Library synthesis using solution phase capping of solid phase derived intermediates

An efficient protocol for the preparation of combinatorial libraries is described. The methodology first deploys solid phase chemistry to synthesize a 96-well array of intermediates linked to resin via a latent reactive functionality such as a benzyl ether, tert-amine or thioether. Cleavage from the resin is accompanied by transformation of the linker to a reactive functionality, namely a benzyl halide, sec-amine or thiol. Aliquots of this array of reactive intermediates are each capped with a different solution phase reactant to deliver the final library in 96-well format, ready for high throughput screening.