DFT modeling of the decomposition pathway suggests that the process occurs in a stepwise manner (Figure ). The first step involved C5 protonation via dihydrogen phosphate to form Int I, followed by attack of hydrogen phosphate at C6 to form the functionally inactive product. A concerted mechanism could also be envisioned; however, it is not supported at this level of theory (see section 3 of the supplemental information for discussion). In each evaluated NCB, TS I corresponds to the highest energy barrier. As a result, these NCBs follow the stability trend of F1a = G1a > A1a > H1a, which is comparable to the experimental study that found the stability in phosphate buffer of F1a and G1a to be equivalent and higher than that of A1a and H1a. The species product labeled on the reaction scheme in Figure does not necessarily represent the final decomposed species, and has been known to further decompose into another final product. However, because experimental rates of decomposition are measured by the disappearance of the 1,4-dihydropyridine moiety and our calculated values are consistent with experiment, we do not consider further decomposition. BNAH (F1a), P2NAH (G1a), and P3NAH (H1a). Calculations were performed with the level of theory ωB97M-V/def2-TZVP/SMD(water)//PBE0-D3(BJ)/6-31+G(d)/SMD(water). After identifying TS I as a predictor of NCB stability, we sought a simpler stability representation that would be more suitable for high-throughput calculations. Optimization of transition state structures often requires more computationally intensive protocols and manual intervention.