Figures S1 show the results from the conformer search. One can clearly see how the pool of molecules is heavily decreased by the conformer search. Ideally the quality of the GA output should be high enough that most or all of them should be viable molecules after the search. However, only 4 conformers where used during GA runs. As such, the stereoisomer checks where done with few conformers and it is possible that increasing the number of conformers tried for each ligand orientation would lead to new configurations and then these configurations would not be stable when performing a GFN2 optimization. Nevertheless, the conformer search ensured that the molecules that remained where likely to have a more accurate representation of the score and to have more reasonable geometries. After the conformer search the 10 lowest energy conformers where passed to def2-TZVP/PBE single point calculations to obtain new lowest energy conformers at the DFT level. Then the molecules where filtered based on these new scores as described in the main text. An example of how this SP refinement helped select better structure are shown in Figure . The final verification step was the def2-TZVP/PBE optimization of the new lowest energy conformers. The resulting reaction and protonation energy distributions for the 1 neutral and 2 neutral ligand configurations are shown in Figure and Figure . At this level where conformers are def2-TZVP/PBE optimized there is a large portion of molecules with positive protonation energies (Fig. and Fig. ). This is where we applied the second filter to obtain the final populations (90+70) for which we attempt to compute full catalytic cycles. A random selection of 40 of these catalysts are seen in Figure for the 1 neutral ligand catalysts and in Figure for the 2 neutral ligand catalysts.