Title: Learning to Plan Chemical Syntheses,
Abstract: From medicines to materials, small organic molecules are indispensable for
human well-being. To plan their syntheses, chemists employ a problem solving
technique called retrosynthesis. In retrosynthesis, target molecules are
recursively transformed into increasingly simpler precursor compounds until a
set of readily available starting materials is obtained. Computer-aided
retrosynthesis would be a highly valuable tool, however, past approaches were
slow and provided results of unsatisfactory quality. Here, we employ Monte
Carlo Tree Search (MCTS) to efficiently discover retrosynthetic routes. MCTS
was combined with an expansion policy network that guides the search, and an
"in-scope" filter network to pre-select the most promising retrosynthetic
steps. These deep neural networks were trained on 12 million reactions, which
represents essentially all reactions ever published in organic chemistry. Our
system solves almost twice as many molecules and is 30 times faster in
comparison to the traditional search method based on extracted rules and
hand-coded heuristics. Finally after a 60 year history of computer-aided
synthesis planning, chemists can no longer distinguish between routes generated
by a computer system and real routes taken from the scientific literature. We
anticipate that our method will accelerate drug and materials discovery by
assisting chemists to plan better syntheses faster, and by enabling fully
automated robot synthesis.