DirectMultiStep: Direct Route Generation for Multistep Retrosynthesis.

Abstract

Traditional computer-aided synthesis planning (CASP) methods rely on iterative single-step predictions, leading to exponential search space growth that limits efficiency and scalability. We introduce a series of transformer-based models that leverage a mixture of experts approach to directly generate multistep synthetic routes as a single string, conditionally predicting each transformation based on all preceding ones. Our DMS Explorer XL model, which requires only target compounds as input, outperforms state-of-the-art methods on the PaRoutes dataset with 1.9x and 3.1x improvements in Top-1 accuracy on the n₁ and n₅ test sets, respectively. Providing additional information, such as the desired number of steps and starting materials, enables both a reduction in model size and an increase in accuracy, highlighting the benefits of incorporating more constraints into the prediction process. The top-performing DMS-Flex (Duo) model scores 25-50% higher on Top-1 and Top-10 accuracies for both n₁ and n₅ sets. Additionally, our models successfully predict routes for the FDA-approved drugs not included in the training data, demonstrating strong generalization capabilities. While the limited diversity of the training set may affect performance on less common reaction types, our multistep-first approach presents a promising direction toward fully automated retrosynthetic planning.