridging the gap between predictive accuracy and mechanistic understanding in data-driven reaction outcome prediction.

Reasoning models are large language models that emit a long chain-of-thought before answering, providing both higher accuracy and explicit reasoning for their response. A major question has been whether language model reasoning generalizes beyond mathematics, programming, and logic, where most previous work has focused. We demonstrate that reasoning models can be post-trained for chemistry without additional domain pretraining, and require substantially less data compared to contemporary domain-specific models. We report ether0, a 24B parameter LLM (based on Mistral-Small-24B) that can reason in natural language and respond with chemical structures. This reasoning model was trained with reinforcement learning on 640,730 experimentally-grounded chemistry problems across 375 tasks ranging from synthesizability, to blood-brain barrier permeability, to human receptor activity, to scent. Our model exceeds general-purpose chemistry models, frontier models, and human experts on molecular design tasks. It is also more data efficient relative to specialized models. We anticipate that this method can be applied to train data-efficient language models specialized for tasks across a wide variety of scientific domains.

Large Language Models (LLMs) with strong abilities in natural language processing tasks have emerged and have been rapidly applied in various kinds of areas such as science, finance and software engineering. However, the capability of LLMs to advance the field of chemistry remains unclear. In this paper,we establish a comprehensive benchmark containing 8 practical chemistry tasks, including 1) name prediction, 2) property prediction, 3) yield prediction, 4) reaction prediction, 5) retrosynthesis (prediction of reactants from products), 6)text-based molecule design, 7) molecule captioning, and 8) reagent selection. Our analysis draws on widely recognized datasets including BBBP, Tox21, PubChem, USPTO, and ChEBI, facilitating a broad exploration of the capacities of LLMs within the context of practical chemistry. Three GPT models (GPT-4, GPT-3.5,and Davinci-003) are evaluated for each chemistry task in zero-shot and few-shot in-context learning settings with carefully selected demonstration examples and specially crafted prompts. The key results of our investigation are 1) GPT-4 outperforms the other two models among the three evaluated; 2) GPT models exhibit less competitive performance in tasks demanding precise understanding of molecular SMILES representation, such as reaction prediction and retrosynthesis;3) GPT models demonstrate strong capabilities in text-related explanation tasks such as molecule captioning; and 4) GPT models exhibit comparable or better performance to classical machine learning models when applied to chemical problems that can be transformed into classification or ranking tasks, such as property prediction, and yield prediction.

Large language models (LLMs) achieve strong performance across diverse tasks, largely driven by high-quality web data used in pre-training. However, recent studies indicate this data source is rapidly depleting. Synthetic data emerges as a promising alternative, but it remains unclear whether synthetic datasets exhibit predictable scalability comparable to raw pre-training data. In this work, we systematically investigate the scaling laws of synthetic data by introducing SynthLLM, a scalable framework that transforms pre-training corpora into diverse, high-quality synthetic datasets. Our approach achieves this by automatically extracting and recombining high-level concepts across multiple documents using a graph algorithm. Key findings from our extensive mathematical experiments on SynthLLM include: (1) SynthLLM generates synthetic data that reliably adheres to the rectified scaling law across various model sizes; (2) Performance improvements plateau near 300B tokens; and (3) Larger models approach optimal performance with fewer training tokens. For instance, an 8B model peaks at 1T tokens, while a 3B model requires 4T. Moreover, comparisons with existing synthetic data generation and augmentation methods demonstrate that SynthLLM achieves superior performance and scalability. Our findings highlight synthetic data as a scalable and reliable alternative to organic pre-training corpora, offering a viable path toward continued improvement in model performance.

The success of language models, especially transformer-based architectures, has trickled into other domains giving rise to "scientific language models" that operate on small molecules, proteins or polymers. In chemistry, language models contribute to accelerating the molecule discovery cycle as evidenced by promising recent findings in early-stage drug discovery. Here, we review the role of language models in molecular discovery, underlining their strength in de novo drug design, property prediction and reaction chemistry. We highlight valuable open-source software assets thus lowering the entry barrier to the field of scientific language modeling. Last, we sketch a vision for future molecular design that combines a chatbot interface with access to computational chemistry tools. Our contribution serves as a valuable resource for researchers, chemists, and AI enthusiasts interested in understanding how language models can and will be used to accelerate chemical discovery.

Generating novel molecules with out-of-distribution properties is a major challenge in molecular discovery. While supervised learning methods generate high-quality molecules similar to those in a dataset, they struggle to generalize to out-of-distribution properties. Reinforcement learning can explore new chemical spaces but often conducts 'reward-hacking' and generates non-synthesizable molecules. In this work, we address this problem by integrating a state-of-the-art supervised learning method, STGG+, in an active learning loop. Our approach iteratively generates, evaluates, and fine-tunes STGG+ to continuously expand its knowledge. We denote this approach STGG+AL. We apply STGG+AL to the design of organic pi-functional materials, specifically two challenging tasks: 1) generating highly absorptive molecules characterized by high oscillator strength and 2) designing absorptive molecules with reasonable oscillator strength in the near-infrared (NIR) range. The generated molecules are validated and rationalized in-silico with time-dependent density functional theory. Our results demonstrate that our method is highly effective in generating novel molecules with high oscillator strength, contrary to existing methods such as reinforcement learning (RL) methods. We open-source our active-learning code along with our Conjugated-xTB dataset containing 2.9 million pi-conjugated molecules and the function for approximating the oscillator strength and absorption wavelength (based on sTDA-xTB).

Accurately classifying chemical structures is essential for cheminformatics and bioinformatics, including tasks such as identifying bioactive compounds of interest, screening molecules for toxicity to humans, finding non-organic compounds with desirable material properties, or organizing large chemical libraries for drug discovery or environmental monitoring. However, manual classification is labor-intensive and difficult to scale to large chemical databases. Existing automated approaches either rely on manually constructed classification rules, or the use of deep learning methods that lack explainability. This work presents an approach that uses generative artificial intelligence to automatically write chemical classifier programs for classes in the Chemical Entities of Biological Interest (ChEBI) database. These programs can be used for efficient deterministic run-time classification of SMILES structures, with natural language explanations. The programs themselves constitute an explainable computable ontological model of chemical class nomenclature, which we call the ChEBI Chemical Class Program Ontology (C3PO). We validated our approach against the ChEBI database, and compared our results against state of the art deep learning models. We also demonstrate the use of C3PO to classify out-of-distribution examples taken from metabolomics repositories and natural product databases. We also demonstrate the potential use of our approach to find systematic classification errors in existing chemical databases, and show how an ensemble artificial intelligence approach combining generated ontologies, automated literature search, and multimodal vision models can be used to pinpoint potential errors requiring expert validation

Large language models (LLMs) have made impressive progress in chemistry applications, including molecular property prediction, molecular generation, experimental protocol design, etc. However, the community lacks a dialogue-based model specifically designed for chemistry. The challenge arises from the fact that most chemical data and scientific knowledge are primarily stored in structured databases, and the direct use of these structured data compromises the model's ability to maintain coherent dialogue. To tackle this issue, we develop a novel template-based instruction construction method that transforms structured knowledge into plain dialogue, making it suitable for language model training. By leveraging this approach, we develop ChemLLM, the first large language model dedicated to chemistry, capable of performing various tasks across chemical disciplines with smooth dialogue interaction. ChemLLM beats GPT-3.5 on all three principal tasks in chemistry, i.e., name conversion, molecular caption, and reaction prediction, and surpasses GPT-4 on two of them. Remarkably, ChemLLM also shows exceptional adaptability to related mathematical and physical tasks despite being trained mainly on chemical-centric corpora. Furthermore, ChemLLM demonstrates proficiency in specialized NLP tasks within chemistry, such as literature translation and cheminformatic programming. ChemLLM opens up a new avenue for exploration within chemical studies, while our method of integrating structured chemical knowledge into dialogue systems sets a new frontier for developing LLMs across various scientific fields. Codes, Datasets, and Model weights are publicly accessible at hf.co/AI4Chem/ChemLLM-7B-Chat.

Progress in computer-aided synthesis planning (CASP) is obscured by the lack of standardized evaluation infrastructure and the reliance on metrics that prioritize topological completion over chemical validity. We introduce RetroCast, a unified evaluation suite that standardizes heterogeneous model outputs into a common schema to enable statistically rigorous, apples-to-apples comparison. The framework includes a reproducible benchmarking pipeline with stratified sampling and bootstrapped confidence intervals, accompanied by SynthArena, an interactive platform for qualitative route inspection. We utilize this infrastructure to evaluate leading search-based and sequence-based algorithms on a new suite of standardized benchmarks. Our analysis reveals a divergence between "solvability" (stock-termination rate) and route quality; high solvability scores often mask chemical invalidity or fail to correlate with the reproduction of experimental ground truths. Furthermore, we identify a "complexity cliff" in which search-based methods, despite high solvability rates, exhibit a sharp performance decay in reconstructing long-range synthetic plans compared to sequence-based approaches. We release the full framework, benchmark definitions, and a standardized database of model predictions to support transparent and reproducible development in the field.

Large language models (LLMs) have emerged as powerful tools in chemistry, significantly impacting molecule design, property prediction, and synthesis optimization. This review highlights LLM capabilities in these domains and their potential to accelerate scientific discovery through automation. We also review LLM-based autonomous agents: LLMs with a broader set of tools to interact with their surrounding environment. These agents perform diverse tasks such as paper scraping, interfacing with automated laboratories, and synthesis planning. As agents are an emerging topic, we extend the scope of our review of agents beyond chemistry and discuss across any scientific domains. This review covers the recent history, current capabilities, and design of LLMs and autonomous agents, addressing specific challenges, opportunities, and future directions in chemistry. Key challenges include data quality and integration, model interpretability, and the need for standard benchmarks, while future directions point towards more sophisticated multi-modal agents and enhanced collaboration between agents and experimental methods. Due to the quick pace of this field, a repository has been built to keep track of the latest studies: https://github.com/ur-whitelab/LLMs-in-science.

