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The formation of C–N bonds by Pd-catalyzed cross-coupling is one of the most widely practiced reactions in chemical synthesis. Typical reaction conditions involve either a strong base, which limits the scope of substrates, or an insoluble, inorganic base, which complicates running reactions on a large scale. Reaction conditions for C–N couplings with a base that is both mild and soluble are needed. We report the discovery of a combination of a phosphorinane ligand (L147) and a soluble carboxylate base, potassium 2-ethylhexanoate (K-2-EH), which leads to the coupling of a wide range of base-sensitive coupling partners. To explore the enhanced substrate scope of the reaction with this base and catalyst, we evaluated the scope using representative reactants selected from published partners, using chemical descriptors and clustering to ensure their chemical diversity. These results show that the combination of this phosphorinane ligand and K-2-EH can couple primary aliphatic amines, amides, sulfonamides, and heteroaromatic nucleophiles as well as acidic secondary nitrogen nucleophiles, such as arylamines, heteroarylamines, and amides, with a range of electrophiles. A side-by-side comparison to form selected coupling products in the presence of a range of previously reported bases and ligands showed that the products that decomposed under standard reaction conditions were stable with K-2-EH as a base. Finally, models of quantitative structure–reactivity relationships, trained on ligand screening data, were developed to help reveal the structural features that engender reactivity.