{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:08:06Z","timestamp":1788570486374,"version":"build-2803163510"},"reference-count":80,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T00:00:00Z","timestamp":1768262400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation of Tianchi Innovation Leading Talent Project","award":["51052300410"],"award-info":[{"award-number":["51052300410"]}]},{"name":"Science Foundation for Distinguished Young Scholars of Xinjiang Uygur Autonomous Region","award":["2022D01E34"],"award-info":[{"award-number":["2022D01E34"]}]},{"name":"Program for Tianshan Innovative Research Team of Xinjiang Uygur Autonomous Region","award":["2025D14005"],"award-info":[{"award-number":["2025D14005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The introduction of cyano groups into aza-heterocyclic compounds plays a pivotal role in accessing diverse derivatives that are essential for the development of natural products, pharmaceuticals, and agrochemicals. Herein, we report a unified strategy for the direct ortho-C-H cyanation of a broad range of heterocyclic N-oxides, including pyridine, quinoline, isoquinoline, and pyrimidine derivatives. This transformation proceeds under mild conditions without the need for external activating agents or catalysts, and has been successfully applied to structurally complex, biologically relevant molecules. Compared to existing methodologies, our approach offers several distinct advantages: the use of non-prefunctionalized heteroarene substrates, environmentally benign reaction solvents, operational simplicity, broad substrate scope, and high efficiency in generating diverse ortho-cyanated heterocyclic compounds. Moreover, the method demonstrates considerable potential for scalable synthesis.<\/jats:p>","DOI":"10.3390\/molecules31020276","type":"journal-article","created":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T11:42:58Z","timestamp":1768304578000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Formal Synthesis of Ortho-Cyanated N-Heterocycles via Direct, Metal-Free Cyanation of N-Oxides Under Benign Conditions"],"prefix":"10.3390","volume":"31","author":[{"given":"Hua","family":"Xiao","sequence":"first","affiliation":[{"name":"State Key Laboratory of Chemistry and Utilization of Carbon Based Energy Resources, College of Chemistry, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reziyamu","family":"Wufuer","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences and Institute of Materia Medica, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4855-0576","authenticated-orcid":false,"given":"Dong","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Chemistry and Utilization of Carbon Based Energy Resources, College of Chemistry, Xinjiang University, Urumqi 830017, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5283","DOI":"10.1021\/jo200553g","article-title":"Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin \u03b22","volume":"76","author":"Garner","year":"2011","journal-title":"J. Org. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12933","DOI":"10.1021\/acs.jafc.1c04953","article-title":"Recent Advances in the Pesticide Activities of 2-Cyanoacrylate Derivatives","volume":"69","author":"Liu","year":"2021","journal-title":"J. Agric. Food. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7902","DOI":"10.1021\/jm100762r","article-title":"Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore","volume":"53","author":"Fleming","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1021\/acs.jmedchem.0c01786","article-title":"U.S. FDA Approved Drugs from 2015\u2013June 2020: A Perspective","volume":"64","author":"Bhutani","year":"2021","journal-title":"J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11622","DOI":"10.1021\/acs.jmedchem.4c01122","article-title":"An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013\u20132023)","volume":"67","author":"Marshall","year":"2024","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10257","DOI":"10.1021\/jm501100b","article-title":"Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals","volume":"57","author":"Vitaku","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1080\/00397911.2016.1151051","article-title":"Synthesis of 4-amino-2,6-diaryl-5-cyanopyrimidines as antimicrobial agents","volume":"46","author":"Monteiro","year":"2016","journal-title":"Synth. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1080\/10406638.2021.2019800","article-title":"Synthesis, In Silico Study and Antibacterial Evaluation of New Cyanopyridine Based Scaffold","volume":"43","author":"Ismail","year":"2023","journal-title":"Polycyclic Aromat. Compd."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13985","DOI":"10.1021\/acs.jafc.5c00554","article-title":"Heteroarylcyanovinyl Benzimidazoles as New Antibacterial Skeleton with Large Potential To Combat Bacterial Infections","volume":"73","author":"Li","year":"2025","journal-title":"J. Agric. Food. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bailly, C., and Gao, J.-M. (2020). Erinacine A and related cyathane diterpenoids: Molecular diversity and mechanisms underlying their neuroprotection and anticancer activities. Pharmacol. Res., 159.","DOI":"10.1016\/j.phrs.2020.104953"},{"key":"ref_11","first-page":"138","article-title":"Virtual Combinatorial Library Design, Synthesis and In vitro Anticancer Assessment of -2-Amino-3-Cyanopyridine Derivatives","volume":"21","author":"Sanal","year":"2018","journal-title":"Comb. Chem. High. T. Scr."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Shaldam, M.A., Khalil, A.F., Almahli, H., Jaballah, M.Y., Angeli, A., Khaleel, E.F., Badi, R.M., Elkaeed, E.B., Supuran, C.T., and Eldehna, W.M. (2024). Identification of 3-(5-cyano-6-oxo-pyridin-2-yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity. Arch. Pharm., 357.","DOI":"10.1002\/ardp.202300449"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1016\/j.ejmech.2013.08.032","article-title":"Synthesis, antimicrobial, antioxidant activities of novel 6-aryl-5-cyano thiouracil derivatives","volume":"69","author":"Mohamed","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zebbiche, Z., \u015eekerci, G., Houssem, B., K\u00fc\u00e7\u00fckbay, F., Tekin, S., K\u00fc\u00e7\u00fckbay, H., and Boumoud, B. (2025). Synthesis and Biological Assessment of Cyanopyridine-Based 1,3,4-Oxadiazole Derivatives: Anticancer Potential, Antioxidant Activity, Molecular Docking, and DFT Calculations. J. Biochem. Mol. Toxicol., 39.","DOI":"10.1002\/jbt.70346"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhang, P., Liu, S., Zhao, Z., You, L., Harrison, M.D., and Zhang, Z. (2021). Enzymatic acylation of cyanidin-3-glucoside with fatty acid methyl esters improves stability and antioxidant activity. Food Chem., 343.","DOI":"10.1016\/j.foodchem.2020.128482"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1039\/C5OB02517F","article-title":"Antimalarial activity of novel 4-cyano-3-methylisoquinoline inhibitors against Plasmodium falciparum: Design, synthesis and biological evaluation","volume":"14","author":"Buskes","year":"2016","journal-title":"Org. Biomol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.aihch.2024.04.001","article-title":"Chapter One\u2014Metal free C(sp2)H functionalization of nitrogen heterocycles","volume":"144","author":"Charushin","year":"2024","journal-title":"Adv. Heterocycl. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1002\/cber.18840170219","article-title":"Ueber die Ersetzung der Amidgruppe durch Chlor in den aromatischen Substanzen","volume":"17","author":"Sandmeyer","year":"1884","journal-title":"Ber. Dtsch. Chem. Ges."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1002\/cber.188401702202","article-title":"Ueber die Ersetzung der Amid-gruppe durch Chlor, Brom und Cyan in den aromatischen Substanzen","volume":"17","author":"Sandmeyer","year":"1884","journal-title":"Ber. Dtsch. Chem. Ges."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1002\/cber.19190520840","article-title":"Das am Ringkohlenstoff gebundene Halogen und sein Ersatz durch andere Substituenten. I. Mitteilung: Ersatz des Halogens durch die Carboxylgruppe","volume":"52","author":"Rosenmund","year":"1919","journal-title":"Ber. Dtsch. Chem. Ges."