Accurate prediction of atomistic, thermodynamic, and kinetic properties from molecular structures underpins materials innovation. Existing computational and experimental approaches lack the scalability required to efficiently navigate chemical space. Scientific foundation models trained on large unlabeled datasets offer a path toward exploring chemical space across diverse application domains. Here we develop MIST, a family of molecular foundation models with up to an order of magnitude more parameters and data than prior works. Trained using a novel tokenization scheme that comprehensively captures nuclear, electronic, and geometric information, MIST learns from a diverse range of molecules. MIST models have been fine-tuned to predict more than 400 structure -- property relationships and match or exceed state-of-the-art performance across benchmarks spanning physiology, electrochemistry, and quantum chemistry. We demonstrate the ability of these models to solve real-world problems across chemical space, including multiobjective electrolyte solvent screening, olfactory perception mapping, isotope half-life prediction, stereochemical reasoning for chiral organometallic compounds, and binary and multi-component mixture property prediction. Probing MIST models using mechanistic interpretability methods reveals identifiable patterns and trends not explicitly present in the training data, suggesting that the models learn generalizable scientific concepts. We formulate hyperparameter-penalized Bayesian neural scaling laws and use them to reduce the computational cost of model development by an order of magnitude. The methods and findings presented here represent a significant step toward accelerating materials discovery, design, and optimization using foundation models and provide valuable guidance for training compute-optimal scientific foundation models.

Deep generative models have recently achieved superior performance in 3D molecule generation. Most of them first generate atoms and then add chemical bonds based on the generated atoms in a post-processing manner. However, there might be no corresponding bond solution for the temporally generated atoms as their locations are generated without considering potential bonds. We define this problem as the atom-bond inconsistency problem and claim it is the main reason for current approaches to generating unrealistic 3D molecules. To overcome this problem, we propose a new diffusion model called MolDiff which can generate atoms and bonds simultaneously while still maintaining their consistency by explicitly modeling the dependence between their relationships. We evaluated the generation ability of our proposed model and the quality of the generated molecules using criteria related to both geometry and chemical properties. The empirical studies showed that our model outperforms previous approaches, achieving a three-fold improvement in success rate and generating molecules with significantly better quality.

Retrosynthesis planning poses a formidable challenge in the organic chemical industry, particularly in pharmaceuticals. Single-step retrosynthesis prediction, a crucial step in the planning process, has witnessed a surge in interest in recent years due to advancements in AI for science. Various deep learning-based methods have been proposed for this task in recent years, incorporating diverse levels of additional chemical knowledge dependency. This paper introduces UAlign, a template-free graph-to-sequence pipeline for retrosynthesis prediction. By combining graph neural networks and Transformers, our method can more effectively leverage the inherent graph structure of molecules. Based on the fact that the majority of molecule structures remain unchanged during a chemical reaction, we propose a simple yet effective SMILES alignment technique to facilitate the reuse of unchanged structures for reactant generation. Extensive experiments show that our method substantially outperforms state-of-the-art template-free and semi-template-based approaches. Importantly, Our template-free method achieves effectiveness comparable to, or even surpasses, established powerful template-based methods. Scientific contribution: We present a novel graph-to-sequence template-free retrosynthesis prediction pipeline that overcomes the limitations of Transformer-based methods in molecular representation learning and insufficient utilization of chemical information. We propose an unsupervised learning mechanism for establishing product-atom correspondence with reactant SMILES tokens, achieving even better results than supervised SMILES alignment methods. Extensive experiments demonstrate that UAlign significantly outperforms state-of-the-art template-free methods and rivals or surpasses template-based approaches, with up to 5\% (top-5) and 5.4\% (top-10) increased accuracy over the strongest baseline.

Accurate thermochemical data with sub-chemical accuracy (i.e., within pm1 kcal mol^{-1} from sufficiently accurate experimental or theoretical reference data) is essential for the development and improvement of computational chemistry methods. Challenging thermochemical properties such as heats of formation and total atomization energies (TAEs) are of particular interest because they rigorously test the ability of computational chemistry methods to accurately describe complex chemical transformations involving multiple bond rearrangements. Yet, existing thermochemical datasets that confidently reach this level of accuracy are limited in either size or scope. Datasets with highly accurate reference values include a small number of data points, and larger datasets provide less accurate data or only cover a narrow portion of the chemical space. The existing datasets are therefore insufficient for developing data-driven methods with predictive accuracy over a large chemical space. The Microsoft Research Accurate Chemistry Collection (MSR-ACC) will address this challenge. Here, it offers the MSR-ACC/TAE25 dataset of 76,879 total atomization energies obtained at the CCSD(T)/CBS level via the W1-F12 thermochemical protocol. The dataset is constructed to exhaustively cover chemical space for all elements up to argon by enumerating and sampling chemical graphs, thus avoiding bias towards any particular subspace of the chemical space (such as drug-like, organic, or experimentally observed molecules). With this first dataset in MSR-ACC, we enable data-driven approaches for developing predictive computational chemistry methods with unprecedented accuracy and scope.

Precise recognition, editing, and generation of molecules are essential prerequisites for both chemists and AI systems tackling various chemical tasks. We present MolLangBench, a comprehensive benchmark designed to evaluate fundamental molecule-language interface tasks: language-prompted molecular structure recognition, editing, and generation. To ensure high-quality, unambiguous, and deterministic outputs, we construct the recognition tasks using automated cheminformatics tools, and curate editing and generation tasks through rigorous expert annotation and validation. MolLangBench supports the evaluation of models that interface language with different molecular representations, including linear strings, molecular images, and molecular graphs. Evaluations of state-of-the-art models reveal significant limitations: the strongest model (o3) achieves 79.2% and 78.5% accuracy on recognition and editing tasks, which are intuitively simple for humans, and performs even worse on the generation task, reaching only 29.0% accuracy. These results highlight the shortcomings of current AI systems in handling even preliminary molecular recognition and manipulation tasks. We hope MolLangBench will catalyze further research toward more effective and reliable AI systems for chemical applications.

Polymeric nano- and micro-scale particles have critical roles in tackling critical healthcare and energy challenges with their miniature characteristics. However, tailoring their synthesis process to meet specific design targets has traditionally depended on domain expertise and costly trial-and-errors. Recently, modeling strategies, particularly Bayesian optimization (BO), have been proposed to aid materials discovery for maximized/minimized properties. Coming from practical demands, this study for the first time integrates constrained and composite Bayesian optimization (CCBO) to perform efficient target value optimization under black-box feasibility constraints and limited data for laboratory experimentation. Using a synthetic problem that simulates electrospraying, a model nanomanufacturing process, CCBO strategically avoided infeasible conditions and efficiently optimized particle production towards predefined size targets, surpassing standard BO pipelines and providing decisions comparable to human experts. Further laboratory experiments validated CCBO capability to guide the rational synthesis of poly(lactic-co-glycolic acid) (PLGA) particles with diameters of 300 nm and 3.0 mum via electrospraying. With minimal initial data and unknown experiment constraints, CCBO reached the design targets within 4 iterations. Overall, the CCBO approach presents a versatile and holistic optimization paradigm for next-generation target-driven particle synthesis empowered by artificial intelligence (AI).

The task of chemical reaction predictions (CRPs) plays a pivotal role in advancing drug discovery and material science. However, its effectiveness is constrained by the vast and uncertain chemical reaction space and challenges in capturing reaction selectivity, particularly due to existing methods' limitations in exploiting the data's inherent knowledge. To address these challenges, we introduce a data-curated self-feedback knowledge elicitation approach. This method starts from iterative optimization of molecular representations and facilitates the extraction of knowledge on chemical reaction types (RTs). Then, we employ adaptive prompt learning to infuse the prior knowledge into the large language model (LLM). As a result, we achieve significant enhancements: a 14.2% increase in retrosynthesis prediction accuracy, a 74.2% rise in reagent prediction accuracy, and an expansion in the model's capability for handling multi-task chemical reactions. This research offers a novel paradigm for knowledge elicitation in scientific research and showcases the untapped potential of LLMs in CRPs.

Chemical similarity searches are widely used in-silico methods for identifying new drug-like molecules. These methods have historically relied on structure-based comparisons to compute molecular similarity. Here, we use a chemical language model to create a vector-based chemical search. We extend implementations by creating a prompt engineering strategy that utilizes two different chemical string representation algorithms: one for the query and the other for the database. We explore this method by reviewing the search results from five drug-like query molecules (penicillin G, nirmatrelvir, zidovudine, lysergic acid diethylamide, and fentanyl) and three dye-like query molecules (acid blue 25, avobenzone, and 2-diphenylaminocarbazole). We find that this novel method identifies molecules that are functionally similar to the query, indicated by the associated patent literature, and that many of these molecules are structurally distinct from the query, making them unlikely to be found with traditional chemical similarity search methods. This method may aid in the discovery of novel structural classes of molecules that achieve target functionality.

Advancements in machine learning and artificial intelligence are transforming materials discovery. Yet, the availability of structured experimental data remains a bottleneck. The vast corpus of scientific literature presents a valuable and rich resource of such data. However, manual dataset creation from these resources is challenging due to issues in maintaining quality and consistency, scalability limitations, and the risk of human error and bias. Therefore, in this work, we develop a chemist AI agent, powered by large language models (LLMs), to overcome these challenges by autonomously creating structured datasets from natural language text, ranging from sentences and paragraphs to extensive scientific research articles. Our chemist AI agent, Eunomia, can plan and execute actions by leveraging the existing knowledge from decades of scientific research articles, scientists, the Internet and other tools altogether. We benchmark the performance of our approach in three different information extraction tasks with various levels of complexity, including solid-state impurity doping, metal-organic framework (MOF) chemical formula, and property relations. Our results demonstrate that our zero-shot agent, with the appropriate tools, is capable of attaining performance that is either superior or comparable to the state-of-the-art fine-tuned materials information extraction methods. This approach simplifies compilation of machine learning-ready datasets for various materials discovery applications, and significantly ease the accessibility of advanced natural language processing tools for novice users in natural language. The methodology in this work is developed as an open-source software on https://github.com/AI4ChemS/Eunomia.

