were used with k ξ = 100 kcal • mol -1 • Å-2 for all the windows. We first performed the primitive approximation PIMD (PRIMPIMD) with 16 beads for each QM atom for 1-ns per window, and then an additional 1-ns simulation was performed for each of the first 16 windows (with RC between -0.15 Å and 0.60 Å) to improve the convergence in this region. The temperature was regulated using the "middle scheme" Langevin thermostat. The step size was set to 0.5 fs. Configurations were saved every 1000 steps (500 fs) for single point energy calculations at the DFT level, as well as the SQM level. Due to the symmetry of the molecule, we only calculated the PMF along the CV with positive values. The potential of mean force at the SQM level was generated via the MBAR analysis, and that at the DFT level was calculated with the MsTP and was smoothed using the Gaussian process regression. 66