The S_N2 nucleophilic substitution reaction is a vital organic transformation used for drug and natural product synthesis. Nucleophiles like cyanide, oxygen, nitrogen, sulfur, or phosphorous replace halogens or sulfonyl esters, forming new bonds. Isocyanides exhibit unique C-centered lone pair σ and π* orbitals, enabling diverse radical and multicomponent reactions. Despite this, their nucleophilic potential in S_N2 reactions remains unexplored. We have uncovered that isocyanides act as versatile nucleophiles in S_N2 reactions with alkyl halides. This yields highly substituted secondary amides through in situ nitrilium ion hydrolysis introducing an alternative bond break compared to classical amide synthesis. This novel 3-component process accommodates various isocyanide and electrophile structures, functional groups, scalability, late-stage drug modifications, and complex compound synthesis. This reaction greatly expands chemical diversity, nearly doubling the classical amid coupling’s chemical space. Notably, the isocyanide nucleophile presents an unconventional Umpolung amide carbanion synthon (R-NHC(-) = O), an alternative to classical amide couplings.