. This allows us to filter out complexes with strained geometries, such as the one shown on the left in Figure , using a simple 2D approach. For the remaining combinations of C-H bonds and directing groups, the corresponding intermediate substrate-Pd(OAc)-complex is generated. For each complex 3N rot + 3 conformers are generated with ETKDG, here N rot is the number of rotatable bonds in the substrate. The conformers are clustered based on their RMSD with a cutoff of 1.0 Å and the conformer corresponding to the centroid of each cluster is retained. The remaining conformers of each complex are optimized using GFN1-xTB in the implicit solvent model ALPB with parameters for CH 2 Cl 2 . After each optimization, the geometry of the complex is analyzed to determine whether the connectivity has changed. The connectivity of the complex before and after optimization is compared only for bonds not involving the transition metal since the determination of bonds to transition metals is prone to errors. Instead, the geometry of the four atoms adjacent to the transition metal (the two oxygen atoms from the acetate moiety, the carbon atom from the reaction site, and the hetero atom from the directing group) is analyzed without regard for connectivity. All four atoms have to lie within a plane after the optimization for the optimization to be considered successful. This is determined by calculating the angle between the normal vectors of the plane spanned by Pd, the reaction site and the hetero atom of the directing group and the plane spanned by Pd and the two oxygen atoms of the acetate moiety. This angle has to be below 5 • for the atoms to be considered to be within a plane.