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Here, we describe an automated solid\u2010phase flow synthesis (SPS\u2010flow) platform for diversity\u2010oriented analogue generation of an HTS\u2010derived, non\u2010peptidic small\u2010molecule hit scaffold. A benzodiazepine hit against cyclin\u2010dependent kinase 11B (CDK11B) was selected as a proof\u2010of\u2010concept and translated into a modular 10\u201311\u2010step synthetic sequence through fragment\u2010guided retrosynthetic design. A sterically tuned triazene linker on 2\u2010chlorotrityl resin was developed to tolerate diverse reaction conditions while enabling traceless cleavage and post\u2010synthetic diazonium diversification, and Chemical Recipe File (CRF)\u2010based control coordinated continuous\u2010, circulation\u2010, and stop\u2010flow operations within a unified automated workflow. The platform enabled the synthesis of 42 benzodiazepine analogues in 5%\u201333% overall yields, with each sequence completed within approximately 45\u201348\u00a0h from a common resin\u2010bound precursor. Within the explored first\u2010generation design space, the library rapidly defined the synthetic accessibility and preliminary structure\u2013activity landscape of the scaffold under SPS\u2010flow conditions, supporting early triage of the series and demonstrating that SPS\u2010flow can be used as a programmable platform for automated multistep diversification and early\u2010stage drug optimization.<\/jats:p>","DOI":"10.1002\/anie.1500194","type":"journal-article","created":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:26:37Z","timestamp":1793255197000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Automated Solid\u2010Phase Flow Synthesis for Scaffold Diversification of a High\u2010Throughput Screening Hit"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5335-3948","authenticated-orcid":false,"given":"Zhenyang","family":"Yu","sequence":"first","affiliation":[{"name":"Department 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