The goal of this application is to design and construct pilot scale libraries comprised of novel heterocycles with an emphasis on skeletal, stereochemical and peripheral functional group (FG) diversity. In particular, we will focus our initial efforts on libraries comprised of sulfur and phosphorus-containing small molecules and analogues thereof, we term generally as S- and P-heterocycles. We aim to design and construct the following libraries using a "linchpin to scaffolds to library" paradigm where a combination of linchpin design, reaction manifolds and in silico diversity screening (PubChem) will guide our efforts in mining unique chemical space in a dynamic manner. Integration of an array of facilitated synthetic protocols utilizing immobilized reagents and technologies developed in our laboratory will enable pilot-scale libraries construction. High-throughput purification via mass-directed fractionation will be used in all cases to verify compound purity and identity. The libraries synthesized will comprise of individual sublibraries of ~40-100 compounds per linchpin in sufficient quantities (10-15 mg) and high purity (>90%) for HTS on numerous platforms within the MLSCN. We are projecting delivery of 750 compounds per year. Ultimately, these libraries will be evaluated via the Molecular Library Screening Network (MLSCN) in order to uncover lead structures for further development. We are well positioned to meet this goal by employing methodologies developed in our laboratories that focus on scaffolds that are designed according to medicinal chemistry principles, and use efficient scaffold generation/diversification strategies and facilitated synthetic protocols for library production. Overall, this platform will enable us to produce scalable, diverse libraries based on multiple novel scaffolds and allow us to probe both biological and chemical space in a dynamic manner.