With the NES approach, some of the transformations in this set can potentially be challenging for standard RBFE calculations if the chimeric molecule is not set up carefully. Those transformations involve stereo center inversions (compound 02 → compound 03) and ring forming/ring breaking transformations (isopropyl to cyclopropyl transformations). For the latter, chimeric molecules should be created where the entire group is included in the transformation rather than forming/breaking a ring. The chiral inversion transformation was potentially not handled correctly in the NES protocol, possibly due to a bug in the OpenEye implementation.