Despite significant progress of generative models in the natural sciences, their controllability remains challenging. One fundamentally missing aspect of molecular or protein generative models is an inductive bias that can reflect continuous properties of interest. To that end, we propose the Regression Transformer (RT), a novel method that abstracts regression as a conditional sequence modeling problem. This introduces a new paradigm of multitask language models which seamlessly bridge sequence regression and conditional sequence generation. We thoroughly demonstrate that, despite using a nominal-scale training objective, the RT matches or surpasses the performance of conventional regression models in property prediction tasks of small molecules, proteins and chemical reactions. Critically, priming the same model with continuous properties yields a highly competitive conditional generative model that outperforms specialized approaches in a substructure-constrained, property-driven molecule generation benchmark. Our dichotomous approach is facilitated by a novel, alternating training scheme that enables the model to decorate seed sequences by desired properties, e.g., to optimize reaction yield. In sum, the RT is the first report of a multitask model that concurrently excels at predictive and generative tasks in biochemistry. This finds particular application in property-driven, local exploration of the chemical or protein space and could pave the road toward foundation models in material design. The code to reproduce all experiments of the paper is available at: https://github.com/IBM/regression-transformer

Diffusion models have demonstrated remarkable success in various domains, including molecular generation. However, conditional molecular generation remains a fundamental challenge due to an intrinsic trade-off between targeting specific chemical properties and generating meaningful samples from the data distribution. In this work, we present Time-Aware Conditional Synthesis (TACS), a novel approach to conditional generation on diffusion models. It integrates adaptively controlled plug-and-play "online" guidance into a diffusion model, driving samples toward the desired properties while maintaining validity and stability. A key component of our algorithm is our new type of diffusion sampler, Time Correction Sampler (TCS), which is used to control guidance and ensure that the generated molecules remain on the correct manifold at each reverse step of the diffusion process at the same time. Our proposed method demonstrates significant performance in conditional 3D molecular generation and offers a promising approach towards inverse molecular design, potentially facilitating advancements in drug discovery, materials science, and other related fields.

Simulating rare events, such as the transformation of a reactant into a product in a chemical reaction typically requires enhanced sampling techniques that rely on heuristically chosen collective variables (CVs). We propose using differentiable simulations (DiffSim) for the discovery and enhanced sampling of chemical transformations without a need to resort to preselected CVs, using only a distance metric. Reaction path discovery and estimation of the biasing potential that enhances the sampling are merged into a single end-to-end problem that is solved by path-integral optimization. This is achieved by introducing multiple improvements over standard DiffSim such as partial backpropagation and graph mini-batching making DiffSim training stable and efficient. The potential of DiffSim is demonstrated in the successful discovery of transition paths for the Muller-Brown model potential as well as a benchmark chemical system - alanine dipeptide.

Large Language Models (LLMs) have shown growing potential in molecular sciences, but they often produce chemically inaccurate descriptions and struggle to recognize or justify potential errors. This raises important concerns about their robustness and reliability in scientific applications. To support more rigorous evaluation of LLMs in chemical reasoning, we present the MolErr2Fix benchmark, designed to assess LLMs on error detection and correction in molecular descriptions. Unlike existing benchmarks focused on molecule-to-text generation or property prediction, MolErr2Fix emphasizes fine-grained chemical understanding. It tasks LLMs with identifying, localizing, explaining, and revising potential structural and semantic errors in molecular descriptions. Specifically, MolErr2Fix consists of 1,193 fine-grained annotated error instances. Each instance contains quadruple annotations, i.e,. (error type, span location, the explanation, and the correction). These tasks are intended to reflect the types of reasoning and verification required in real-world chemical communication. Evaluations of current state-of-the-art LLMs reveal notable performance gaps, underscoring the need for more robust chemical reasoning capabilities. MolErr2Fix provides a focused benchmark for evaluating such capabilities and aims to support progress toward more reliable and chemically informed language models. All annotations and an accompanying evaluation API will be publicly released to facilitate future research.

Leveraging new data sources is a key step in accelerating the pace of materials design and discovery. To complement the strides in synthesis planning driven by historical, experimental, and computed data, we present an automated method for connecting scientific literature to synthesis insights. Starting from natural language text, we apply word embeddings from language models, which are fed into a named entity recognition model, upon which a conditional variational autoencoder is trained to generate syntheses for arbitrary materials. We show the potential of this technique by predicting precursors for two perovskite materials, using only training data published over a decade prior to their first reported syntheses. We demonstrate that the model learns representations of materials corresponding to synthesis-related properties, and that the model's behavior complements existing thermodynamic knowledge. Finally, we apply the model to perform synthesizability screening for proposed novel perovskite compounds.

In recent decades, chemistry publications and patents have increased rapidly. A significant portion of key information is embedded in molecular structure figures, complicating large-scale literature searches and limiting the application of large language models in fields such as biology, chemistry, and pharmaceuticals. The automatic extraction of precise chemical structures is of critical importance. However, the presence of numerous Markush structures in real-world documents, along with variations in molecular image quality, drawing styles, and noise, significantly limits the performance of existing optical chemical structure recognition (OCSR) methods. We present MolParser, a novel end-to-end OCSR method that efficiently and accurately recognizes chemical structures from real-world documents, including difficult Markush structure. We use a extended SMILES encoding rule to annotate our training dataset. Under this rule, we build MolParser-7M, the largest annotated molecular image dataset to our knowledge. While utilizing a large amount of synthetic data, we employed active learning methods to incorporate substantial in-the-wild data, specifically samples cropped from real patents and scientific literature, into the training process. We trained an end-to-end molecular image captioning model, MolParser, using a curriculum learning approach. MolParser significantly outperforms classical and learning-based methods across most scenarios, with potential for broader downstream applications. The dataset is publicly available.

Proof assistants like Lean have revolutionized mathematical proof verification, ensuring high accuracy and reliability. Although large language models (LLMs) show promise in mathematical reasoning, their advancement in formal theorem proving is hindered by a lack of training data. To address this issue, we introduce an approach to generate extensive Lean 4 proof data derived from high-school and undergraduate-level mathematical competition problems. This approach involves translating natural language problems into formal statements, filtering out low-quality statements, and generating proofs to create synthetic data. After fine-tuning the DeepSeekMath 7B model on this synthetic dataset, which comprises 8 million formal statements with proofs, our model achieved whole-proof generation accuracies of 46.3% with 64 samples and 52% cumulatively on the Lean 4 miniF2F test, surpassing the baseline GPT-4 at 23.0% with 64 samples and a tree search reinforcement learning method at 41.0%. Additionally, our model successfully proved 5 out of 148 problems in the Lean 4 Formalized International Mathematical Olympiad (FIMO) benchmark, while GPT-4 failed to prove any. These results demonstrate the potential of leveraging large-scale synthetic data to enhance theorem-proving capabilities in LLMs. Both the synthetic dataset and the model will be made available to facilitate further research in this promising field.

Transformer-based models trained on large and general purpose datasets consisting of molecular strings have recently emerged as a powerful tool for successfully modeling various structure-property relations. Inspired by this success, we extend the paradigm of training chemical language transformers on large-scale chemical datasets to generative tasks in this work. Specifically, we propose GP-MoLFormer, an autoregressive molecular string generator that is trained on more than 1.1B (billion) chemical SMILES. GP-MoLFormer uses a 46.8M parameter transformer decoder model with linear attention and rotary positional encodings as the base architecture. GP-MoLFormer's utility is evaluated and compared with that of existing baselines on three different tasks: de novo generation, scaffold-constrained molecular decoration, and unconstrained property-guided optimization. While the first two are handled with no additional training, we propose a parameter-efficient fine-tuning method for the last task, which uses property-ordered molecular pairs as input. We call this new approach pair-tuning. Our results show GP-MoLFormer performs better or comparable with baselines across all three tasks, demonstrating its general utility for a variety of molecular generation tasks. We further report strong memorization of training data in GP-MoLFormer generations, which has so far remained unexplored for chemical language models. Our analyses reveal that training data memorization and novelty in generations are impacted by the quality and scale of the training data; duplication bias in training data can enhance memorization at the cost of lowering novelty. We further establish a scaling law relating inference compute and novelty in generations.

Large-scale pre-training methodologies for chemical language models represent a breakthrough in cheminformatics. These methods excel in tasks such as property prediction and molecule generation by learning contextualized representations of input tokens through self-supervised learning on large unlabeled corpora. Typically, this involves pre-training on unlabeled data followed by fine-tuning on specific tasks, reducing dependence on annotated datasets and broadening chemical language representation understanding. This paper introduces a large encoder-decoder chemical foundation models pre-trained on a curated dataset of 91 million SMILES samples sourced from PubChem, which is equivalent to 4 billion of molecular tokens. The proposed foundation model supports different complex tasks, including quantum property prediction, and offer flexibility with two main variants (289M and 8times289M). Our experiments across multiple benchmark datasets validate the capacity of the proposed model in providing state-of-the-art results for different tasks. We also provide a preliminary assessment of the compositionality of the embedding space as a prerequisite for the reasoning tasks. We demonstrate that the produced latent space is separable compared to the state-of-the-art with few-shot learning capabilities.

Web agents struggle to adapt to new websites due to the scarcity of environment specific tasks and demonstrations. Recent works have explored synthetic data generation to address this challenge, however, they suffer from data quality issues where synthesized tasks contain hallucinations that cannot be executed, and collected trajectories are noisy with redundant or misaligned actions. In this paper, we propose SynthAgent, a fully synthetic supervision framework that aims at improving synthetic data quality via dual refinement of both tasks and trajectories. Our approach begins by synthesizing diverse tasks through categorized exploration of web elements, ensuring efficient coverage of the target environment. During trajectory collection, we refine tasks when conflicts with actual observations are detected, mitigating hallucinations while maintaining task consistency. After collection, we conduct trajectory refinement with a global context to mitigate potential noise or misalignments. Finally, we fine-tune open-source web agents on the refined synthetic data to adapt them to the target environment. Experimental results demonstrate that SynthAgent outperforms existing synthetic data methods, validating the importance of high-quality synthetic supervision. The code will be publicly available at https://github.com/aiming-lab/SynthAgent.

