This dual modeling approach was applied to a rarelyused protocol for sustainable amidation reactions. By examining a range of different substrate combinations, insights into the different kinetics for each substrate were gained. Accordingly, a better understanding of the compatible reaction substrates can be inferred. We then expanded this approach to the two-step synthesis of the API benznidazole, where both alkylation and amidation reactions proved to be amenable to this approach. The developed reaction models were also utilized for in silico optimization, whereby different objectives, and the trade-offs between them, can be rapidly explored without additional experimental effort.