While impressive progress resulting in millions of lives saved has been made by the pharmaceutical industry by providing highly effective vaccines against the continuing worldwide pandemic, rates of infection and deaths caused by COVID-19 continue to plague society. Newly developed treatments involving antivirals have recently been introduced that add significantly to the toolbox of drugs currently available, which include Merck's molnupiravir 3 and Pfizer's nirmatrelvir. The latter was approved for emergency use by the FDA in late 2021 and has been enthusiastically distributed by the medical profession as an effective treatment, being projected to bring in revenues on the order of 22 billion dollars in 2022 alone. The route being used by Pfizer and its collaborators has evolved from the initial disclosure in 2021, with improvements leading to a 5-step commercial process that affords nirmatrelvir in 46% overall yield. The sequence features reductions not only in step count (from 7 to 5), but also noted are several "green" metrics, such as PMI/step (21), cumulative PMI (108), and energy usage (1513 MJ). Several other laboratories have also described very recent synthetic efforts towards further improving the route to nirmatrelvir, looking to lower the overall cost associated with making this important target. For example, Nuckols and Shanahan have described a route that improves the overall yield by ca. 10%. Likewise, Ruijter and Turner have also contributed, using a chemoenzymatic approach. Our interest in developing a process that is both economical and environmentally responsible led us to recently disclose a 3-pot, 7-step sequence 8 that focuses on facile formation of 2-mercaptopyridinederived thioester intermediates 9a,9b that can then be converted to the targeted peptides, as shown in Scheme 1. This technology shows considerable promise as an alternative to traditional peptide coupling reagents, since it converts carboxylic acids to amides/peptides under very green conditions; e.g., either neat or in aqueous micellar media. Without isolation, introduction of the amine leads to the desired amide/peptide. Applying this approach, we were able to prepare nirmatrelvir in 70% overall isolated yield. 8 Scheme 1: A previous, 7-step, 3-pot sequence to Nirmatrelvir.