Modern Large Language Models (LLMs) are excellent at generating synthetic data. However, their performance in sensitive domains such as text detoxification has not received proper attention from the scientific community. This paper explores the possibility of using LLM-generated synthetic toxic data as an alternative to human-generated data for training models for detoxification. Using Llama 3 and Qwen activation-patched models, we generated synthetic toxic counterparts for neutral texts from ParaDetox and SST-2 datasets. Our experiments show that models fine-tuned on synthetic data consistently perform worse than those trained on human data, with a drop in performance of up to 30% in joint metrics. The root cause is identified as a critical lexical diversity gap: LLMs generate toxic content using a small, repetitive vocabulary of insults that fails to capture the nuances and variety of human toxicity. These findings highlight the limitations of current LLMs in this domain and emphasize the continued importance of diverse, human-annotated data for building robust detoxification systems.

The recent advances in neural language models have also been successfully applied to the field of chemistry, offering generative solutions for classical problems in molecular design and synthesis planning. These new methods have the potential to optimize laboratory operations and fuel a new era of data-driven automation in scientific discovery. However, specialized models are still typically required for each task, leading to the need for problem-specific fine-tuning and neglecting task interrelations. The main obstacle in this field is the lack of a unified representation between natural language and chemical representations, complicating and limiting human-machine interaction. Here, we propose a multi-domain, multi-task language model to solve a wide range of tasks in both the chemical and natural language domains. By leveraging multi-task learning, our model can handle chemical and natural language concurrently, without requiring expensive pre-training on single domains or task-specific models. Interestingly, sharing weights across domains remarkably improves our model when benchmarked against state-of-the-art baselines on single-domain and cross-domain tasks. In particular, sharing information across domains and tasks gives rise to large improvements in cross-domain tasks, the magnitude of which increase with scale, as measured by more than a dozen of relevant metrics. Our work suggests that such models can robustly and efficiently accelerate discovery in physical sciences by superseding problem-specific fine-tuning and enhancing human-model interactions.

The rapid expansion of chemistry literature poses significant challenges for researchers seeking to efficiently access domain-specific knowledge. To support advancements in chemistry-focused natural language processing (NLP), we present ChemRxivQuest, a curated dataset of 970 high-quality question-answer (QA) pairs derived from 155 ChemRxiv preprints across 17 subfields of chemistry. Each QA pair is explicitly linked to its source text segment to ensure traceability and contextual accuracy. ChemRxivQuest was constructed using an automated pipeline that combines optical character recognition (OCR), GPT-4o-based QA generation, and a fuzzy matching technique for answer verification. The dataset emphasizes conceptual, mechanistic, applied, and experimental questions, enabling applications in retrieval-based QA systems, search engine development, and fine-tuning of domain-adapted large language models. We analyze the dataset's structure, coverage, and limitations, and outline future directions for expansion and expert validation. ChemRxivQuest provides a foundational resource for chemistry NLP research, education, and tool development.

Deep neural networks have brought remarkable breakthroughs in medical image analysis. However, due to their data-hungry nature, the modest dataset sizes in medical imaging projects might be hindering their full potential. Generating synthetic data provides a promising alternative, allowing to complement training datasets and conducting medical image research at a larger scale. Diffusion models recently have caught the attention of the computer vision community by producing photorealistic synthetic images. In this study, we explore using Latent Diffusion Models to generate synthetic images from high-resolution 3D brain images. We used T1w MRI images from the UK Biobank dataset (N=31,740) to train our models to learn about the probabilistic distribution of brain images, conditioned on covariables, such as age, sex, and brain structure volumes. We found that our models created realistic data, and we could use the conditioning variables to control the data generation effectively. Besides that, we created a synthetic dataset with 100,000 brain images and made it openly available to the scientific community.

Chemical language models (CLMs) are prominent for their effectiveness in exploring chemical space and enabling molecular engineering. However, while exploring chemical-linguistic space, CLMs suffer from the gap between natural language and molecular representations. This challenge is primarily due to the inherent modeling differences between molecules and texts: molecules operate unified modeling to learn chemical space, while natural language sequentially models the semantic space. Additionally, the limited availability of high-quality text-to-molecule datasets further exacerbates this challenge. To address the problem, we first verified the information bias in molecular representations from different perspectives. We then developed the Heterogeneous Molecular Encoding (HME) framework, a unified molecular encoder compressing the molecular features from fragment sequence, topology, and conformation with Q-learning. To better model chemical-linguistic space, we further constructed the MCMoD dataset, which contains over one million molecules with various conditions, including properties, fragments, and descriptions. Experimentally, HME promotes CLMs to achieve chemical-linguistic sharing space exploration: (1) chemical space exploration with linguistic guidance, where HME achieves significant improvements (+37.8\% FCD) for molecular design in multiple constraints, even in zero-shot scenarios; (2) linguistic space exploration with molecular guidance, where HME generates textual descriptions with high qualities (+11.6\% BLEU) for molecules. These results highlight the precision of HME in handling multi-objective and cross-domain tasks, as well as its remarkable generalization capability on unseen task combinations. HME offers a new perspective on navigating chemical-linguistic sharing space, advancing the potential of CLMs in both fundamental research and practical applications in chemistry.

Accurately identifying the synthesis conditions of metal-organic frameworks (MOFs) is essential for guiding experimental design, yet remains challenging because relevant information in the literature is often scattered, inconsistent, and difficult to interpret. We present MOFh6, a large language model driven system that reads raw articles or crystal codes and converts them into standardized synthesis tables. It links related descriptions across paragraphs, unifies ligand abbreviations with full names, and outputs structured parameters ready for use. MOFh6 achieved 99% extraction accuracy, resolved 94.1% of abbreviation cases across five major publishers, and maintained a precision of 0.93 +/- 0.01. Processing a full text takes 9.6 s, locating synthesis descriptions 36 s, with 100 papers processed for USD 4.24. By replacing static database lookups with real-time extraction, MOFh6 reshapes MOF synthesis research, accelerating the conversion of literature knowledge into practical synthesis protocols and enabling scalable, data-driven materials discovery.

Many examples of cooperation exist in biology. In chemical systems however, which can sometimes be quite complex, we do not appear to observe intricate cooperative interactions. A key question for the origin of life, is then how can molecular cooperation first arise in an abiotic system prior to the emergence of biological replication. We postulate that selection at the molecular level is a driving force behind the complexification of chemical systems, particularly during the origins of life. In the theory of multilevel selection the two selective forces are: within-group and between-group, where the former tends to favor "selfish" replication of individuals and the latter favor cooperation between individuals enhancing the replication of the group as a whole. These forces can be quantified using the Price equation, which is a standard tool used in evolutionary biology to quantify evolutionary change. Our central claim is that replication and heredity in chemical systems are subject to selection, and quantifiable using the multilevel Price equation. We demonstrate this using the Graded Autocatalysis Replication Domain computer model, describing simple protocell composed out of molecules and its replication, which respectively analogue to the group and the individuals. In contrast to previous treatments of this model, we treat the lipid molecules themselves as replicating individuals and the protocells they form as groups of individuals. Our goal is to demonstrate how evolutionary biology tools and concepts can be applied in chemistry and we suggest that molecular cooperation may arise as a result of group selection. Further, the biological relation of parent-progeny is proposed to be analogue to the reactant-product relation in chemistry, thus allowing for tools from evolutionary biology to be applied to chemistry and would deepen the connection between chemistry and biology.

We propose a simple auto-encoder framework for molecule generation. The molecular graph is first encoded into a continuous latent representation z, which is then decoded back to a molecule. The encoding process is easy, but the decoding process remains challenging. In this work, we introduce a simple two-step decoding process. In a first step, a fully connected neural network uses the latent vector z to produce a molecular formula, for example CO_2 (one carbon and two oxygen atoms). In a second step, a graph convolutional neural network uses the same latent vector z to place bonds between the atoms that were produced in the first step (for example a double bond will be placed between the carbon and each of the oxygens). This two-step process, in which a bag of atoms is first generated, and then assembled, provides a simple framework that allows us to develop an efficient molecule auto-encoder. Numerical experiments on basic tasks such as novelty, uniqueness, validity and optimized chemical property for the 250k ZINC molecules demonstrate the performances of the proposed system. Particularly, we achieve the highest reconstruction rate of 90.5\%, improving the previous rate of 76.7\%. We also report the best property improvement results when optimization is constrained by the molecular distance between the original and generated molecules.

Transition state (TS) structures define the critical geometries and energy barriers underlying chemical reactivity, yet their fleeting nature renders them experimentally elusive and drives the reliance on costly, high-throughput density functional theory (DFT) calculations. Here, we introduce TS-GEN, a conditional flow-matching generative model that maps samples from a simple Gaussian prior directly to transition-state saddle-point geometries in a single, deterministic pass. By embedding both reactant and product conformations as conditioning information, TS-GEN learns to transport latent noise to true TS structures via an optimal-transport path, effectively replacing the iterative optimization common in nudged-elastic band or string-method algorithms. TS-GEN delivers unprecedented accuracy, achieving a root-mean-square deviation of 0.004 mathring{A} (vs. 0.103 mathring{A} for prior state-of-the-art) and a mean barrier-height error of 1.019 {rm kcal/mol} (vs. 2.864 {rm kcal/mol}), while requiring only 0.06 {rm s} GPU time per inference. Over 87% of generated TSs meet chemical-accuracy criteria (<1.58 {rm kcal/mol} error), substantially outpacing existing methods. TS-GEN also exhibits strong transferability to out-of-distribution reactions from a larger database. By uniting sub-angstrom precision, sub-second speed, and broad applicability, TS-GEN will be highly useful for high-throughput exploration of complex reaction networks, paving the way to the exploration of novel chemical reaction mechanisms.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

Optical Chemical Structure Recognition (OCSR) is crucial for digitizing chemical knowledge by converting molecular images into machine-readable formats. While recent vision-language models (VLMs) have shown potential in this task, their image-captioning approach often struggles with complex molecular structures and inconsistent annotations. To overcome these challenges, we introduce GTR-Mol-VLM, a novel framework featuring two key innovations: (1) the Graph Traversal as Visual Chain of Thought mechanism that emulates human reasoning by incrementally parsing molecular graphs through sequential atom-bond predictions, and (2) the data-centric principle of Faithfully Recognize What You've Seen, which addresses the mismatch between abbreviated structures in images and their expanded annotations. To support model development, we constructed GTR-CoT-1.3M, a large-scale instruction-tuning dataset with meticulously corrected annotations, and introduced MolRec-Bench, the first benchmark designed for a fine-grained evaluation of graph-parsing accuracy in OCSR. Comprehensive experiments demonstrate that GTR-Mol-VLM achieves superior results compared to specialist models, chemistry-domain VLMs, and commercial general-purpose VLMs. Notably, in scenarios involving molecular images with functional group abbreviations, GTR-Mol-VLM outperforms the second-best baseline by approximately 14 percentage points, both in SMILES-based and graph-based metrics. We hope that this work will drive OCSR technology to more effectively meet real-world needs, thereby advancing the fields of cheminformatics and AI for Science. We will release GTR-CoT at https://github.com/opendatalab/GTR-CoT.

