ABSTRACT There is an important need to develop novel synthetic methodology that enables efficient access to valuable fragments in pharmaceutical research using abundantly available reagents. With this goal in mind, many modern advances have applied technologies such as transition metal catalysis, photocatalysis, or electrochemistry; in contrast, this proposal draws mechanistic inspiration from these approaches while using only cheap inorganic Lewis basic salts to promote challenging and novel coupling reactions. The long-term goal of this proposal is to develop alternative cross-coupling reactions using Lewis bases as promoters to provide synthetic chemists new tools to assemble pharmaceuticals. These advancements would be extremely valuable to drug discovery chemists and provide a cost-effective route to complex drug fragments. To address this need, novel and general Lewis base-promoted cross-coupling methodologies enabled by highly reducing silane-derived species are proposed. Three specific transformations are described, including the reductive coupling of activated arenes with organosilanes, carbonyl derivatives, and alkyl electrophiles. The successful development of the processes outlined in this proposal will introduce a practical route to functionalized benzylic amines, ethers, and diarylmethanes that are ubiquitous in biologically active compounds. Finally, the direct reduction of carbon- halogen bonds will enable the late-stage modification of commercial drugs to allow for intense structure-activity relationship studies. This proposal advances strategies inspired by modern technology using simple common reagents in a straightforward approach to access valuable drug fragments in a mild and efficient manner to ultimately accelerate drug discovery and improve human health. To achieve the overall goal of this proposal, we have outlined a rigorous training plan. The specific aims outlined in this proposal describe three reductive coupling processes involving base-promoted reductive arylation of alkyl electrophiles and carbonyl derivatives. The reagents and starting materials in these processes are abundantly available, inexpensive, and practical, which will allow for the rapid uptake of this methodology. Key mechanistic investigation through successful implementation of this training plan will allow for elucidation of other novel coupling reactions and expansion of the initial discovery scope. The chemistry department at Colorado State University is an excellent environment for successful training because of the collaborative atmosphere between world-renowned organic chemists who are leaders in their respective fields. CSU’s stat-of-the-art facilities will enable the unhindered development of the chemistry proposed. Furthermore, CSU has a variety of educational resources including instructional coaching services, professional development, and writing workshops. These important resources will be assets to the implementation of the training pl...