R^3: End-to-End Reasoning-based Planning for Multi-step Retrosynthesis via Reinforcement Learning
YiFei Wang, Qizhi Pei, Jiangtao Feng, Yuntian Shi, Yi Duan, Lihao Wang, Lei Bai Shanghai AI Laboratory, Lijun Wu Shanghai Artificial Intelligence Laboratory 等 10 位作者
Multi-step retrosynthetic planning is a fundamental challenge in organic chemistry, traditionally modeled as a combinatorial search problem guided by single-step prediction models. However, this search-centric paradigm often disconnects from the explicit chemical reasoning processes employed by human experts. In this paper, we propose R^3 (Reinforced Reasoning Retrosynthesis), a novel framework that reformulates this task as end-to-end generative reasoning. Instead of traversing a search tree, R^3 simulates the problem-solving logic of chemists to directly generate complete synthetic pathways. To achieve this, we initialize the model with domain knowledge and employ end-to-end Reinforcement Learning (RL) to optimize the entire planning policy. Experimental results on Retrobench show that R^3 achieves a state-of-the-art Top-1 accuracy of 43.7%, demonstrating that generative reasoning offers a superior alternative to traditional search algorithms in solving complex retrosynthetic problems.
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Proceedings of the 64th Annual Meeting of the Association for Computational Linguistics (Volume 1: Long Papers) · 2026 · 正式发表