AbstractThe development of a robust process for a Pd-catalyzed Buchwald–Hartwig C–N coupling reaction to manufacture PF-06842874, a clinical candidate for the treatment of pulmonary arterial hypertension, on kilogram scale is reported. The variability in reaction kinetics initially encountered was resolved via the use of sodium tert-butoxide as a homogeneous base and a careful selection of precatalyst by examination of the catalyst activation mechanism. Extraction with aqueous acid followed by careful pH adjustment allowed us to isolate the product with excellent purge of impurities. The process was successfully implemented in up to 18 kg demonstration.