Rethinking Molecule Synthesizability with Chain-of-Reaction

• URL: http://arxiv.org/abs/2509.16084v1
• Date: Fri, 19 Sep 2025 15:29:57 GMT
• Title: Rethinking Molecule Synthesizability with Chain-of-Reaction
• Authors: Seul Lee, Karsten Kreis, Srimukh Prasad Veccham, Meng Liu, Danny Reidenbach, Saee Paliwal, Weili Nie, Arash Vahdat,
• Abstract summary: We introduce ReaSyn, a generative framework for synthesizable projection.<n>We propose a novel perspective that views synthetic pathways akin to reasoning paths in large language models (LLMs)<n>With the CoR notation, ReaSyn can get dense supervision in every reaction step to explicitly learn chemical reaction rules.
• Score: 47.744071119775676
• License: http://creativecommons.org/licenses/by/4.0/
• Abstract: A well-known pitfall of molecular generative models is that they are not guaranteed to generate synthesizable molecules. There have been considerable attempts to address this problem, but given the exponentially large combinatorial space of synthesizable molecules, existing methods have shown limited coverage of the space and poor molecular optimization performance. To tackle these problems, we introduce ReaSyn, a generative framework for synthesizable projection where the model explores the neighborhood of given molecules in the synthesizable space by generating pathways that result in synthesizable analogs. To fully utilize the chemical knowledge contained in the synthetic pathways, we propose a novel perspective that views synthetic pathways akin to reasoning paths in large language models (LLMs). Specifically, inspired by chain-of-thought (CoT) reasoning in LLMs, we introduce the chain-of-reaction (CoR) notation that explicitly states reactants, reaction types, and intermediate products for each step in a pathway. With the CoR notation, ReaSyn can get dense supervision in every reaction step to explicitly learn chemical reaction rules during supervised training and perform step-by-step reasoning. In addition, to further enhance the reasoning capability of ReaSyn, we propose reinforcement learning (RL)-based finetuning and goal-directed test-time compute scaling tailored for synthesizable projection. ReaSyn achieves the highest reconstruction rate and pathway diversity in synthesizable molecule reconstruction and the highest optimization performance in synthesizable goal-directed molecular optimization, and significantly outperforms previous synthesizable projection methods in synthesizable hit expansion. These results highlight ReaSyn's superior ability to navigate combinatorially-large synthesizable chemical space.

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