{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T22:40:41Z","timestamp":1792536041216,"version":"4.5.0"},"reference-count":48,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T00:00:00Z","timestamp":1792540800000},"content-version":"vor","delay-in-days":114,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Chem"],"DOI":"10.1038\/s42004-026-02096-2","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T17:07:21Z","timestamp":1782752841000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Machine-learning-assisted continuous flow synthesis of clonidine"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6485-3606","authenticated-orcid":false,"given":"Cloudius R.","family":"Sagandira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2263-5248","authenticated-orcid":false,"given":"Sinazo","family":"Nqeketo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Pomberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0494-643X","authenticated-orcid":false,"given":"Daniel","family":"Wigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Len","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"2096_CR1","unstructured":"National Academies of Sciences, Engineering, and Medicine. Building Resilience into the Nation\u2019s Medical Product Supply Chains. (eds Shore, C., Brown, L. & Hopp, W. J.), (National Academies Press, 2022)."},{"key":"2096_CR2","unstructured":"International Federation of Pharmaceutical Manufacturers & Associations (IFPMA). The Pharmaceutical Industry and Global Health: IFPMA Facts and Figures 2022, accessed 16 April 2026, https:\/\/www.ifpma.org\/wp-content\/uploads\/2023\/01\/i2023_IFPMA-Facts-And-Figures-2022.pdf (IFPMA, 2022)."},{"key":"2096_CR3","unstructured":"Accelerating Global Health: Pathways to Health Equity for the G20. (eds Khemka, N. M. & Reddy, S.), accessed 16 April 2026, https:\/\/www.undp.org\/india\/publications\/accelerating-global-health-pathways-health-equity-g20 (Observer Research Foundation, 2023)."},{"key":"2096_CR4","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/s41514-024-00148-2","volume":"10","author":"CH Jones","year":"2024","unstructured":"Jones, C. H. & Dolsten, M. Healthcare on the brink: navigating the challenges of an aging society in the United States. NPJ Aging 10, 22 (2024).","journal-title":"NPJ Aging"},{"key":"2096_CR5","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.3390\/jpm12081295","volume":"12","author":"R Filip","year":"2022","unstructured":"Filip, R., Gheorghita Puscaselu, R., Anchidin-Norocel, L., Dimian, M. & Savage, W. K. Global challenges to public health care systems during the COVID-19 pandemic: a review of pandemic measures and problems. J. Pers. Med. 12, 1295 (2022).","journal-title":"J. Pers. Med."},{"key":"2096_CR6","unstructured":"Aon. 2025 Life Sciences Outlook: Building Preparedness to Mitigate Risks and Capture Human Capital Opportunities,accessed 16 April 2026, https:\/\/www.aon.com\/en\/insights\/articles\/2025-life-sciences-outlook (Aon plc, 2025)."},{"key":"2096_CR7","doi-asserted-by":"publisher","first-page":"2532","DOI":"10.1039\/D4RE00299G","volume":"9","author":"S Nqeketo","year":"2024","unstructured":"Nqeketo, S. & Sagandira, C. R. Towards continuous flow manufacturing of active pharmaceutical ingredients in Africa: a perspective. React. Chem. Eng. 9, 2532\u20132551 (2024).","journal-title":"React. Chem. Eng."},{"key":"2096_CR8","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1039\/D1RE00483B","volume":"7","author":"CR Sagandira","year":"2022","unstructured":"Sagandira, C. R. et al. Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients. React. Chem. Eng. 7, 214\u2013244 (2022).","journal-title":"React. Chem. Eng."},{"key":"2096_CR9","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1126\/science.aaf1337","volume":"352","author":"A Adamo","year":"2016","unstructured":"Adamo, A. et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352, 61\u201367 (2016).","journal-title":"Science"},{"key":"2096_CR10","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1039\/D0RE00273A","volume":"5","author":"Z F\u00fcl\u00f6p","year":"2020","unstructured":"F\u00fcl\u00f6p, Z., Szemesi, P., Bana, P., \u00c9les, J. & Greiner, I. Evolution of flow-oriented design strategies in the continuous preparation of pharmaceuticals. React. Chem. Eng. 5, 1527\u20131555 (2020).","journal-title":"React. Chem. Eng."