Synthesis of chemical libraries combined with high-content screening has emerged as a valuable strategy for the discovery and optimization of new agents capable of modulating complex metabolic and signaling pathways. Our contribution to this rapidly expanding field has been in developing new methods, strategies and concepts for rapid assembly of chemical libraries featuring unprecedented levels of skeletal diversity. We have completed the synthesis of 1200-member library that incorporates 20 structurally diverse scaffolds. The development of this strategy was enabled by our recently disclosed siloxyalkyne-alkene metathesis. In addition, we have developed a novel format for multiparallel synthesis, which entails a three-dimensional delivery of reactants to an array of interconnected reaction wells. Conceptually similar to the split-and-pool synthesis, this method, however, eliminates the encoding-decoding manipulations and offers improved throughput compared to the conventional robotically driven parallel synthesis.