We then turned to the synthesis of the commercially important active pharmaceutical ingredient moclobemide which is marketed in more than 50 countries worldwide. Importantly, mechanosyntheses of moclobemide had previously been reported by ball milling and by extrusion, although in both cases activated substrates (esters) or coupling reagents were needed for the amide bond formation to take place. In our case, after milling an equimolar mixture of 6 and 7 for 1 h at room temperature, we observed the formation of a new crystalline product 8, as confirmed by PXRD analysis (Fig. ). Nevertheless, subjecting a mixture of 6 and 7 to two thermo-milling cycles for 1 h at 190 °C resulted in a quantitative conversion to moclobemide 9 (Fig. ). Interestingly, PXRD analysis of the crude reaction mixture confirmed the formation of 9 and its crystal phase purity. Finally, to demonstrate that our methodology is atom-efficient, we performed green chemistry metrics, specifically atom economy (AE) and environmental factor (E-factor). In the case of amide 5, our methodology accounts for 92.1% AE and 1.24 E-factor (ESI Fig. ). On the other hand, for moclobemide 9 it is even higher (93.7% AE) and 1.07 E-factor (ESI Fig. ).