PROJECT SUMMARY Nickel-catalyzed cross-coupling reactions have become a widely used method in chemical synthesis. A recent milestone in Ni catalysis was the advancement of C-N and C-O couplings via strategic activation of Ni amide and Ni alkoxide intermediates to promote reductive elimination as the bond-formation step in catalysis. With remarkable success of this strategy in cross couplings of aryl halides with amines and alcohols, it is desirable to leverage the reactivity of Ni amides and alkoxides for broad catalytic applications including alkyne additions with amines (hydroamination) and alcohols (hydroetherification). Such reactions of alkyne hydro(hetero)functionalization create valuable carbon-heteroatom bonds via atom-efficient combination of abundant building blocks (i.e. alkynes and amine/alcohols), although their demonstrations in Ni catalysis have been scarce. The overall objective of this proposal is to develop nickel-based catalysts for alkyne hydrofunctionalization reactions assisted by directing groups. The long-term goal of our proposed research is to advance the general strategy of alkyne hydrofunctionalization for selective and atom-efficient construction of carbon-heteroatom bonds using abundant building blocks. Our study is based on the central hypothesis that alkyne-tethered directing groups such as 2-pyridyl moiety can enhance reaction efficiency, regio- and stereo-selectivity for Ni-catalyzed alkyne hydroamination and hydroetherification reactions via reactivity modulation of relevant Ni amide and alkoxide intermediates. We aim to test this hypothesis by conducting experimental and computational studies on structure-reactivity correlations of proposed organonickel intermediates guided by Machine Learning. The obtained mechanistic insights will guide the rational design of Ni catalysts and ancillary ligands for broad-scope alkyne hydrofunctionalization reactions. The feasibility of this research is demonstrated by our published and unpublished results on several Ni- catalyzed alkyne hydroamination and hydroetherification reactions. This proposal includes Three Specific Aims: (1) To improve the reaction scope and efficiency of Ni-catalyzed hydroetherification of 2-pyridylalkynes. (2) To advance relevant mechanism understanding and rational catalyst design guided by Machine Learning. (3) To develop Ni- catalyzed broad-scope alkyne hydrofunctionalization reactions with directing-group assistance. Our proposed research is innovative because it advances alkyne hydrofunctionalization as a general strategy for Ni-catalyzed carbon-heteroatom bond construction. Results from these studies are significant because they provide efficient catalytic methods that utilize simple and abundant building blocks to synthesize nitrogen- and oxygen-containing compounds of biomedical relevance.