Multistep retrosynthesis combining a disconnection aware triple transformer loop with a route penalty score guided tree search

Computer-aided synthesis planning (CASP) aims to automatically learn organic reactivity from literature and perform retrosynthesis of unseen molecules. CASP systems must learn reactions sufficiently precisely to propose realistic disconnections while avoiding overfitting to leave room for diverse options, and explore possible routes such as to allow short synthetic sequences to emerge. Herein we report a CASP tool proposing original solutions to both challenges. First, we use a triple transformer loop (TTL) predicting starting materials (T1), reagents (T2), and products (T3) to explore diverse disconnections obtained by tagging potentially reacting atoms both systematically and using templates. Second, we integrate TTL into a multistep tree search algorithm (TTLA) prioritizing sequences using a route penalty score (RPScore) considering the number of steps, their confidence score, and the simplicity of all intermediates along the route. Our approach favours short synthetic routes to commercial starting materials, as exemplified by retrosynthetic analyses of recently approved drugs.