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Here, we report a flavin\u2010photocatalyzed platform that converts complex piperazine\u2010containing drugs into persistent tetrahydropyrazine intermediates that serve as versatile branch points for downstream functionalization. Under blue\u2010light irradiation, riboflavin tetraacetate (RFTA) promotes sequential\n                    <jats:italic>\u03b1<\/jats:italic>\n                    \u2010 and\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010C\u2500H bond cleavage of\n                    <jats:italic>N<\/jats:italic>\n                    \u2010alkyl,\n                    <jats:italic>N<\/jats:italic>\n                    \u2010aryl, and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010heteroaryl piperazines under mild conditions and with tolerance of diverse functional groups. The resulting drug\u2010derived tetrahydropyrazines can be isolated or directly telescoped into reactions with electrophiles and nucleophiles, enabling late\u2010stage access to cyclopropyl\u2010, trifluoromethyl\u2010, carbonyl\u2010, amide\u2010, and cyano\u2010substituted piperazine analogues. By decoupling C\u2500H oxidation from subsequent bond construction, this two\u2010stage strategy enables transformations that would otherwise be incompatible with flavin\u2010mediated oxidation. The utility of this approach is demonstrated through the rapid preparation of diverse analogues of piperazine\u2010based pharmaceuticals and a preliminary structure\u2013activity relationship (SAR) study of erastin, which reveals that piperazine\u2010core substitution and stereochemistry can substantially influence cellular activity. Stern\u2013Volmer quenching experiments, cyclic voltammetry, and characterization of intermediates formed under photoirradiation provide insight into the reaction mechanism. This work establishes drug\u2010derived tetrahydropyrazines as practical late\u2010stage intermediates for expanding medicinally relevant chemical space around piperazine\u2010containing drug leads.\n                  <\/jats:p>","DOI":"10.1002\/anie.6711809","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:02:58Z","timestamp":1788346978000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Drug\u2010Derived Tetrahydropyrazines for Late\u2010Stage\n                    <i>\u03b1<\/i>\n                    \u2010 and\n                    <i>\u03b2<\/i>\n                    \u2010Functionalization of Piperazine\u2010Based Pharmaceuticals"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7161-3378","authenticated-orcid":false,"given":"Soichiro","family":"Mori","sequence":"first","affiliation":[{"name":"Department of Chemistry The Herbert Wertheim UF Scripps 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