Retro-R1: LLM-based Agentic Retrosynthesis

Wei Liu, Jiangtao Feng, Hongli Yu, Yuxuan Song, Yuqiang Li, Shufei Zhang, LEI BAI, Wei-Ying Ma, Hao Zhou

Keywords: Reinforcement Learning, Retrosynthesis Planning, LLM-based Agent

TL;DR: An LLM-based retrosynthesis planning agent trained end-to-end with Agentic Reinforcement Learning.

Abstract: Retrosynthetic planning is a fundamental task in chemical discovery. Due to the vast combinatorial search space, identifying viable synthetic routes remains a significant challenge--even for expert chemists. Recent advances in Large Language Models (LLMs), particularly equipped with reinforcement learning, have demonstrated strong human-like reasoning and planning abilities, especially in mathematics and code problem solving. This raises a natural question: Can the reasoning capabilities of LLMs be harnessed to develop an AI chemist capable of learning effective policies for multi-step retrosynthesis? In this study, we introduce Retro-R1, a novel LLM-based retrosynthesis agent trained via reinforcement learning to design molecular synthesis pathways. Unlike prior approaches, which typically rely on single-turn, question-answering formats, Retro-R1 interacts dynamically with plug-in single-step retrosynthesis tools and learns from environmental feedback. Experimental results show that Retro-R1 achieves a 55.79\% pass@1 success rate, surpassing the previous state of the art by 8.95\%. Notably, Retro-R1 demonstrates strong generalization to out-of-domain test cases, where existing methods tend to fail despite their high in-domain performance. Our work marks a significant step toward equipping LLMs with advanced, chemist-like reasoning abilities, highlighting the promise of reinforcement learning for enabling data-efficient, generalizable, and sophisticated scientific problem-solving in LLM-based agents.

Primary Area: Deep learning (e.g., architectures, generative models, optimization for deep networks, foundation models, LLMs)

Submission Number: 22012