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2859","DOI":"10.3987\/COM-04-10228","article-title":"Palladium(II)-Mediated Nucleophilic Cyanation of 4-Substituted Quinoline 1-Oxide in the Presence of Trimethylsilyl Cyanide and an Oxidant","volume":"63","author":"Tagawa","year":"2004","journal-title":"Heterocycles"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"10139","DOI":"10.1021\/ja5049303","article-title":"Synthesis and Late-Stage Functionalization of Complex Molecules through C\u2013H Fluorination and Nucleophilic Aromatic Substitution","volume":"136","author":"Fier","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1055\/s-2005-861849","article-title":"Preparation of Cyanopyridines by Direct Cyanation","volume":"2005","author":"Katritzky","year":"2005","journal-title":"Synthesis"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14733","DOI":"10.1002\/chem.201703931","article-title":"C\u2212H Cyanation of 6-Ring N-Containing Heteroaromatics","volume":"23","author":"Elbert","year":"2017","journal-title":"Chem. Eur. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9499","DOI":"10.1021\/jacs.7b05414","article-title":"A Bifunctional Reagent Designed for the Mild, Nucleophilic Functionalization of Pyridines","volume":"139","author":"Fier","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/adsc.202000910","article-title":"Recent Advances in the Synthesis of C2-Functionalized Pyridines and Quinolines Using N-Oxide Chemistry","volume":"363","author":"Wang","year":"2021","journal-title":"Adv. Synth. Catal."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3407","DOI":"10.1021\/acs.orglett.9b01141","article-title":"Catalytic Selective Metal-Free Cross-Coupling of Heteroaromatic N-Oxides with Organosilanes","volume":"21","author":"Puthanveedu","year":"2019","journal-title":"Org. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1360\/SSC-2023-0052","article-title":"Recent progress in C2\u2013H functionalization of pyridine and quinoline N-oxides","volume":"53","author":"Kaijuan","year":"2023","journal-title":"Sci. Sin. Chim."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1002\/adsc.202100284","article-title":"Nucleophilic Halogenation of Heterocyclic N-Oxides: Recent Progress and a Practical Guide","volume":"363","author":"Malykhin","year":"2021","journal-title":"Adv. Synth. Catal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1002\/adsc.202200200","article-title":"Visible-Light-Mediated C-2 Functionalization and Deoxygenative Strategies in Heterocyclic N-Oxides","volume":"364","author":"Singh","year":"2022","journal-title":"Adv. Synth. Catal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5886","DOI":"10.1021\/acs.joc.6b00593","article-title":"Metal-Free, Phosphonium Salt-Mediated Sulfoximination of Azine N-Oxides: Approach for the Synthesis of N-Azine Sulfoximines","volume":"81","author":"Aithagani","year":"2016","journal-title":"J. Org. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1021\/cr200251d","article-title":"Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition to N-Activated Pyridines","volume":"112","author":"Bull","year":"2012","journal-title":"Chem. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1021\/ol303218p","article-title":"An Efficient, Regioselective Amination of 3,5-Disubstituted Pyridine N-Oxides Using Saccharin as an Ammonium Surrogate","volume":"15","author":"Farrell","year":"2013","journal-title":"Org. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2890","DOI":"10.1021\/ol301173m","article-title":"A New and Useful Method for the Macrocyclization of Linear Peptides","volume":"14","author":"Londregan","year":"2012","journal-title":"Org. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1021\/ol3034675","article-title":"Regioselective Bromination of Fused Heterocyclic N-Oxides","volume":"15","author":"Wengryniuk","year":"2013","journal-title":"Org. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4289","DOI":"10.1021\/acs.orglett.9b01474","article-title":"2-Position-Selective Trifluoromethylthiolation of Six-Membered Heteroaromatic Compounds","volume":"21","author":"Muta","year":"2019","journal-title":"Org. