Project Summary/Abstract Organic synthesis is a rate-limiting factor in drug discovery, and consequently, advances in synthetic methods relevant to bioactive molecule preparation can be a powerful driving force to accelerate the discovery of new small molecule therapeutics for unmet medical needs. Research in the Hilinski laboratory is focused on addressing unsolved challenges in catalysis and synthesis that have immediate relevance to the contemporary practice of drug discovery, and that have the potential for broad impact as widespread platforms for new reaction discovery and/or synthetic planning. We are also invested in the direct application of small molecule synthesis to drug discovery, in collaborative projects that use small molecules to engage new biological targets for cancer treatment. This MIRA application outlines our recent endeavors and future plans in two areas: (1) catalytic, selective C–H functionalization, and (2) novel cycloaddition reactions. In the first area, research in the field of intermolecular, site selective C(sp3)–H hydroxylation and amination has advanced considerably in recent years, but has reached a major barrier in the desire to transition from substrate-controlled selectivity to catalyst controlled selectivity. To address these and other challenges, we have established a program in organocatalytic atom-transfer C–H functionalization and over the past several years have shown that our catalytic platform, focused on iminium salt and amine catalysts, competes with or exceeds metal-catalyzed methods in reactivity and selectivity, and also that it has the flexibility to enable multiple types of atom transfer (i.e. both hydroxylation and amination). Having established this foundation, we are now beginning to better understand the unique mechanistic details of these reactions and the influence of catalyst structure on reactivity and selectivity. Our goals over the next five years are to use amine catalysis to override substrate control of C–H hydroxylation site selectivity and to develop enantioselective C–H hydroxylation methods, and to use iminium catalysis to expand both the scope and selectivity among benzylic, unactivated tertiary, and unactivated secondary C–H bonds in late-stage C–H amination applications. Distinct from our research on C–H functionalization, we have also established a program on the invention of new regioselective and stereoselective cycloaddition reactions targeting nitrogen-containing heterocycles and carbocycles appended to nitrogen-containing heterocycles, two major structural motifs in drug discovery. Described in this application is our recent discovery of Lewis acid catalysis of a virtually unexplored variant of the Diels-Alder reaction – one that uses vinylazaarenes as dienophiles. Over the next five years, we intend to pursue our long-term goal of establishing this as a strategy- level synthetic approach by expanding this chemistry to include hetero Diels-Alder reactions to form azaare...