Recent advancements in language models have started a new era of superior information retrieval and content generation, with embedding models playing an important role in optimizing data representation efficiency and performance. While benchmarks like the Massive Text Embedding Benchmark (MTEB) have standardized the evaluation of general domain embedding models, a gap remains in specialized fields such as chemistry, which require tailored approaches due to domain-specific challenges. This paper introduces a novel benchmark, the Chemical Text Embedding Benchmark (ChemTEB), designed specifically for the chemical sciences. ChemTEB addresses the unique linguistic and semantic complexities of chemical literature and data, offering a comprehensive suite of tasks on chemical domain data. Through the evaluation of 34 open-source and proprietary models using this benchmark, we illuminate the strengths and weaknesses of current methodologies in processing and understanding chemical information. Our work aims to equip the research community with a standardized, domain-specific evaluation framework, promoting the development of more precise and efficient NLP models for chemistry-related applications. Furthermore, it provides insights into the performance of generic models in a domain-specific context. ChemTEB comes with open-source code and data, contributing further to its accessibility and utility.

We report a series of deep learning models to solve complex forward and inverse design problems in molecular modeling and design. Using both diffusion models inspired by nonequilibrium thermodynamics and attention-based transformer architectures, we demonstrate a flexible framework to capture complex chemical structures. First trained on the QM9 dataset and a series of quantum mechanical properties (e.g. homo, lumo, free energy, heat capacity, etc.), we then generalize the model to study and design key properties of deep eutectic solvents. In addition to separate forward and inverse models, we also report an integrated fully prompt-based multi-task generative pretrained transformer model that solves multiple forward, inverse design, and prediction tasks, flexibly and within one model. We show that the multi-task generative model has the overall best performance and allows for flexible integration of multiple objectives, within one model, and for distinct chemistries, suggesting that synergies emerge during training of this large language model. Trained jointly in tasks related to the QM9 dataset and deep eutectic solvents (DESs), the model can predict various quantum mechanical properties and critical properties to achieve deep eutectic solvent behavior. Several novel combinations of DESs are proposed based on this framework.

While various models and computational tools have been proposed for structure and property analysis of molecules, generating molecules that conform to all desired structures and properties remains a challenge. Here, we introduce a multi-constraint molecular generation large language model, TSMMG, which, akin to a student, incorporates knowledge from various small models and tools, namely, the 'teachers'. To train TSMMG, we construct a large set of text-molecule pairs by extracting molecular knowledge from these 'teachers', enabling it to generate novel molecules that conform to the descriptions through various text prompts. We experimentally show that TSMMG remarkably performs in generating molecules meeting complex, natural language-described property requirements across two-, three-, and four-constraint tasks, with an average molecular validity of over 99% and success ratio of 82.58%, 68.03%, and 67.48%, respectively. The model also exhibits adaptability through zero-shot testing, creating molecules that satisfy combinations of properties that have not been encountered. It can comprehend text inputs with various language styles, extending beyond the confines of outlined prompts, as confirmed through empirical validation. Additionally, the knowledge distillation feature of TSMMG contributes to the continuous enhancement of small models, while the innovative approach to dataset construction effectively addresses the issues of data scarcity and quality, which positions TSMMG as a promising tool in the domains of drug discovery and materials science.

Recent developments in deep learning have made remarkable progress in speeding up the prediction of quantum chemical (QC) properties by removing the need for expensive electronic structure calculations like density functional theory. However, previous methods learned from 1D SMILES sequences or 2D molecular graphs failed to achieve high accuracy as QC properties primarily depend on the 3D equilibrium conformations optimized by electronic structure methods, far different from the sequence-type and graph-type data. In this paper, we propose a novel approach called Uni-Mol+ to tackle this challenge. Uni-Mol+ first generates a raw 3D molecule conformation from inexpensive methods such as RDKit. Then, the raw conformation is iteratively updated to its target DFT equilibrium conformation using neural networks, and the learned conformation will be used to predict the QC properties. To effectively learn this update process towards the equilibrium conformation, we introduce a two-track Transformer model backbone and train it with the QC property prediction task. We also design a novel approach to guide the model's training process. Our extensive benchmarking results demonstrate that the proposed Uni-Mol+ significantly improves the accuracy of QC property prediction in various datasets. We have made the code and model publicly available at https://github.com/dptech-corp/Uni-Mol.

Small molecules are essential to drug discovery, and graph-language models hold promise for learning molecular properties and functions from text. However, existing molecule-text datasets are limited in scale and informativeness, restricting the training of generalizable multimodal models. We present MolTextNet, a dataset of 2.5 million high-quality molecule-text pairs designed to overcome these limitations. To construct it, we propose a synthetic text generation pipeline that integrates structural features, computed properties, bioactivity data, and synthetic complexity. Using GPT-4o-mini, we create structured descriptions for 2.5 million molecules from ChEMBL35, with text over 10 times longer than prior datasets. MolTextNet supports diverse downstream tasks, including property prediction and structure retrieval. Pretraining CLIP-style models with Graph Neural Networks and ModernBERT on MolTextNet yields improved performance, highlighting its potential for advancing foundational multimodal modeling in molecular science. Our dataset is available at https://huggingface.co/datasets/liuganghuggingface/moltextnet.

Recent improvements in synthetic data generation make it possible to produce images that are highly photorealistic and indistinguishable from real ones. Furthermore, synthetic generation pipelines have the potential to generate an unlimited number of images. The combination of high photorealism and scale turn the synthetic data into a promising candidate for potentially improving various machine learning (ML) pipelines. Thus far, a large body of research in this field has focused on using synthetic images for training, by augmenting and enlarging training data. In contrast to using synthetic data for training, in this work we explore whether synthetic data can be beneficial for model selection. Considering the task of image classification, we demonstrate that when data is scarce, synthetic data can be used to replace the held out validation set, thus allowing to train on a larger dataset.

We seek to automate the design of molecules based on specific chemical properties. In computational terms, this task involves continuous embedding and generation of molecular graphs. Our primary contribution is the direct realization of molecular graphs, a task previously approached by generating linear SMILES strings instead of graphs. Our junction tree variational autoencoder generates molecular graphs in two phases, by first generating a tree-structured scaffold over chemical substructures, and then combining them into a molecule with a graph message passing network. This approach allows us to incrementally expand molecules while maintaining chemical validity at every step. We evaluate our model on multiple tasks ranging from molecular generation to optimization. Across these tasks, our model outperforms previous state-of-the-art baselines by a significant margin.

Recent advancements in large language models have opened new possibilities for generative molecular drug design. We present Chemlactica and Chemma, two language models fine-tuned on a novel corpus of 110M molecules with computed properties, totaling 40B tokens. These models demonstrate strong performance in generating molecules with specified properties and predicting new molecular characteristics from limited samples. We introduce a novel optimization algorithm that leverages our language models to optimize molecules for arbitrary properties given limited access to a black box oracle. Our approach combines ideas from genetic algorithms, rejection sampling, and prompt optimization. It achieves state-of-the-art performance on multiple molecular optimization benchmarks, including an 8% improvement on Practical Molecular Optimization compared to previous methods. We publicly release the training corpus, the language models and the optimization algorithm.

Models based on machine learning can enable accurate and fast molecular property predictions, which is of interest in drug discovery and material design. Various supervised machine learning models have demonstrated promising performance, but the vast chemical space and the limited availability of property labels make supervised learning challenging. Recently, unsupervised transformer-based language models pretrained on a large unlabelled corpus have produced state-of-the-art results in many downstream natural language processing tasks. Inspired by this development, we present molecular embeddings obtained by training an efficient transformer encoder model, MoLFormer, which uses rotary positional embeddings. This model employs a linear attention mechanism, coupled with highly distributed training, on SMILES sequences of 1.1 billion unlabelled molecules from the PubChem and ZINC datasets. We show that the learned molecular representation outperforms existing baselines, including supervised and self-supervised graph neural networks and language models, on several downstream tasks from ten benchmark datasets. They perform competitively on two others. Further analyses, specifically through the lens of attention, demonstrate that MoLFormer trained on chemical SMILES indeed learns the spatial relationships between atoms within a molecule. These results provide encouraging evidence that large-scale molecular language models can capture sufficient chemical and structural information to predict various distinct molecular properties, including quantum-chemical properties.

Molecular representation is a foundational element in our understanding of the physical world. Its importance ranges from the fundamentals of chemical reactions to the design of new therapies and materials. Previous molecular machine learning models have employed strings, fingerprints, global features, and simple molecular graphs that are inherently information-sparse representations. However, as the complexity of prediction tasks increases, the molecular representation needs to encode higher fidelity information. This work introduces a novel approach to infusing quantum-chemical-rich information into molecular graphs via stereoelectronic effects. We show that the explicit addition of stereoelectronic interactions significantly improves the performance of molecular machine learning models. Furthermore, stereoelectronics-infused representations can be learned and deployed with a tailored double graph neural network workflow, enabling its application to any downstream molecular machine learning task. Finally, we show that the learned representations allow for facile stereoelectronic evaluation of previously intractable systems, such as entire proteins, opening new avenues of molecular design.

