By devising a high throughput QM/MM MD workflow, we were able to study the C-N coupling reaction dynamics of a supramolecular Cu-calix [8]arene catalyst under experimental conditions. This development is a crucial step towards a predictive operando model for complex catalytic reactions. It allowed us to extract not only reaction energies and barriers with uncertainties, but also provides insights into the intricate dynamic nature of the macrocyclic transition-metal catalyst in explicit solvent.