},{"key":"2096_CR11","doi-asserted-by":"publisher","first-page":"3199","DOI":"10.1016\/j.xphs.2017.06.015","volume":"106","author":"MM Nasr","year":"2017","unstructured":"Nasr, M. M. et al. Regulatory perspectives on continuous pharmaceutical manufacturing: moving from theory to practice: September 26-27, 2016, International Symposium on the Continuous Manufacturing of Pharmaceuticals. J. Pharm. Sci. 106, 3199\u20133206 (2017).","journal-title":"J. Pharm. Sci."},{"key":"2096_CR12","unstructured":"Almaya, A. & Bou\u00e9, K. Regulatory Aspects and Global Acceptance of Continuous Manufacturing. Pharm. Eng. Vol. 41, accessed 16 April 2026, https:\/\/ispe.org\/pharmaceutical-engineering\/july-august-2021\/regulatory-aspects-global-acceptance-continuous (International Society for Pharmaceutical Engineering, 2021)."},{"key":"2096_CR13","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1021\/acs.oprd.5b00325","volume":"20","author":"R Porta","year":"2016","unstructured":"Porta, R., Benaglia, M. & Puglisi, A. Flow chemistry: recent developments in the synthesis of pharmaceutical products. Org. Process Res. Dev. 20, 2\u201325 (2016).","journal-title":"Org. Process Res. Dev."},{"key":"2096_CR14","doi-asserted-by":"crossref","unstructured":"Pe\u00f1a, L. F. et al. Continuous flow chemistry: a novel technology for the synthesis of marine drugs. Mar. Drugs 21, 402 (2023).","DOI":"10.3390\/md21070402"},{"key":"2096_CR15","doi-asserted-by":"publisher","first-page":"6992","DOI":"10.3390\/molecules26226992","volume":"26","author":"BJ Reizman","year":"2021","unstructured":"Reizman, B. J. et al. Continuous flow synthesis of anticancer drugs. Molecules 26, 6992 (2021).","journal-title":"Molecules"},{"key":"2096_CR16","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s41981-020-00134-1","volume":"11","author":"MB Sagandira","year":"2021","unstructured":"Sagandira, M. B., Sagandira, C. R. & Watts, P. Continuous flow synthesis of xylidines via biphasic nitration of xylenes and nitro-reduction. J. Flow Chem. 11, 193\u2013208 (2021).","journal-title":"J. Flow Chem."},{"key":"2096_CR17","unstructured":"U.S. Food and Drug Administration. Q13 Continuous Manufacturing of Drug Substances and Drug Products, accessed 16 April 2026, https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/q13-continuous-manufacturing-drug-substances-and-drug-products (FDA, 2023)."},{"key":"2096_CR18","unstructured":"Keenan, J. EMA Gives Nod to Janssen for Continuous Manufacturing of HIV Drug, accessed 16 April 2026, https:\/\/www.fiercepharma.com\/manufacturing\/ema-gives-nod-to-janssen-for-continuous-manufacturing-hiv-drug (FiercePharma, 2017)."},{"key":"2096_CR19","doi-asserted-by":"crossref","unstructured":"Kondo, M. et al. Bayesian optimization-driven parallel-screening of multiple parameters for the flow synthesis of biaryl compounds. Commun. Chem. 5, 148 (2022).","DOI":"10.1038\/s42004-022-00764-7"},{"key":"2096_CR20","doi-asserted-by":"publisher","first-page":"3790","DOI":"10.1021\/acs.jcim.4c00292","volume":"64","author":"DS Wigh","year":"2024","unstructured":"Wigh, D. S., Arrowsmith, J., Pomberger, A., Felton, K. C. & Lapkin, A. A. ORDerly: data sets and benchmarks for chemical reaction data. J. Chem. Inf. Model. 64, 3790\u20133798 (2024).","journal-title":"J. Chem. Inf. Model."},{"key":"2096_CR21","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1021\/acs.oprd.4c00533","volume":"29","author":"P Jorayev","year":"2025","unstructured":"Jorayev, P. et al. Machine learning-driven optimization of continuous-flow photoredox amine synthesis. Org. Process Res. Dev. 29, 1411\u20131422 (2025).","journal-title":"Org. Process Res. Dev."},{"key":"2096_CR22","doi-asserted-by":"publisher","first-page":"957","DOI":"10.1021\/acscentsci.3c00050","volume":"9","author":"CJ Taylor","year":"2023","unstructured":"Taylor, C. J. et al. Accelerated chemical reaction optimization using multi-task learning. ACS Cent. Sci. 9, 957\u2013968 (2023).","journal-title":"ACS Cent. Sci."},{"key":"2096_CR23","doi-asserted-by":"publisher","first-page":"110376","DOI":"10.1016\/j.cep.2025.110376","volume":"215","author":"J Guo","year":"2025","unstructured":"Guo, J., Chai, K., Luo, G., Su, W. & Su, A. Prior knowledge-based multi-round multi-objective Bayesian optimization: continuous flow synthesis and scale-up of O-methylisourea. Chem. Eng. Process. Process Intensif. 215, 110376 (2025).","journal-title":"Chem. Eng. Process. Process Intensif."