Generative models are becoming a tool of choice for exploring the molecular space. These models learn on a large training dataset and produce novel molecular structures with similar properties. Generated structures can be utilized for virtual screening or training semi-supervised predictive models in the downstream tasks. While there are plenty of generative models, it is unclear how to compare and rank them. In this work, we introduce a benchmarking platform called Molecular Sets (MOSES) to standardize training and comparison of molecular generative models. MOSES provides a training and testing datasets, and a set of metrics to evaluate the quality and diversity of generated structures. We have implemented and compared several molecular generation models and suggest to use our results as reference points for further advancements in generative chemistry research. The platform and source code are available at https://github.com/molecularsets/moses.

Cluster analysis relies on effective benchmarks for evaluating and comparing different algorithms. Simulation studies on synthetic data are popular because important features of the data sets, such as the overlap between clusters, or the variation in cluster shapes, can be effectively varied. Unfortunately, creating evaluation scenarios is often laborious, as practitioners must translate higher-level scenario descriptions like "clusters with very different shapes" into lower-level geometric parameters such as cluster centers, covariance matrices, etc. To make benchmarks more convenient and informative, we propose synthetic data generation based on direct specification of high-level scenarios, either through verbal descriptions or high-level geometric parameters. Our open-source Python package repliclust implements this workflow, making it easy to set up interpretable and reproducible benchmarks for cluster analysis. A demo of data generation from verbal inputs is available at https://demo.repliclust.org.

In this work, we introduce ChemBFN, a language model that handles chemistry tasks based on Bayesian flow networks working on discrete data. A new accuracy schedule is proposed to improve the sampling quality by significantly reducing the reconstruction loss. We show evidence that our method is appropriate for generating molecules with satisfied diversity even when a smaller number of sampling steps is used. A classifier-free guidance method is adapted for conditional generation. It is also worthwhile to point out that after generative training, our model can be fine-tuned on regression and classification tasks with the state-of-the-art performance, which opens the gate of building all-in-one models in a single module style. Our model has been open sourced at https://github.com/Augus1999/bayesian-flow-network-for-chemistry.

Nuclear Magnetic Resonance (NMR) spectroscopy is one of the most powerful and widely used tools for molecular structure elucidation in organic chemistry. However, the interpretation of NMR spectra to determine unknown molecular structures remains a labor-intensive and expertise-dependent process, particularly for complex or novel compounds. Although recent methods have been proposed for molecular structure elucidation, they often underperform in real-world applications due to inherent algorithmic limitations and limited high-quality data. Here, we present NMR-Solver, a practical and interpretable framework for the automated determination of small organic molecule structures from ^1H and ^{13}C NMR spectra. Our method introduces an automated framework for molecular structure elucidation, integrating large-scale spectral matching with physics-guided fragment-based optimization that exploits atomic-level structure-spectrum relationships in NMR. We evaluate NMR-Solver on simulated benchmarks, curated experimental data from the literature, and real-world experiments, demonstrating its strong generalization, robustness, and practical utility in challenging, real-life scenarios. NMR-Solver unifies computational NMR analysis, deep learning, and interpretable chemical reasoning into a coherent system. By incorporating the physical principles of NMR into molecular optimization, it enables scalable, automated, and chemically meaningful molecular identification, establishing a generalizable paradigm for solving inverse problems in molecular science.

Graph neural networks (GNNs) have been used extensively for addressing problems in drug design and discovery. Both ligand and target molecules are represented as graphs with node and edge features encoding information about atomic elements and bonds respectively. Although existing deep learning models perform remarkably well at predicting physicochemical properties and binding affinities, the generation of new molecules with optimized properties remains challenging. Inherently, most GNNs perform poorly in whole-graph representation due to the limitations of the message-passing paradigm. Furthermore, step-by-step graph generation frameworks that use reinforcement learning or other sequential processing can be slow and result in a high proportion of invalid molecules with substantial post-processing needed in order to satisfy the principles of stoichiometry. To address these issues, we propose a representation-first approach to molecular graph generation. We guide the latent representation of an autoencoder by capturing graph structure information with the geometric scattering transform and apply penalties that structure the representation also by molecular properties. We show that this highly structured latent space can be directly used for molecular graph generation by the use of a GAN. We demonstrate that our architecture learns meaningful representations of drug datasets and provides a platform for goal-directed drug synthesis.

Recent advances in synthetic methods enable designing subunits that self-assemble into structures with well-defined sizes and architectures, but yields are frequently suppressed by the formation of off-target metastable structures. Increasing the complexity (number of distinct inter-subunit interaction types) can inhibit off-target structures, but leads to slower kinetics and higher synthesis costs. Here, we use icosahedral shells formed of programmable triangular subunits as a model system, and identify design principles that produce the highest target yield at the lowest complexity. We use a symmetry-based construction to create a range of design complexities, starting from the maximal symmetry Caspar-Klug assembly up to the fully addressable, zero-symmetry assembly. Kinetic Monte Carlo simulations reveal that the most prominent defects leading to off-target assemblies are a class of disclinations. We derive symmetry-based rules for identifying the optimal (lowest-complexity, highest-symmetry) design that inhibits these disclinations, leading to robust, high-fidelity assembly of targets with arbitrarily large sizes. Optimal complexity varies non-monotonically with target size, with `magic' sizes appearing for high-symmetry designs in which symmetry axes do not intersect vertices of the triangular net. The optimal designs at magic sizes require 12 times fewer inequivalent interaction-types than the (minimal symmetry) fully addressable construction.

Pretrained neural networks have attracted significant interest in chemistry and small molecule drug design. Embeddings from these models are widely used for molecular property prediction, virtual screening, and small data learning in molecular chemistry. This study presents the most extensive comparison of such models to date, evaluating 25 models across 25 datasets. Under a fair comparison framework, we assess models spanning various modalities, architectures, and pretraining strategies. Using a dedicated hierarchical Bayesian statistical testing model, we arrive at a surprising result: nearly all neural models show negligible or no improvement over the baseline ECFP molecular fingerprint. Only the CLAMP model, which is also based on molecular fingerprints, performs statistically significantly better than the alternatives. These findings raise concerns about the evaluation rigor in existing studies. We discuss potential causes, propose solutions, and offer practical recommendations.

Traditional molecular string representations, such as SMILES, often pose challenges for AI-driven molecular design due to their non-sequential depiction of molecular substructures. To address this issue, we introduce Sequential Attachment-based Fragment Embedding (SAFE), a novel line notation for chemical structures. SAFE reimagines SMILES strings as an unordered sequence of interconnected fragment blocks while maintaining full compatibility with existing SMILES parsers. It streamlines complex generative tasks, including scaffold decoration, fragment linking, polymer generation, and scaffold hopping, while facilitating autoregressive generation for fragment-constrained design, thereby eliminating the need for intricate decoding or graph-based models. We demonstrate the effectiveness of SAFE by training an 87-million-parameter GPT2-like model on a dataset containing 1.1 billion SAFE representations. Through extensive experimentation, we show that our SAFE-GPT model exhibits versatile and robust optimization performance. SAFE opens up new avenues for the rapid exploration of chemical space under various constraints, promising breakthroughs in AI-driven molecular design.

Building generalist models has recently demonstrated remarkable capabilities in diverse scientific domains. Within the realm of molecular learning, several studies have explored unifying diverse tasks across diverse domains. However, negative conflicts and interference between molecules and knowledge from different domain may have a worse impact in threefold. First, conflicting molecular representations can lead to optimization difficulties for the models. Second, mixing and scaling up training data across diverse tasks is inherently challenging. Third, the computational cost of refined pretraining is prohibitively high. To address these limitations, this paper presents Omni-Mol, a scalable and unified LLM-based framework for direct instruction tuning. Omni-Mol builds on three key components to tackles conflicts: (1) a unified encoding mechanism for any task input; (2) an active-learning-driven data selection strategy that significantly reduces dataset size; (3) a novel design of the adaptive gradient stabilization module and anchor-and-reconcile MoE framework that ensures stable convergence. Experimentally, Omni-Mol achieves state-of-the-art performance across 15 molecular tasks, demonstrates the presence of scaling laws in the molecular domain, and is supported by extensive ablation studies and analyses validating the effectiveness of its design. The code and weights of the powerful AI-driven chemistry generalist are open-sourced at: https://anonymous.4open.science/r/Omni-Mol-8EDB.

Understanding and designing biomolecules, such as proteins and small molecules, is central to advancing drug discovery, synthetic biology, and enzyme engineering. Recent breakthroughs in Artificial Intelligence (AI) have revolutionized biomolecular research, achieving remarkable accuracy in biomolecular prediction and design. However, a critical gap remains between AI's computational power and researchers' intuition, using natural language to align molecular complexity with human intentions. Large Language Models (LLMs) have shown potential to interpret human intentions, yet their application to biomolecular research remains nascent due to challenges including specialized knowledge requirements, multimodal data integration, and semantic alignment between natural language and biomolecules. To address these limitations, we present InstructBioMol, a novel LLM designed to bridge natural language and biomolecules through a comprehensive any-to-any alignment of natural language, molecules, and proteins. This model can integrate multimodal biomolecules as input, and enable researchers to articulate design goals in natural language, providing biomolecular outputs that meet precise biological needs. Experimental results demonstrate InstructBioMol can understand and design biomolecules following human instructions. Notably, it can generate drug molecules with a 10% improvement in binding affinity and design enzymes that achieve an ESP Score of 70.4, making it the only method to surpass the enzyme-substrate interaction threshold of 60.0 recommended by the ESP developer. This highlights its potential to transform real-world biomolecular research.

