TS3 exhibits an energy barrier of 7.68 kcal mol -1 , characterized by r C 1 -O LG = 3.98 Å and r C 1 -O Nu = 2.78 Å (Fig. ). This TS corresponds to a conformational transition from a ( 4 H 3 )-like (Inter2) to a skew-boat ( 1 S 3 )-like (PS) structure, which is the same as the one reported in Ref. 67. Following TS3, the bond between the nucleophile and anomeric centre is formed. The barrierless nature of this step is corroborated by a geometry scan along r C 1 -O Nu from 3 Å to 1.5 Å, conducted at the ground-truth level of theory (PBE-D3BJ/def2-TZVP) with implicit solvent (Fig. ), and has been observed in other glycosylation reactions. Overall, the mechanism of R3 follows a stepwise S N i pathway, consistent with previously published AIMD simulations for a similar system in DCM. This involves an initial dissociative TS (TS1) leading to a conformations change to form an oxocarbenium intermediate (Inter2), followed by conformational change resulting in a barrierless nucleophilic attack step forming PS (Fig. ). The experimentally observed mechanism shift with temperature may arise from the dissociation of contact ion pairs in DCM as temperature increases. It is important to note that we have achieved this conclusion without a preliminary assumption of the reaction mechanism. To highlight the computational efficiency of the presented approach, three independent 300-ps WTMetaD simulations for this system (284 heavy atoms in total) simulated with linear ACE potential took approximately six days using 24 CPUs, corresponding to 0.004% of the time required for AIMD. The computational cost of the simulations can be further reduced by more efficient implementation of MLP, e.g., using GPU acceleration.