68 catalysts with E values in the target range could be identified over 40 generations. Figure shows the evolution of the score (blue) and the calculated E (red) of the best catalyst over 40 generations. This task appears to be more challenging than previous ones, since it takes 22 generations without SA constraint until a catalyst with E in the target range is discovered. The final catalyst candidates are all anionic which appears to stabilize the reactant in intermediate 2. Figure shows the structure of the bestperforming catalyst candidate with the interaction between the ligand and reactant in blue. This can be seen as an example of what the structure of the ligand would need to look like in order for the catalyst to fall within the target energy range. The unusual structure with a deprotonated NHC is not expected to be a stable complex and could most likely not be synthesised. Yet, the structure could be useful for further optimization while considering the need for noncovalent interactions between the ligand and the reactant.