The ability to replicate higher-level results is further supported by the very strong correlation in the bottom panels of Figure with R 2 coefficients of 0.98 and 0.99 for MCAs and MAAs, respectively. These results actually outperform the ML models of Tavakoli et al. , which achieved 10-fold cross-validation R 2 coefficients of 0.92 ± 0.02 and 0.94 ± 0.02 for MCAs and MAAs, respectively. Of course, the better performance comes with a higher computational cost, although the median wall time for this data is less than two minutes using eight CPU cores (Intel(R) Xeon(R) CPU X5550 @ 2.67GHz). In fact, the timings can be further improved due to the handling of structures and conformers being embarrassingly parallel. Alternatively, omitting the single-point r 2 SCAN-3c SMD(DMSO) calculations will greatly reduce the computational cost without impacting the above results significantly as seen in Figure in the supporting information. It should be noted that the molecules in the bottom panels of Figure have on average ∼ 10 heavy atoms and ∼ 6 identified electrophilic and nucleophilic sites.