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Here, we report a nickel\u2010catalyzed three\u2010component reductive difluoroalkylation\u2010amination strategy of enamides for the direct access to the \u03b1\u2010amidyl\u2010\u03b2\u2010difluoroalkyl amines. This strategy utilizes carboamination of alkene with nitrogen electrophiles and fluoroalkyl chlorides to simultaneously forge C\u2500C and C(sp\n                    <jats:sup>3<\/jats:sup>\n                    )\u2010N bond, being compatible with various chlorodifluoroacetamides and nitrogen electrophiles, including amino acid\u2010derived or drug\u2010derived substrates. The synthetic method features with broad substrate scope, mild conditions, high functional group tolerance, and easy handling. Control experiments and DFT calculations are performed to elucidate the mechanism of the reaction, and an S\n                    <jats:sub>H<\/jats:sub>\n                    2 pathway regarding C\u2500N bond\u2010forming step is proposed. More remarkably, the products \u03b1\u2010amidyl\u2010\u03b2\u2010difluoroalkyl amines exhibit prominent anti\u2010inflammatory activity both in vitro and in vivo, indicating promising applications of this strategy in medicinal chemistry and drug development.\n                  <\/jats:p>","DOI":"10.1002\/advs.76993","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T11:26:01Z","timestamp":1785756361000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nickel\u2010Catalyzed Three\u2010Component Difluoroalkylation\u2010Amination for the Direct Access to Anti\u2010Inflammatory \u03b2\u2010Difluoroalkyl Amines"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2942-6094","authenticated-orcid":false,"given":"Chang","family":"Xu","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural 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