The modern pharmaceutical industry is increasingly focused on sustainable production processes and innovative technologies that minimize environmental impacts and comply with green chemistry principles. Mechanochemistry, an essentially solvent-free technique, has shown great potential as a powerful tool for advancing the sustainability goals in the synthesis of active pharmaceutical ingredients (APIs). By eliminating solvents from the production chain, mechanochemistry can offer improved safety profiles and minimize the amount of generated waste, as solvents can account for up to 90% of the total mass consumed and are major contributors to the overall toxicity profile in a typical industrial process. Nitrogen-containing functional groups predominate in bioactive molecules and carbonnitrogen (C-N) bond-forming reactions are widely used in the synthesis of APIs. For instance, nitrogen atom derivatizations are involved in about 80% of all heteroatom alkylation and arylation reactions in the synthesis of drug candidates. Thus, the development of sustainable amide-coupling techniques along with the direct nucleophilic substitution of alcohols (e.g., for preparation of amines) have been listed among the top green chemistry research priorities by the American Chemical Society Green Chemistry Pharmaceutical Roundtable (ACS GCIPR). Advances in employing mechanochemistry for constructing C-N bonds relevant to API synthesis, including the preparation of hydantoin derivatives, amides, bioactive peptides, aliphatic and aromatic amines, sulfonylurea drugs, hydrazones, and sydnones have been described in the literature.