Paper Detail
Bogdan Zagribelnyy, Ivan Ilin, Nikita Bondarev, Maksim Kuznetsov, Mathieu Reymond, Vladimir Aladinskiy, Alex Aliper, Alex Zhavoronkov
Single-step retrosynthesis is a central component of computer-aided synthesis planning, yet its intrinsically one-to-many nature is poorly captured by single-answer evaluation and benchmarking protocols. To address this, we introduce Top-K prompting as a robust training and inference paradigm to better capture diverse, plausible reaction predictions. We compile CREED-CCV-2+USPTO-XL, an ultra-large-scale dataset of ~45.6 million verified reactions to train the C3LM (Chemistry Constraint-Consistent Language Model). By integrating fine-tuning with ChemCensor-based and novelty-oriented rewards, our model achieves state-of-the-art performance on the OOD URSA-expert-2026 benchmark. Further analysis of reaction uniqueness shows that LLMs and conventional models explore complementary reaction spaces, motivating ensemble-based retrosynthesis systems. Overall, our results establish Top-K, plausibility-aware training as a practical new direction for robust future LLM-based synthesis planning.
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@article{zagribelnyy2026training,
title = {Training Chemical Plausibility-Aware Large Language Models for Single-Step Retrosynthesis},
author = {Bogdan Zagribelnyy and Ivan Ilin and Nikita Bondarev and Maksim Kuznetsov and Mathieu Reymond and Vladimir Aladinskiy and Alex Aliper and Alex Zhavoronkov},
year = {2026},
abstract = {Single-step retrosynthesis is a central component of computer-aided synthesis planning, yet its intrinsically one-to-many nature is poorly captured by single-answer evaluation and benchmarking protocols. To address this, we introduce Top-K prompting as a robust training and inference paradigm to better capture diverse, plausible reaction predictions. We compile CREED-CCV-2+USPTO-XL, an ultra-large-scale dataset of \textasciitilde{}45.6 million verified reactions to train the C3LM (Chemistry Constraint-Consisten},
url = {https://arxiv.org/abs/2608.18940},
keywords = {cs.LG, cs.AI, cs.CE, cs.CL, Top-K prompting, single-step retrosynthesis, computer-aided synthesis planning, CREED-CCV-2+USPTO-XL, C3LM, ChemCensor, OOD URSA-expert-2026, ensemble-based retrosynthesis, LLM-based synthesis planning, huggingface daily},
eprint = {2608.18940},
archiveprefix = {arXiv},
}
{}