The 1-pot thioesterification/amide bond formation featured in this sequence, which uses di-2pyridyldithiocarbonate (DPDTC) 17 to activate the carboxylic acid, avoids traditional peptide coupling reagents (e.g., HATU, DCC, COMU, T3P, etc.) and epimerization, and Scheme 1. The Overall Route to Nirmatrelvir allows for facile removal of the (odorless) 2mercaptopyridine by-product via an in-flask extraction with limited amounts of aqueous hydroxide. In contrast to the by-products of conventional amide bond coupling reagents, 18 benign 2-mercaptopyridine can also be easily recovered for recycling to DPDTC (see SI-1, section 4). Both intermediate thioesters 3 and 7 are stable, isolable species constituting activated carboxylic acids, potentially simplifying their large-scale manufacture and distribution compared to other activated species. In this sequence, however, their individual isolation/purification was not required.