As a fundamental task in computational chemistry, retrosynthesis prediction aims to identify a set of reactants to synthesize a target molecule. Existing template-free approaches only consider the graph structures of the target molecule, which often cannot generalize well to rare reaction types and large molecules. Here, we propose T-Rex, a text-assisted retrosynthesis prediction approach that exploits pre-trained text language models, such as ChatGPT, to assist the generation of reactants. T-Rex first exploits ChatGPT to generate a description for the target molecule and rank candidate reaction centers based both the description and the molecular graph. It then re-ranks these candidates by querying the descriptions for each reactants and examines which group of reactants can best synthesize the target molecule. We observed that T-Rex substantially outperformed graph-based state-of-the-art approaches on two datasets, indicating the effectiveness of considering text information. We further found that T-Rex outperformed the variant that only use ChatGPT-based description without the re-ranking step, demonstrate how our framework outperformed a straightforward integration of ChatGPT and graph information. Collectively, we show that text generated by pre-trained language models can substantially improve retrosynthesis prediction, opening up new avenues for exploiting ChatGPT to advance computational chemistry. And the codes can be found at https://github.com/lauyikfung/T-Rex.

Knowledge of mixtures' phase equilibria is crucial in nature and technical chemistry. Phase equilibria calculations of mixtures require activity coefficients. However, experimental data on activity coefficients is often limited due to high cost of experiments. For an accurate and efficient prediction of activity coefficients, machine learning approaches have been recently developed. However, current machine learning approaches still extrapolate poorly for activity coefficients of unknown molecules. In this work, we introduce the SMILES-to-Properties-Transformer (SPT), a natural language processing network to predict binary limiting activity coefficients from SMILES codes. To overcome the limitations of available experimental data, we initially train our network on a large dataset of synthetic data sampled from COSMO-RS (10 Million data points) and then fine-tune the model on experimental data (20 870 data points). This training strategy enables SPT to accurately predict limiting activity coefficients even for unknown molecules, cutting the mean prediction error in half compared to state-of-the-art models for activity coefficient predictions such as COSMO-RS, UNIFAC, and improving on recent machine learning approaches.

Chemical representation learning has gained increasing interest due to the limited availability of supervised data in fields such as drug and materials design. This interest particularly extends to chemical language representation learning, which involves pre-training Transformers on SMILES sequences -- textual descriptors of molecules. Despite its success in molecular property prediction, current practices often lead to overfitting and limited scalability due to early convergence. In this paper, we introduce a novel chemical language representation learning framework, called MolTRES, to address these issues. MolTRES incorporates generator-discriminator training, allowing the model to learn from more challenging examples that require structural understanding. In addition, we enrich molecular representations by transferring knowledge from scientific literature by integrating external materials embedding. Experimental results show that our model outperforms existing state-of-the-art models on popular molecular property prediction tasks.

Generative models for structure-based drug design (SBDD) have shown promising results in recent years. Existing works mainly focus on how to generate molecules with higher binding affinity, ignoring the feasibility prerequisites for generated 3D poses and resulting in false positives. We conduct thorough studies on key factors of ill-conformational problems when applying autoregressive methods and diffusion to SBDD, including mode collapse and hybrid continuous-discrete space. In this paper, we introduce MolCRAFT, the first SBDD model that operates in the continuous parameter space, together with a novel noise reduced sampling strategy. Empirical results show that our model consistently achieves superior performance in binding affinity with more stable 3D structure, demonstrating our ability to accurately model interatomic interactions. To our best knowledge, MolCRAFT is the first to achieve reference-level Vina Scores (-6.59 kcal/mol) with comparable molecular size, outperforming other strong baselines by a wide margin (-0.84 kcal/mol). Code is available at https://github.com/AlgoMole/MolCRAFT.

Generating new molecules is fundamental to advancing critical applications such as drug discovery and material synthesis. Flows can generate molecules effectively by inverting the encoding process, however, existing flow models either require artifactual dequantization or specific node/edge orderings, lack desiderata such as permutation invariance, or induce discrepancy between the encoding and the decoding steps that necessitates post hoc validity correction. We circumvent these issues with novel continuous normalizing E(3)-equivariant flows, based on a system of node ODEs coupled as a graph PDE, that repeatedly reconcile locally toward globally aligned densities. Our models can be cast as message-passing temporal networks, and result in superlative performance on the tasks of density estimation and molecular generation. In particular, our generated samples achieve state-of-the-art on both the standard QM9 and ZINC250K benchmarks.

Recent advances in language models have enabled framing molecule generation as sequence modeling. However, existing approaches often rely on single-objective reinforcement learning, limiting their applicability to real-world drug design, where multiple competing properties must be optimized. Traditional multi-objective reinforcement learning (MORL) methods require costly retraining for each new objective combination, making rapid exploration of trade-offs impractical. To overcome these limitations, we introduce Mol-MoE, a mixture-of-experts (MoE) architecture that enables efficient test-time steering of molecule generation without retraining. Central to our approach is a preference-based router training objective that incentivizes the router to combine experts in a way that aligns with user-specified trade-offs. This provides improved flexibility in exploring the chemical property space at test time, facilitating rapid trade-off exploration. Benchmarking against state-of-the-art methods, we show that Mol-MoE achieves superior sample quality and steerability.

While large language models (LLMs) have integrated images, adapting them to graphs remains challenging, limiting their applications in materials and drug design. This difficulty stems from the need for coherent autoregressive generation across texts and graphs. To address this, we introduce Llamole, the first multimodal LLM capable of interleaved text and graph generation, enabling molecular inverse design with retrosynthetic planning. Llamole integrates a base LLM with the Graph Diffusion Transformer and Graph Neural Networks for multi-conditional molecular generation and reaction inference within texts, while the LLM, with enhanced molecular understanding, flexibly controls activation among the different graph modules. Additionally, Llamole integrates A* search with LLM-based cost functions for efficient retrosynthetic planning. We create benchmarking datasets and conduct extensive experiments to evaluate Llamole against in-context learning and supervised fine-tuning. Llamole significantly outperforms 14 adapted LLMs across 12 metrics for controllable molecular design and retrosynthetic planning.

Inspired by the principle of deliberate practice in human learning, we propose Deliberate Practice for Synthetic Data Generation (DP), a novel framework that improves sample efficiency through dynamic synthetic data generation. Prior work has shown that scaling synthetic data is inherently challenging, as naively adding new data leads to diminishing returns. To address this, pruning has been identified as a key mechanism for improving scaling, enabling models to focus on the most informative synthetic samples. Rather than generating a large dataset and pruning it afterward, DP efficiently approximates the direct generation of informative samples. We theoretically show how training on challenging, informative examples improves scaling laws and empirically validate that DP achieves better scaling performance with significantly fewer training samples and iterations. On ImageNet-100, DP generates 3.4x fewer samples and requires six times fewer iterations, while on ImageNet-1k, it generates 8x fewer samples with a 30 percent reduction in iterations, all while achieving superior performance compared to prior work.

Catalyst discovery and optimization is key to solving many societal and energy challenges including solar fuels synthesis, long-term energy storage, and renewable fertilizer production. Despite considerable effort by the catalysis community to apply machine learning models to the computational catalyst discovery process, it remains an open challenge to build models that can generalize across both elemental compositions of surfaces and adsorbate identity/configurations, perhaps because datasets have been smaller in catalysis than related fields. To address this we developed the OC20 dataset, consisting of 1,281,040 Density Functional Theory (DFT) relaxations (~264,890,000 single point evaluations) across a wide swath of materials, surfaces, and adsorbates (nitrogen, carbon, and oxygen chemistries). We supplemented this dataset with randomly perturbed structures, short timescale molecular dynamics, and electronic structure analyses. The dataset comprises three central tasks indicative of day-to-day catalyst modeling and comes with pre-defined train/validation/test splits to facilitate direct comparisons with future model development efforts. We applied three state-of-the-art graph neural network models (CGCNN, SchNet, Dimenet++) to each of these tasks as baseline demonstrations for the community to build on. In almost every task, no upper limit on model size was identified, suggesting that even larger models are likely to improve on initial results. The dataset and baseline models are both provided as open resources, as well as a public leader board to encourage community contributions to solve these important tasks.

In recent years, Large Language Models (LLMs) have achieved significant success in natural language processing (NLP) and various interdisciplinary areas. However, applying LLMs to chemistry is a complex task that requires specialized domain knowledge. This paper provides a thorough exploration of the nuanced methodologies employed in integrating LLMs into the field of chemistry, delving into the complexities and innovations at this interdisciplinary juncture. Specifically, our analysis begins with examining how molecular information is fed into LLMs through various representation and tokenization methods. We then categorize chemical LLMs into three distinct groups based on the domain and modality of their input data, and discuss approaches for integrating these inputs for LLMs. Furthermore, this paper delves into the pretraining objectives with adaptations to chemical LLMs. After that, we explore the diverse applications of LLMs in chemistry, including novel paradigms for their application in chemistry tasks. Finally, we identify promising research directions, including further integration with chemical knowledge, advancements in continual learning, and improvements in model interpretability, paving the way for groundbreaking developments in the field.

Molecule generation is advancing rapidly in chemical discovery and drug design. Flow matching methods have recently set the state of the art (SOTA) in unconditional molecule generation, surpassing score-based diffusion models. However, diffusion models still lead in property-guided generation. In this work, we introduce PropMolFlow, a novel approach for property-guided molecule generation based on geometry-complete SE(3)-equivariant flow matching. Integrating five different property embedding methods with a Gaussian expansion of scalar properties, PropMolFlow outperforms previous SOTA diffusion models in conditional molecule generation across various properties while preserving the stability and validity of the generated molecules, consistent with its unconditional counterpart. Additionally, it enables faster inference with significantly fewer time steps compared to baseline models. We highlight the importance of validating the properties of generated molecules through DFT calculations performed at the same level of theory as the training data. Specifically, our analysis identifies properties that require DFT validation and others where a pretrained SE(3) geometric vector perceptron regressors provide sufficiently accurate predictions on generated molecules. Furthermore, we introduce a new property metric designed to assess the model's ability to propose molecules with underrepresented property values, assessing its capacity for out-of-distribution generalization. Our findings reveal shortcomings in existing structural metrics, which mistakenly validate open-shell molecules or molecules with invalid valence-charge configurations, underscoring the need for improved evaluation frameworks. Overall, this work paves the way for developing targeted property-guided generation methods, enhancing the design of molecular generative models for diverse applications.

