For the here considered substrate, this procedure reduces the number of complexes to optimize with GFN1-xTB from 30 to 9, the complexes are shown in Figure . This procedure involves several force-field optimizations, which increase the overall wall time by ∼ 10 seconds for the here shown substrate compared to the previously reported approach. From here on, we follow the same procedure as for the ortho-directing groups and correctly predict the reaction site H 2 , which is the only one within the 1 kcal/mol energy threshold at the GFN1-xTB level.