This grant applications combines innovative new methods for diversity oriented synthesis emanating from the Brummond group with powerful new methods for strategic separation emanating from the Curran group. The premise of this work is that diversity oriented synthesis is currently limited by the perceived notion that it should be conducted either in solution or on the solid phase. Proposed within are hybrid methods combining Solid Phase Organic Synthesis and Fluorous techniques. New combined fluorous/solid phase methods will leverage the favorable features of both methods to give more compounds in a better state of purity that either alone. The power of the combination method will be demonstrated by applying them to a diverging strategy for assembling multiple, architecturally unique compounds from a single pivotal substrate using an allenic Alder-ene and Pauson-Khand reaction. The successful demonstration of this combination approach will subsequently be applied to Diversity-Oriented Synthesis for the preparation of natural product-like libraries of high molecular complexity and diversity. The advantages of the hybrid methods will be assessed by comparing them to the solid phase synthesis. The synthesis of novel fluorous tags and scavengers including fluorous thiols, fluorous isonitriles and fluorous dienophiles will be effected, and the validation of use of these compounds in representative reaction and separation schemes. The technology and know-how employed during the research phase by successfully preparing small libraries of compounds (30-200 compounds, 1-2 mg each) will be transferred to the Diversity Oriented Synthesis (DOS) facility for the development phase. This facility will independently validate the methods established by our research groups by preparing libraries of 500-10,000 pure single compounds in quantities of 10-20 mg each. Assays evaluating the biological activity and/or protein binding affinity of both the small research libraries and the larger development libraries and the larger development libraries will be performed as outlined in the DOS core part of this proposal. As biological data begins to come back, we expect that natural collaborations will be established and we also expect that some of the libraries from the later part of this work will begin to incorporate structure design components based on targets identified in the preliminary biological screens.