A solvent-free thermo-mechanochemical synthesis of amides from carboxylic acids and amines, performed in an extruder, in the absence of coupling agents, additives, or catalyst is reported. A Bayesian optimization (BO) approach, incorporating an active and soft constraint, was developed, able to handle holistically various parameters (temperature, reaction time, excess of starting materials) while targeting a high conversion and sustainability. The methodology proved to be straightforward, high-y