Conformational searching calculations were conducted in MacroModel (V13.4) 30 with OPLS4 31 force field. DFT calculations were conducted with Gaussian 16 (Revision A.03). All optimizations were performed at the B3LYP-D3/6-31G(d) level of theory. Single-point energy calculations were carried out at the ωB97X-D/6-311G(d,p) level of theory. 37 3D images of the optimised structures were generated with CYLview20. We have explored the conformational space of key ground state structures thoroughly. CONPFASS was used to assist the DFT reoptimizations of force field structures with confidence that key stable structures are obtained at a reduced computational cost (). The default setting was used for generating the priority list for re-optimizing conformers. On average, we are more than 87% confident that the global minimum structure has been obtained after re-optimizing less than 37% of the conformers from the conformational searching output file (SI Section 1.D). The VRAI-selectivity algorithm 11 was utilized to account for the effects of reaction dynamics on reaction selectivity. Before running the main algorithm, an energy check was run at the ωB97XD/6-311g(d,p)//B3LYP-D3/6-31g(d) level of theory to ensure that the second transition states (TS II s) are lower in Gibbs free energy than the first transition state (TS I ). Otherwise, the programme would proceed to calculate the product percentages with the transition state theory (TST). The main VRAI-selectivity algorithm takes the geometries and frequency of the TS I , intermediate and products as inputs. The frequency analyses were conducted at the B3LYP-D3/6-31G(d) level of theory in this study. The dimensionality of the potential energy surface (PES) is reduced to two dimensions by examining the bond differences between the products or between a product and TS I based on their geometries (Figure ). The major product is determined by the direction in which the imaginary eigenvector of TS I points relative to the intermediate on the 2D PES.