},{"key":"2096_CR24","doi-asserted-by":"publisher","first-page":"1958","DOI":"10.1039\/D4DD00223G","volume":"3","author":"R Liu","year":"2024","unstructured":"Liu, R., Wang, Z., Yang, W., Cao, J. & Tao, S. Self-optimizing Bayesian for continuous flow synthesis process. Digit. Discov. 3, 1958\u20131966 (2024).","journal-title":"Digit. Discov."},{"key":"2096_CR25","doi-asserted-by":"publisher","first-page":"3089","DOI":"10.1021\/acs.chemrev.2c00798","volume":"123","author":"CJ Taylor","year":"2023","unstructured":"Taylor, C. J. et al. A brief introduction to chemical reaction optimization. Chem. Rev. 123, 3089\u20133126 (2023).","journal-title":"Chem. Rev."},{"key":"2096_CR26","doi-asserted-by":"publisher","unstructured":"Khodadadi, A. N. et al. Accelerating rational organoborazine discovery: predicted by machine learning, synthesized under continuous flow. Green Synth. Catal. https:\/\/doi.org\/10.1016\/j.gresc.2025.04.007 (2025).","DOI":"10.1016\/j.gresc.2025.04.007"},{"key":"2096_CR27","doi-asserted-by":"publisher","first-page":"68181","DOI":"10.1021\/acsami.4c14279","volume":"16","author":"JH Dunlap","year":"2024","unstructured":"Dunlap, J. H. et al. Continuous flow chemistry and Bayesian optimization for polymer-functionalized carbon nanotube-based chemiresistive methane sensors. ACS Appl. Mater. Interfaces 16, 68181\u201368196 (2024).","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"2096_CR28","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1053\/bean.2000.0079","volume":"14","author":"H St\u00e4hle","year":"2000","unstructured":"St\u00e4hle, H. A historical perspective: development of clonidine. Best Pract. Res. Clin. Anaesthesiol. 14, 237\u2013246 (2000).","journal-title":"Best Pract. Res. Clin. Anaesthesiol."},{"key":"2096_CR29","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1055\/s-1987-27847","volume":"1987","author":"NR Ayyangar","year":"1987","unstructured":"Ayyangar, N. R., Brahme, K. C. & Srinivasan, K. V. A novel synthesis of clonidine, an antihypertensive drug from o chloronitrobenzene. Synthesis 1987, 64\u201365 (1987).","journal-title":"Synthesis"},{"key":"2096_CR30","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1089\/cap.2006.0098","volume":"17","author":"AF Arnsten","year":"2007","unstructured":"Arnsten, A. F., Scahill, L. & Findling, R. L. Alpha-2 adrenergic receptor agonists for the treatment of attention-deficit\/hyperactivity disorder: emerging concepts from new data. J. Child Adolesc. Psychopharmacol. 17, 393\u2013406 (2007).","journal-title":"J. Child Adolesc. Psychopharmacol."},{"key":"2096_CR31","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3810\/pgm.2010.09.2204","volume":"122","author":"FR Sallee","year":"2010","unstructured":"Sallee, F. R. The role of alpha-2-adrenergic agonists in attention-deficit\/hyperactivity disorder. Postgrad. Med. 122, 78\u201387 (2010).","journal-title":"Postgrad. Med."},{"key":"2096_CR32","first-page":"105","volume":"2","author":"X Ming","year":"2011","unstructured":"Ming, X., Mulvey, M., Mohanty, S. & Patel, V. Safety and efficacy of clonidine and clonidine extended-release in the treatment of children and adolescents with attention deficit and hyperactivity disorders. Adolesc. Health Med. Ther. 2, 105 (2011).","journal-title":"Adolesc. Health Med. Ther."},{"key":"2096_CR33","first-page":"e27639","volume":"14","author":"J Gripshover","year":"2022","unstructured":"Gripshover, J. & Kosten, T. Managing opioid withdrawal in an outpatient setting with lofexidine or clonidine. Cureus 14, e27639 (2022).","journal-title":"Cureus"},{"key":"2096_CR34","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/j.1875-9114.1981.tb03561.x","volume":"1","author":"AM Washton","year":"1981","unstructured":"Washton, A. M. & Resnick, R. B. Clonidine in opiate withdrawal: review and appraisal of clinical findings. Pharmacotherapy 1, 140\u2013146 (1981).","journal-title":"Pharmacotherapy"},{"key":"2096_CR35","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.japh.2019.10.004","volume":"60","author":"AK Kuszmaul","year":"2020","unstructured":"Kuszmaul, A. K., Palmer, E. C. & Frederick, E. K. Lofexidine versus clonidine for mitigation of opioid withdrawal symptoms: a systematic review. J. Am. Pharm. Assoc. 60, 145\u2013152 (2020).","journal-title":"J. Am. Pharm. Assoc."},{"key":"2096_CR36","unstructured":"Neumann, P. Certain 4 substituted amino 2,1,3 benzothiadiazoles. U.S. Patent 3,843,668 (1974)."},{"key":"2096_CR37","unstructured":"Zeile, K., Haaptmann, K.