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5642","DOI":"10.1039\/C7GC02304A","article-title":"A base-free, ultrasound accelerated one-pot synthesis of 2-sulfonylquinolines in water","volume":"19","author":"Xie","year":"2017","journal-title":"Green Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1002\/adsc.201801185","article-title":"Hypervalent Iodine(III)-Mediated Regioselective Cyanation of Quinoline N-Oxides with Trimethylsilyl Cyanide","volume":"361","author":"Xu","year":"2019","journal-title":"Adv. Synth. Catal."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5616","DOI":"10.1002\/adsc.201901103","article-title":"Regioselective Cyanation of Six-Membered N-Heteroaromatic Compounds Under Metal-, Activator-, Base- and Solvent-Free Conditions","volume":"361","author":"Sarmah","year":"2019","journal-title":"Adv. Synth. Catal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9181","DOI":"10.1021\/acs.orglett.3c03742","article-title":"Phosphonium Salt-Promoted C2\u2013H Functionalization of Heterocyclic N-Oxides","volume":"25","author":"Ma","year":"2023","journal-title":"Org. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4659","DOI":"10.1039\/D3GC05178A","article-title":"Green and fast 2-aryloxylation\/amination of quinolines","volume":"26","author":"Bu","year":"2024","journal-title":"Green Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7788","DOI":"10.1039\/D5GC00249D","article-title":"Sustainable synthesis of heteroaryl ethers from azine N-oxides via phosphoramide catalysis","volume":"27","author":"Liu","year":"2025","journal-title":"Green Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5625","DOI":"10.1021\/acs.orglett.5c01350","article-title":"C3\u2013H Trifluoroacetylation of Quinolines and Pyridines: Access to Heteroaryl Ketones, Carboxylic Acids, and Amides","volume":"27","author":"Wang","year":"2025","journal-title":"Org. Lett."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Xu, L., Wang, X., Yang, D., Yang, X., and Wang, D. (2025). Direct C3\u2212H Alkylation and Alkenylation of Quinolines with Enones. Angew. Chem. Int., 64.","DOI":"10.1002\/anie.202580162"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1039\/C5GC01008J","article-title":"CHEM21 selection guide of classical- and less classical-solvents","volume":"18","author":"Prat","year":"2016","journal-title":"Green Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3134","DOI":"10.1021\/acs.orglett.5b01456","article-title":"Regioselective Metal-Free Cross-Coupling of Quinoline N-Oxides with Boronic Acids","volume":"17","author":"Bering","year":"2015","journal-title":"Org. Lett."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1016\/j.tetlet.2019.06.066","article-title":"A concise synthesis of 3-substituted-7-amino-6-carboxyl-8-azachromones","volume":"60","author":"Gan","year":"2019","journal-title":"Tetrahedron Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1007\/s10593-023-03221-y","article-title":"Parent 5(7)-azachromones and their partially hydrogenated derivatives: Synthesis and physicochemical properties","volume":"59","author":"Malets","year":"2023","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"11275","DOI":"10.1021\/acs.joc.7b02063","article-title":"Access to 8-Azachromones via Activation of C\u2013H in N-Oxides","volume":"82","author":"Wang","year":"2017","journal-title":"J. Org. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Van Aken, K., Strekowski, L., and Patiny, L. (2006). EcoScale, a semi-quantitative tool to select an organic preparation based on economical and ecological parameters. Beilstein J. Org. Chem., 2.","DOI":"10.1186\/1860-5397-2-3"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1039\/C4GC01563K","article-title":"Overcoming barriers to green chemistry in the pharmaceutical industry\u2014The Green Aspiration Level concept","volume":"17","author":"Roschangar","year":"2015","journal-title":"Green Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1016\/j.cclet.2021.02.057","article-title":"The application of clean production in organic synthesis","volume":"32","author":"Jiang","year":"2021","journal-title":"Chin. Chem. Lett."