(3) Screen intermediates from ( ) and ( ) based on reaction energies In this study we screen the found intermediates based on their Gibbs free energies relative to the original reactant system being <30 kcal/mol. The Gibbs free energies are calculated for isolated molecules by the following steps: First we embed 3+3N rot conformers (N rot is the number of rotatable bonds in the molecule) using ETKDGv3 in RDKit. Each conformer is then optimized at the GFN2-xTB level of theory where methanol is modelled as an implicit solvent using the generalized Born and surface area model (GBSA) through the xTB program. 24;29 Following Seumer et al. 5 the conformer with lowest energy at the GFN2-xTB level of theory is optimized at the B3LYP-D3/6-31+G(d,p) level of theory with methanol modelled using the SMD continuum solvent model in Gaussian 16. If the optimization fails to converge or a change in bonding is observed during the optimization, the intermediate is discarded. In case any of the intermediates generated in step ( ) are no longer connected to the main reaction network after screening of the intermediates, these are also discarded.