Creative library design coupled with an established technology platform is an ideal approach for making small molecule libraries. Utilizing fluorous techniques, we aim to produce novel heterocyclic and natural product-like pilot-scale libraries in an innovative, efficient, and cost-controlled manner. This proposal has the following features: (1) More than half of the proposed library scaffolds are closely related to natural products such as mappicine, isaindigotone, sclerotigenin, and gypsetin. The remaining scaffolds are related to specific structural motifs of natural products or related to the characteristics of natural products in a more general sense, but have high structural novelty and diversity. Libraries produced by diversity-oriented synthesis have skeletal, substitution, and stereochemical variations. (2) Highly efficient and reliable fluorous tagging and separation techniques are used to produce most of the proposed libraries. The use of a "rapid synthesis system" as an integrated synthetic platform dramatically reduces time for both reaction and separation. Other cost control techniques such as "two birds with one stone"-type fluorous tagging/ cleavage, sharing common building blocks, and recovering/reusing fluorous tags and silica gel will be used to produce libraries. (3) The effort on library design/development versus library production is balanced. The design and development of pilot-scale libraries is built upon successful in-house chemistry. More effort is directed toward library production to generate compounds for submission, thus meeting NIH goals. The specific aims are: (1) Synthesis of mappicine-type natural product libraries;(2) Synthesis of isaindigotone-type natural product libraries;(3) Synthesis of sclerotigenin-type natural product libraries;(4) Synthesis of novel and diverse nitrogen-containing polycyclic libraries;(5) Synthesis of diketopiperazine-containing natural product-like libraries;(6) Synthesis of polycyclic ether and alkaloid-type libraries. Over the course of a three-year grant period, around 30 library scaffolds will be developed from 6 projects, resulting in 800-1,000 compounds being produced and submitted each year. RFA general guidelines for library production and submission including library size, quality control, sample delivery, data management, and patent issues will be closely followed. Data generated under this RFA including library synthesis procedures and compound characterization, and research resources such as synthetic technologies and instruments, will be shared willingly with future collaborators that have an interest in screening and/or studying the compounds produced in this proposal.