Single-step Retrosynthesis via Reinforcement Learning from Forward Feedback

Abstract:Single-step retrosynthesis is a one-to-many inverse problem, yet most models are trained and evaluated against a single recorded reactant set. Reference-based training gives no explicit positive signal for unrecorded alternatives, and exact-match evaluation rejects non-matching predictions regardless of chemical plausibility. We propose Retrosynthesis via Reinforcement Learning from Forward Feedback (RetroRLFF), which optimizes reactant generation using both reference agreement and forward consistency with the target product. Starting from a supervised decoder-only Transformer, RetroRLFF generates complete reactant candidates and uses a frozen forward reaction model to predict products. A sequence-level reward combines reference agreement and forward consistency while penalizing invalid outputs. Direct Advantage-Based Policy Optimization updates the policy without human preference annotations or a preference-trained reward model. On USPTO-50K, RetroRLFF outperforms all 14 baselines in candidate-level round-trip accuracy at k = 1, 3, 5, and 10. With approximately 50 million parameters, it achieves 90.1% top-1 round-trip accuracy, exceeding R-SMILES, the strongest competing baseline on this metric, by 8.5 percentage points. Compared with its supervised policy, round-trip accuracy increases from 83.1% to 90.1%, while exact-match accuracy is maintained at 57.9% versus 57.5%. In an anonymized expert assessment of 131 randomly selected test cases, organic synthesis experts prefer RetroRLFF over EditRetro in 67.9% of comparisons. These results support forward feedback as a training signal for improving forward consistency while retaining top-1 reference recovery. Expert assessment provides complementary evidence of synthetic feasibility on the selected cases, although neither forward consistency nor expert preference establishes experimental feasibility.

Artificial Intelligence (cs.AI)

arXiv:2610.15141 [cs.AI]

(or arXiv:2610.15141v1 [cs.AI] for this version)

https://doi.org/10.48550/arXiv.2610.15141 Focus to learn more arXiv-issued DOI via DataCite (pending registration)

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