The article discusses the development and application of ynamide coupling reagents in peptide synthesis, aiming to address the challenges of racemization and epimerization in traditional methods. Ynamide coupling reagents, which utilize α-acyloxynamide active esters, offer a racemization-free approach for forming amide and ester bonds. These reagents have been shown to effectively facilitate peptide fragment condensation, head-to-tail cyclization, and precise incorporation of thioamide substitutions into peptide backbones. The first practical inverse peptide synthesis using unprotected amino acids was achieved through a transient protection strategy, demonstrating the utility of ynamide reagents in green chemistry. Additionally, ynamide-mediated ester bond formation enables efficient intermolecular esterification and macrolactonization while preserving α-chirality and conjugated αβ-C=C double bond configurations. A scalable one-step synthetic method for ynamide reagents has been developed, along with a water-removable variant that simplifies purification. The reagents can be recycled, supporting their sustainable industrial application. The article highlights the mechanistic insights, synthetic applications, and future potential of ynamide coupling reagents in advancing peptide synthesis towards more efficient and environmentally friendly processes.The article discusses the development and application of ynamide coupling reagents in peptide synthesis, aiming to address the challenges of racemization and epimerization in traditional methods. Ynamide coupling reagents, which utilize α-acyloxynamide active esters, offer a racemization-free approach for forming amide and ester bonds. These reagents have been shown to effectively facilitate peptide fragment condensation, head-to-tail cyclization, and precise incorporation of thioamide substitutions into peptide backbones. The first practical inverse peptide synthesis using unprotected amino acids was achieved through a transient protection strategy, demonstrating the utility of ynamide reagents in green chemistry. Additionally, ynamide-mediated ester bond formation enables efficient intermolecular esterification and macrolactonization while preserving α-chirality and conjugated αβ-C=C double bond configurations. A scalable one-step synthetic method for ynamide reagents has been developed, along with a water-removable variant that simplifies purification. The reagents can be recycled, supporting their sustainable industrial application. The article highlights the mechanistic insights, synthetic applications, and future potential of ynamide coupling reagents in advancing peptide synthesis towards more efficient and environmentally friendly processes.