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7916","DOI":"10.1039\/D3GC02516K","article-title":"Classic vs. C\u2013H functionalization strategies in the synthesis of APIs: A sustainability comparison","volume":"25","author":"Ferlin","year":"2023","journal-title":"Green Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7512","DOI":"10.1021\/acs.jmedchem.5b01066","article-title":"Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1-Benzyl-2-acylaminomethyl-tetrahydroquinolines","volume":"58","author":"Spadoni","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6341","DOI":"10.1021\/acs.orglett.2c02596","article-title":"Direct Transformation of Nitrogen-Containing Methylheteroarenes to Heteroaryl Nitrile by Sodium Nitrite","volume":"24","author":"Jiang","year":"2022","journal-title":"Org. Lett."},{"key":"ref_56","first-page":"333","article-title":"Synthesis of Nitrile-Functionalized Polydentate N-Heterocycles as Building Blocks for Covalent Triazine Frameworks","volume":"55","author":"Everaert","year":"2021","journal-title":"Synthesis"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1937","DOI":"10.1021\/acschemneuro.7b00098","article-title":"Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2","volume":"8","author":"Zhang","year":"2017","journal-title":"ACS Chem. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Pradhan, S., Maiti, S., Dutta, S., Adam Russell, C., Tyagi, S., and Maiti, D. (2025). A Modular Approach for Accessing 3D Heterocycles via 1,2-Dicyanation of Planar N-Heteroarenes. Angew. Chem. Int. Ed., 64.","DOI":"10.1002\/anie.202412979"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1021\/jm4016203","article-title":"HCV NS5A Replication Complex Inhibitors. Part 4.1 Optimization for Genotype 1a Replicon Inhibitory Activity","volume":"57","author":"Belema","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1248\/cpb.36.930","article-title":"Reactions of 3-Benzoyl-3, 4-dihydro-2-methyl-4-quinazolinecarbonitrile (2-Methylquinazoline Reissert Compound) with Acid, Base, Sodium Hydride, and Electrophiles","volume":"36","author":"Higashino","year":"1988","journal-title":"Chem. Pharm. Bull."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Pochobradsk\u00fd, J., Bart\u00e1\u010dek, J., V\u00e1\u0148a, J., Svoboda, J., Svobodov\u00e1, M., Drabina, P., Pato\u010dka, J., and Sedl\u00e1k, M. (2023). Addressing polar solvent challenges in the heterogenization of palladium catalysed Hayashi-Miyaura reaction on polymer support. React. Funct. Polym., 193.","DOI":"10.1016\/j.reactfunctpolym.2023.105747"},{"key":"ref_62","unstructured":"Chekler, E.L.P., Gilbert, A.M., Unwalla, R.J., Verhoest, P.R., and Anderson, J.T. (2015). Carbonitrile Derivatives as Selective Androgen Receptor Modulators. (WO2015181676)."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8203","DOI":"10.1021\/acs.joc.3c00202","article-title":"Ni-Catalyzed Enantioselective Intramolecular Mizoroki\u2013Heck Reaction for the Synthesis of Phenanthridinone Derivatives","volume":"88","author":"Rachii","year":"2023","journal-title":"J. Org. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1021\/ol070372d","article-title":"Mild and General Methods for the Palladium-Catalyzed Cyanation of Aryl and Heteroaryl Chlorides","volume":"9","author":"Littke","year":"2007","journal-title":"Org. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3735","DOI":"10.1039\/D1OB00260K","article-title":"Highly chemoselective deoxygenation of N-heterocyclic N-oxides under transition metal-free conditions","volume":"19","author":"Kim","year":"2021","journal-title":"Org. Biomol. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1002\/jhet.5570310506","article-title":"3-Amino-2-quinoxalinecarbonitrile. New fused quinoxalines with potential cytotoxic activity","volume":"31","author":"Monge","year":"1994","journal-title":"J. Heterocycl. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"15576","DOI":"10.1021\/jacs.7b08383","article-title":"Tridentate Directing Groups Stabilize 6-Membered Palladacycles in Catalytic Alkene Hydrofunctionalization","volume":"139","author":"Matsuura","year":"2017","journal-title":"J. Am. Chem. Soc."