QM by itself performed worse in every metric in an inversion of the trend seen before. Generally, the MLbased method produced lower MAE and RMSE. This suggested that the split between the two Enamine data sets did not represent as much of an extrapolation as the split from the LEF4000 to tranche 2. The split of the test data set, the FFL-d6, into the subset with known features versus the subset with unknown features also supported this. Only a quarter of the FFL-d6 CF samples were sorted into the subset with unknown features as opposed to around two-thirds of samples in tranche 2 of the LEF (see Table of the supporting information).