For the QM/MM MD simulation, we chose the in-house developed ab-initio quantum mechanical charge field (QMCF) molecular dynamics approach 72 using the link-bond method to describe the bonds crossing between QM and MM. The simulation parameters were set up using the GAFF force-field , using the PyConSolv 1.0.0 tool, with default settings. For the geometry optimization, the PBE0 functional was used with the def2-SVP basis set and D3 dispersion corrections in implicit chloroform, using CPCM. The system was solvated in a cubic periodic box with 1708 chloroform molecules. For detailed information regarding the simulation parameters, see the Supporting Information. The 54 atoms at the centre of the calixarene cage were included in the QM zone (see SI Figure ). The quantum mechanical calculations were performed at two distinct levels. The semi-empirical method GFN2-xTB was utilized, providing a vast speed-up of the QM calculation. As semi-empirical methods require benchmarking, 80-82 a full DFT reference was used, with PBE0/def2-SVP/D3, using Turbomole. A detailed comparison can be found in the SI. To generate an appropriate starting structure the system was equilibrated and a 100ns MM/MD simulation was carried out, using the multistep protocol implemented in PyConSolv. We conducted 152 simulation runs using the QM/MM MD protocol of the reductive elimination step, employing GFN2-xTB as the QM method. Among these runs, 142 simulations captured the reductive elimination step and were utilized for evaluating the reaction barrier and structural analysis of the reaction. As we were only interested in averaging the energy of the ensembles, we used all 152 reaction trajectories to calculate the reaction energy by averaging the energies of the labelled ensembles.