High-throughput chemical synthesis is transforming the data landscape for optimizing small molecules, yet these large-scale campaigns outpace the capabilities of conventional analytical techniques. Consequently, new approaches are needed to reduce cycle times while maintaining data quality. Here, we introduce a “fragmentation-first” strategy which generalizes the analysis of small organic molecules in microtiter plate formats – transforming chemical reaction analysis from minutes to milliseconds. We will touch upon how our high-throughput chemical synthesis platform is now evolving into a hyphenated system which incorporates function prioritization within in vitro assays and follow up re-synthesis experiments executed via automation.