-H. & Stahle, H. Process for the preparation of 3-aryl-amino-1,3-diazacycloalkenes. U.S. Patent 3,262,660 (1965)."},{"key":"2096_CR38","doi-asserted-by":"publisher","first-page":"9883","DOI":"10.1016\/j.tet.2004.08.031","volume":"60","author":"U Heinelt","year":"2004","unstructured":"Heinelt, U. et al. A convenient method for the synthesis of 2-amino substituted aza-heterocycles from N,N\u2032-disubstituted thioureas using TsCl\/NaOH. Tetrahedron 60, 9883\u20139888 (2004).","journal-title":"Tetrahedron"},{"key":"2096_CR39","doi-asserted-by":"publisher","first-page":"1882","DOI":"10.1021\/jo00360a040","volume":"51","author":"CA Maryanoff","year":"1986","unstructured":"Maryanoff, C. A., Stanzione, R. C., Plampin, J. N. & Mills, J. E. A convenient synthesis of guanidines from thioureas. J. Org. Chem. 51, 1882\u20131884 (1986).","journal-title":"J. Org. Chem."},{"key":"2096_CR40","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1021\/jm00390a021","volume":"30","author":"M Dort","year":"1987","unstructured":"Dort, M., Van, Neubig, R. & Counsell, R. E. Radioiodinated p-iodoclonidine: a high-affinity probe for the \u03b1-2-adrenergic receptor. J. Med. Chem. 30, 1241\u20131244 (1987).","journal-title":"J. Med. Chem."},{"key":"2096_CR41","unstructured":"Gluchowski, C. Method for producing amino 2 imidazoline derivatives. U.S. Patent 5,130,441 (1992)."},{"key":"2096_CR42","unstructured":"Bandgar, B. P., Sawant, S. S. & Mukarram, S. M. A process for preparing clonidine or salt thereof. India Patent Application 3307 MUM (2011)."},{"key":"2096_CR43","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.molstruc.2017.05.126","volume":"1146","author":"BH Gayathri","year":"2017","unstructured":"Gayathri, B. H., Dasappa, J. P., Bhavya, N. R., Chandra & Mahendra, M. Synthesis, single crystal X-ray, Hirshfeld surface analysis and characterization of novel 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine. J. Mol. Struct. 1146, 490\u2013498 (2017).","journal-title":"J. Mol. Struct."},{"key":"2096_CR44","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s41981-018-0010-9","volume":"8","author":"CR Sagandira","year":"2018","unstructured":"Sagandira, C. R. & Watts, P. A study on the scale-up of acyl azide synthesis in various continuous flow reactors in homogeneous and biphasic systems. J. Flow Chem. 8, 69\u201379 (2018).","journal-title":"J. Flow Chem."},{"key":"2096_CR45","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1007\/s41981-019-00037-w","volume":"9","author":"CR Sagandira","year":"2019","unstructured":"Sagandira, C. R. & Watts, P. Efficient continuous flow synthesis of ethyl shikimate: the first step in the synthesis of Tamiflu. J. Flow Chem. 9, 79\u201387 (2019).","journal-title":"J. Flow Chem."},{"key":"2096_CR46","doi-asserted-by":"publisher","unstructured":"Dong, B. et al. Accelerated flow synthesis of aripiprazole and brexpiprazole in environmentally benign solvents. Green Synth. Catal. https:\/\/doi.org\/10.1016\/j.gresc.2025.02.001 (2025).","DOI":"10.1016\/j.gresc.2025.02.001"},{"key":"2096_CR47","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1021\/acs.oprd.3c00407","volume":"28","author":"HLD Hayes","year":"2024","unstructured":"Hayes, H. L. D. & Mallia, C. J. Continuous flow chemistry with solids: a review. Org. Process Res. Dev. 28, 1327\u20131354 (2024).","journal-title":"Org. Process Res. Dev."},{"key":"2096_CR48","doi-asserted-by":"crossref","unstructured":"Johnston, Z. et al. Advances in solid handling for continuous flow synthesis of specialty chemicals and pharmaceuticals. Commun. Chem. 9, 101 (2026).","DOI":"10.1038\/s42004-026-01954-3"}],"container-title":["Communications Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42004-026-02096-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42004-026-02096-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42004-026-02096-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T22:28:56Z","timestamp":1792535336000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42004-026-02096-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":48,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2096"],"URL":"https:\/\/doi.org\/10.1038\/s42004-026-02096-2","relation":{},"ISSN":["2399-3669"],"issn-type":[{"value":"2399-3669","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"assertion":[{"value":"12 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"331"}}