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Here, we report a safe and scalable flow\u2010based strategy for the on\u2010demand generation of NCF\n                    <jats:sub>2<\/jats:sub>\n                    R anions using a packed\u2010bed microreactor containing caesium fluoride. This protocol enables the late\u2010stage installation of the CF\n                    <jats:sub>2<\/jats:sub>\n                    group under mild conditions, avoiding the use of hazardous fluorinating agents and minimizing fluorinated waste. This fully modular strategy features three points of diversification (carboxylic acid, sulfonamide, and electrophile), allowing efficient access to a broad range of \u03b1,\u03b1\u2010difluoromethylene amines. The method tolerates a variety of functional groups, supports late\u2010stage functionalization of pharmaceutically relevant scaffolds, and is compatible with downstream cross\u2010coupling reactions, demonstrating the robustness of the reaction protocol. This work provides a versatile platform for the streamlined incorporation of NCF\n                    <jats:sub>2<\/jats:sub>\n                    motifs, expanding the range of synthetic strategies available in medicinal and fluorine chemistry.\n                  <\/jats:p>","DOI":"10.1002\/anie.202517282","type":"journal-article","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T07:13:42Z","timestamp":1761894822000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Flow\u2010Enabled, Modular Access to \u03b1,\u03b1\u2010Difluoromethylene Amines"],"prefix":"10.1002","volume":"64","author":[{"given":"Dmitrii","family":"Nagorn\u00eei","sequence":"first","affiliation":[{"name":"Flow Chemistry Group Van't Hoff Institute for Molecular Sciences (HIMS) University of Amsterdam  Science Park 904 XH Amsterdam 1098 The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Ronco","sequence":"additional","affiliation":[{"name":"Flow Chemistry Group Van't Hoff Institute for Molecular Sciences (HIMS) University of Amsterdam  Science Park 904 XH Amsterdam 1098 The Netherlands"},{"name":"Department of Chemistry University of Pavia  Viale Taramelli Pavia 27100 Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadijah","family":"Anwar","sequence":"additional","affiliation":[{"name":"Flow Chemistry Group Van't Hoff Institute for Molecular Sciences (HIMS) University of Amsterdam  Science Park 904 XH Amsterdam 1098 The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Kaplaneris","sequence":"additional","affiliation":[{"name":"Flow Chemistry Group Van't Hoff Institute for Molecular Sciences (HIMS) University of Amsterdam  Science Park 904 XH Amsterdam 1098 The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James J.","family":"Douglas","sequence":"additional","affiliation":[{"name":"Early Chemical Development Pharmaceutical Sciences R&amp;D  AstraZeneca, Charter Way Macclesfield SK10 2NA UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3107-6927","authenticated-orcid":false,"given":"Timothy","family":"No\u00ebl","sequence":"additional","affiliation":[{"name":"Flow Chemistry Group Van't Hoff Institute for Molecular Sciences (HIMS) University of Amsterdam  Science Park 904 XH Amsterdam 1098 The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10,30]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1039\/B610213C"},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b00258"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr4002879"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/chem.202500662"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.7b01788"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfluchem.2005.02.004"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfluchem.2011.06.011"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022\u20101139(00)81573\u20100"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1246\/bcsj.52.3377"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja2048072"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-1993-22574"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202422899"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1CS00360G"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/op400349g"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0OB02374D"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201206566"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.accounts.8b00079"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c13711"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202506154"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010024\u201001730\u20107"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01457"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41557\u2010025\u201001767\u20102"},{"key":"e_1_2_6_23_1","author":"Zhou F.","journal-title":"Chem. 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