Despite the ubiquity of the amide group, its synthesis is not always straightforward and the existing methods for amide formation score badly from the perspectives of economy and sustainability. This proposal aims to develop unprecedented methodology for amide synthesis, allowing one to access “challenging” representatives. Two routes are proposed to mitigate risk and to provide complementarity. The objective of the proposal is twofold: 1) to expand the available chemical space (allowing one to synthesize challenging amides previously considered inaccessible via library synthesis with existing methods) and 2) to substitute existing syntheses with better ones (delivering higher yields without using toxic reagents and minimizing waste). Achieving these two objectives will have an impact on the discovery of new molecular entities and the improvement of production processes in the fine chemicals sector. The power of the new methodology will be demonstrated on the synthesis of selected real-life examples, APIs (Active Pharmaceutical Ingredients).