4) A set of "custom alerts" predefined in REINVENT, which prevent generation of unphysical ring sizes and unstable reaction groups (Supporting 5) The oracle function (docking or ROCS), with an appropriate score transformation to convert the result to range 0 to 1. For use in ROCS, we transform the ROCS score using a sigmoid function in REINVENT with parameters "Low" = 0.3, "High" = 0.65 and "k" = 0.3., chosen such that the reference ligand score 0.6 receives a score of 0.92. Because desirable docking scores are negative numbers (indicating increasing free energy of binding) , we transformed raw docking scores for use in RL using a reverse sigmoid function in REINVENT with parameters "Low" = -13.5, "High" = -6, and "k" = 0.2 . This is chosen so the reference ligand with docking score -11.4