With the development of computer-assisted techniques, research communities including biochemistry and deep learning have been devoted into the drug discovery field for over a decade. Various applications of deep learning have drawn great attention in drug discovery, such as molecule generation, molecular property prediction, retrosynthesis prediction, and reaction prediction. While most existing surveys only focus on one of the applications, limiting the view of researchers in the community. In this paper, we present a comprehensive review on the aforementioned four aspects, and discuss the relationships among different applications. The latest literature and classical benchmarks are presented for better understanding the development of variety of approaches. We commence by summarizing the molecule representation format in these works, followed by an introduction of recent proposed approaches for each of the four tasks. Furthermore, we review a variety of commonly used datasets and evaluation metrics and compare the performance of deep learning-based models. Finally, we conclude by identifying remaining challenges and discussing the future trend for deep learning methods in drug discovery.

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial datasets spanning a wide variety of chemical endpoints. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary datasets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows.

Recent advances in large language model (LLM) pretraining have shown that simply scaling data quantity eventually leads to diminishing returns, hitting a data wall. In response, the use of synthetic data for pretraining has emerged as a promising paradigm for pushing the frontier of performance. Despite this, the factors affecting synthetic data quality remain poorly understood. In this work, we introduce BeyondWeb, a synthetic data generation framework that produces high-quality synthetic data for pretraining. BeyondWeb significantly extends the capabilities of traditional web-scale datasets, outperforming state-of-the-art synthetic pretraining datasets such as Cosmopedia and Nemotron-CC's high-quality synthetic subset (Nemotron-Synth) by up to 5.1 percentage points (pp) and 2.6pp, respectively, when averaged across a suite of 14 benchmark evaluations. It delivers up to 7.7x faster training than open web data and 2.7x faster than Nemotron-Synth. Remarkably, a 3B model trained for 180B tokens on BeyondWeb outperforms an 8B model trained for the same token budget on Cosmopedia. We also present several insights from BeyondWeb on synthetic data for pretraining: what drives its benefits, which data to rephrase and how, and the impact of model size and family on data quality. Overall, our work shows that there's no silver bullet for generating high-quality synthetic pretraining data. The best outcomes require jointly optimizing many factors, a challenging task that requires rigorous science and practical expertise. Naive approaches can yield modest improvements, potentially at great cost, while well-executed methods can yield transformative improvements, as exemplified by BeyondWeb.

Synthesis procedures play a critical role in materials research, as they directly affect material properties. With data-driven approaches increasingly accelerating materials discovery, there is growing interest in extracting synthesis procedures from scientific literature as structured data. However, existing studies often rely on rigid, domain-specific schemas with predefined fields for structuring synthesis procedures or assume that synthesis procedures are linear sequences of operations, which limits their ability to capture the structural complexity of real-world procedures. To address these limitations, we adopt PROV-DM, an international standard for provenance information, which supports flexible, graph-based modeling of procedures. We present MatPROV, a dataset of PROV-DM-compliant synthesis procedures extracted from scientific literature using large language models. MatPROV captures structural complexities and causal relationships among materials, operations, and conditions through visually intuitive directed graphs. This representation enables machine-interpretable synthesis knowledge, opening opportunities for future research such as automated synthesis planning and optimization.

Self-supervised neural language models have recently achieved unprecedented success, from natural language processing to learning the languages of biological sequences and organic molecules. These models have demonstrated superior performance in the generation, structure classification, and functional predictions for proteins and molecules with learned representations. However, most of the masking-based pre-trained language models are not designed for generative design, and their black-box nature makes it difficult to interpret their design logic. Here we propose BLMM Crystal Transformer, a neural network based probabilistic generative model for generative and tinkering design of inorganic materials. Our model is built on the blank filling language model for text generation and has demonstrated unique advantages in learning the "materials grammars" together with high-quality generation, interpretability, and data efficiency. It can generate chemically valid materials compositions with as high as 89.7\% charge neutrality and 84.8\% balanced electronegativity, which are more than 4 and 8 times higher compared to a pseudo random sampling baseline. The probabilistic generation process of BLMM allows it to recommend tinkering operations based on learned materials chemistry and makes it useful for materials doping. Combined with the TCSP crysal structure prediction algorithm, We have applied our model to discover a set of new materials as validated using DFT calculations. Our work thus brings the unsupervised transformer language models based generative artificial intelligence to inorganic materials. A user-friendly web app has been developed for computational materials doping and can be accessed freely at www.materialsatlas.org/blmtinker.

Large language models (LLMs), especially Explicit Long Chain-of-Thought (CoT) reasoning models like DeepSeek-R1 and QWQ, have demonstrated powerful reasoning capabilities, achieving impressive performance in commonsense reasoning and mathematical inference. Despite their effectiveness, Long-CoT reasoning models are often criticized for their limited ability and low efficiency in knowledge-intensive domains such as molecule discovery. Success in this field requires a precise understanding of domain knowledge, including molecular structures and chemical principles, which is challenging due to the inherent complexity of molecular data and the scarcity of high-quality expert annotations. To bridge this gap, we introduce Mol-R1, a novel framework designed to improve explainability and reasoning performance of R1-like Explicit Long-CoT reasoning LLMs in text-based molecule generation. Our approach begins with a high-quality reasoning dataset curated through Prior Regulation via In-context Distillation (PRID), a dedicated distillation strategy to effectively generate paired reasoning traces guided by prior regulations. Building upon this, we introduce MoIA, Molecular Iterative Adaptation, a sophisticated training strategy that iteratively combines Supervised Fine-tuning (SFT) with Reinforced Policy Optimization (RPO), tailored to boost the reasoning performance of R1-like reasoning models for molecule discovery. Finally, we examine the performance of Mol-R1 in the text-based molecule reasoning generation task, showing superior performance against existing baselines.

Large-scale Vision-Language Models (VLMs) have transformed general-purpose visual recognition through strong zero-shot capabilities. However, their performance degrades significantly in niche, safety-critical domains such as industrial spill detection, where hazardous events are rare, sensitive, and difficult to annotate. This scarcity -- driven by privacy concerns, data sensitivity, and the infrequency of real incidents -- renders conventional fine-tuning of detectors infeasible for most industrial settings. We address this challenge by introducing a scalable framework centered on a high-quality synthetic data generation pipeline. We demonstrate that this synthetic corpus enables effective Parameter-Efficient Fine-Tuning (PEFT) of VLMs and substantially boosts the performance of state-of-the-art object detectors such as YOLO and DETR. Notably, in the absence of synthetic data (SynSpill dataset), VLMs still generalize better to unseen spill scenarios than these detectors. When SynSpill is used, both VLMs and detectors achieve marked improvements, with their performance becoming comparable. Our results underscore that high-fidelity synthetic data is a powerful means to bridge the domain gap in safety-critical applications. The combination of synthetic generation and lightweight adaptation offers a cost-effective, scalable pathway for deploying vision systems in industrial environments where real data is scarce/impractical to obtain. Project Page: https://synspill.vercel.app

Large language models (LLMs) have established great success in the general domain of natural language processing. Their emerging task generalization and free-form dialogue capabilities can greatly help to design Chemical General Intelligence (CGI) to assist real-world research in chemistry. However, the existence of specialized language and knowledge in the field of chemistry, such as the highly informative SMILES notation, hinders the performance of general-domain LLMs in chemistry. To this end, we develop ChemDFM, the first LLM towards CGI. ChemDFM-13B is trained on 34B tokens from chemical literature, textbooks, and instructions as well as various data from the general domain. Therefore, it can store, understand, and reason over chemical knowledge and languages while still possessing advanced free-form language comprehension capabilities. Extensive quantitative evaluation shows that ChemDFM can significantly outperform the representative open-sourced LLMs. Moreover, ChemDFM can also surpass GPT-4 on a great portion of chemical tasks, despite the significant size difference. Further qualitative evaluations demonstrate the efficiency and effectiveness of ChemDFM in real-world research scenarios. We will open-source the ChemDFM model soon.

Retrosynthesis, which aims to find a route to synthesize a target molecule from commercially available starting materials, is a critical task in drug discovery and materials design. Recently, the combination of ML-based single-step reaction predictors with multi-step planners has led to promising results. However, the single-step predictors are mostly trained offline to optimize the single-step accuracy, without considering complete routes. Here, we leverage reinforcement learning (RL) to improve the single-step predictor, by using a tree-shaped MDP to optimize complete routes. Specifically, we propose a novel online training algorithm, called Planning with Dual Value Networks (PDVN), which alternates between the planning phase and updating phase. In PDVN, we construct two separate value networks to predict the synthesizability and cost of molecules, respectively. To maintain the single-step accuracy, we design a two-branch network structure for the single-step predictor. On the widely-used USPTO dataset, our PDVN algorithm improves the search success rate of existing multi-step planners (e.g., increasing the success rate from 85.79% to 98.95% for Retro*, and reducing the number of model calls by half while solving 99.47% molecules for RetroGraph). Additionally, PDVN helps find shorter synthesis routes (e.g., reducing the average route length from 5.76 to 4.83 for Retro*, and from 5.63 to 4.78 for RetroGraph).

Obtaining the desired effect of drugs is highly dependent on their molecular geometries. Thus, the current prevailing paradigm focuses on 3D point-cloud atom representations, utilizing graph neural network (GNN) parametrizations, with rotational symmetries baked in via E(3) invariant layers. We prove that such models must necessarily disregard chirality, a geometric property of the molecules that cannot be superimposed on their mirror image by rotation and translation. Chirality plays a key role in determining drug safety and potency. To address this glaring issue, we introduce a novel field-based representation, proposing reference rotations that replace rotational symmetry constraints. The proposed model captures all molecular geometries including chirality, while still achieving highly competitive performance with E(3)-based methods across standard benchmarking metrics.