The direct synthesis of sulfoxonium ylides from amides by selective N-C(O) cleavage is presented. The reaction proceeds through the nucleophilic addition of dimethylsulfoxonium methylide to the amide bond in acyclic twisted amides under exceedingly mild room temperature conditions. A variety of amides can be employed, and the protocol can be applied to the late-stage derivatization of pharmaceuticals. Mechanistic studies outline the relative order of reactivity of amides.