Abstract: The present invention provides a method of synthesizing a library of chemical compounds with skeletal diversity. Two approaches are used to create skeletal diversity within a library of chemical compounds: (1) the “branching pathways” (or reagent-based) approach; and (2) the “folding pathways” (or substrate-based) approach. Upon exposure to certain reaction conditions the members of the library undergo unique transformations into a diverse collection of molecular skeletons, which can be functionalized and derivatized further to generate a large collection of unique, natural product-like compounds. A furan-based library synthesized using the folding pathways approach is provided, and a polycyclic library created using the braching pathways approach is also provided. The invention also provides materials, reagents, intermediates, and kits useful in the practice of the inventive method as well as method for screening the inventive compounds.