The development of an in situ formed (Xantphos)Pd oxidative addition complex made possible a robust, scalable C− S coupling of a functionalized aryl bromide with 2-mercaptoethanol that ultimately enabled the synthesis of Janus Kinase inhibitor GDC-9918 on a kilogram scale. An insoluble, catalytically inactive, [12]metallacrown-6 palladium(II) complex, [Pd 6 (μ 2 -SCH 2 CH 2 OH) 12 ], was found to form quickly under most reaction conditions in the presence of 2-mercaptoethanol and a Pd catalyst and required up to 12 mol % Pd for full conversion in our generation route. A second-generation process was developed to minimize the formation of the [12]metallacrown-6 palladium(II) complex and enabled the decrease in catalyst loading to 2 mol % Pd. A soluble Pd scavenger, PIX, effectively removed Pd to <5 ppm. Catalytic sodium tungstate oxidation of the resulting thioether smoothly provided crude GDC-9918 that was recrystallized to the desired polymorph and micronized to a particle size distribution suitable for development as an inhalable treatment for asthma.