Four distinct SA metrics were employed in this work: SAscore 10 , SCScore 11 , the AstraZeneca RAscore 8 and SYBA . All of them were executed using default parameters. Additionally, the retrosynthesis-based score ManifoldSA was computed using the Postera Manifold API v1 (). ManifoldSA summarizes retrosynthesis results into a number between 0 (easy) and 1 (difficult) that estimates the synthetic accessibility of a compound. For Figure , compounds were classified as synthesizable if their ManifoldSA < 0.5 and non-synthesizable otherwise. Manifold first performs a tree-search to compute possible retrosynthetic routes from the target molecule to purchasable starting materials, using Molecular Transformer to predict the probability of success of each step. The ManifoldSA is then computed by considering the feasibility and robustness of multiple routes to the molecule, taking into account probability of success at each step of a route. The Manifold algorithm has been used in synthesis-driven de novo design .