},{"key":"ref_68","unstructured":"Yu, G., Gao, D., Chen, Z., and Zhang, W. (2017). Preparation and Characterization of Pyridinothiene Containing Polymer Compounds as Semiconductor Materials. (CN106632410)."},{"key":"ref_69","unstructured":"Payne, A., Castro Pineiro, J.L., Birch, L.M., Khan, A., Braunton, A.J., Kitulagoda, J.E., and Soejima, M. (2015). Preparation of 4-Azaindole Derivatives as Muscarinic M1 Receptor Modulators for Treatment of Cognitive Deficits. (US20150094328)."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1039\/C8QO00322J","article-title":"Copper-catalyzed cyanation of heterocycle C\u2013H bonds with ethyl(ethoxymethylene)cyanoacetate as a cyanating agent and its mechanism","volume":"5","author":"Li","year":"2018","journal-title":"Org. Chem. Front."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4161","DOI":"10.1039\/D0GC00757A","article-title":"HCl\u00b7DMPU-assisted one-pot and metal-free conversion of aldehydes to nitriles","volume":"22","author":"Mudshinge","year":"2020","journal-title":"Green Chem."},{"key":"ref_72","unstructured":"Brown, R.E., Burkamp, F., Doughty, V.A., Fletcher, S.R., Hollingworth, G.J., Jones, B.A., and Sparey, T.J. (2004). Preparation of Amino Heterocycles as Vanilloid Receptor (VR1) Modulators, in Particular Antagonists, for Treating Pain and\/or Inflammation. (WO2004074290)."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"15178","DOI":"10.1021\/acscatal.0c04725","article-title":"Nickel-Coordinated Carbon Nitride as a Metallaphotoredox Platform for the Cross-Coupling of Aryl Halides with Alcohols","volume":"10","author":"Zhao","year":"2020","journal-title":"ACS Catal."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3130","DOI":"10.1016\/j.bmc.2009.03.001","article-title":"Synthesis and structure\u2013activity relationships of amide derivatives of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene) acetic acid as selective arginine vasopressin V2 receptor agonists","volume":"17","author":"Tsukamoto","year":"2009","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_75","unstructured":"Cushman, M.S., Kiselev, E.A., and Morrell, A.E. (2014). Azaindenoisoquinoline Topoisomerase I Inhibitors Useful in the Treatment of Cancer and Preparation Thereof. (US20140187547)."},{"key":"ref_76","unstructured":"Shin, S., Byeon, S., and Kim, H. (2016). Preparation of Pyridine N-Oxide Compounds as Enhancer of Zeste Homolog 2 Inhibitors. (WO2016140501)."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"6106","DOI":"10.1016\/j.bmc.2009.05.069","article-title":"Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor","volume":"17","author":"Ando","year":"2009","journal-title":"Bioorgan. Med. Chem."},{"key":"ref_78","unstructured":"Johns, B.A., and Spaltenstein, A. (2007). 2-oxonaphthyridine-3-carboxamides as HIV Integrase Inhibitors and Their Preparation and Use in the Prevention and Treatment of HIV Infection, AIDS and ARC. (WO2007019101)."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1248\/cpb.33.565","article-title":"Site-Selectivity in the Cyanation of 3-Substituted Pyridine 1-Oxides with Trimethylsilanecarbonitrile","volume":"33","author":"Sakamoto","year":"1985","journal-title":"Chem. Pharm. Bull."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"200","DOI":"10.3998\/ark.5550190.0006.920","article-title":"Synthesis of 2- and 4-hydroxymethyl Loratadine, usual impurities in Loratadine syrup formulations","volume":"2005","author":"Cerrada","year":"2005","journal-title":"Arkivoc"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/2\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T11:43:26Z","timestamp":1768304606000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/2\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,13]]},"references-count":80,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["molecules31020276"],"URL":"https:\/\/doi.org\/10.3390\/molecules31020276","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,13]]}}}