treatment. For all warheads, three rotamers were identified to be at energetic minima, one of them being an antiperiplanar addition and the other two being synclinal. The second synclinal minimum has not been reported in previous studies of thio-Michael additions. Investigation of the non-covalent interactions within these rotamers revealed that synclinal addition at a C α -C β -S-C dihedral angle of around 50 • has the highest magnitude of attractive interactions, enabled by the relative orientations of the reacting fragments, which stabilize the rotamer. Other rotamers have fewer favorable non-covalent interactions due to their conformations, which is why they are less energetically favorable. By characterizing the transition states associated with the nucleophilic addition process, we also observe that synclinal addition has lower energetic barriers and a preferred reaction pathway than anticlinal addition. The mechanistic insights from this study will facilitate the design of favorable reaction pathways with lower energetic barriers, resulting in faster reaction rates and higher yields of the adducts required for CDK12 inhibition and treatment of DM1.