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1-(Ethoxycarbonyl)ethyl Cinnoline-4-carboxylate (32) A solution of 0.75 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 20 ml of benzene was added to a stirred suspension of 0.87 g of 1 in 30 ml of benzene at room temperature. After one hour of stirring, 1.36 g of ethyl 2-bromopropionate was added and the mixture was heated at reflux for 6 hours. The mixture was cooled, diluted with 25 ml of benzene, washed with water, 1 N aqueous sodium bicarbonate, and brine. It then was dried (MgSO4), the solvent was evaporated and the residue was chromatographed on silica gel, using a 1:1 v:v mixture of cyclohexane and ethyl acetate as eluent, to give 32, as a yellow oil.

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Reference:
Patent; E. I. Du Pont de Nemours and Company; US4699651; (1987); A;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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(0509) Compound 110 (292 mg, 2.00 mmol) was refluxed in POCl3 overnight. It was cooled to room temperature and poured into ice water, neutralized with Na2C03. The precipitation was filtered out and washed with water, dried by pulling air through. Product was obtained as light yellow solid. (0510) (243mg, 74%). 1H NMR (400 MHz, chloroform-i/) delta 9.35 (s, 1H), 8.57 (ddd, J= 8.5, 1.4, 0.7 Hz, 1H), 8.20 (ddd, J= 8.2, 1.6, 0.7 Hz, 1H), 7.97 – 7.83 (m, 2H).

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Reference:
Patent; THE REGENTS OF THE UNIVERSITY OF COLORADO, A BODY CORPORATE; YIN, Hang Hubert; ZHANG, Shuting; HU, Zhenyi; (114 pag.)WO2019/89648; (2019); A1;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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10764] To a stirred solution of N1-cyclopropyl-5-fluo- robenzene-1,2-diamine mt-i (500 mg, 3.01 mmol) in DMF (5 mE) under an inert atmosphere was added cinnoline-4- carboxylic acid (524 mg, 3.01 mmol), HATU (1.71 g, 4.51 mmol) and diisopropylethylamine (1 mE, 6.02 mmol) at 00 C. The reaction mixture was stirred at room temperature for 16 h. Afier consumption of starting material (by TEC), the reaction mixture was diluted with water (20 mE) and extracted with EtOAc (2×20 mE). The combined organic extracts were washed with water (20 mE), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain N-(2-(cyclopropylamino)-4-fluorophenyl) cinnoline4-carboxamide (500 mg, crude) as brown solid used in the next step without further purification.10765] EC-MS: m/z 322.9 [M+H] at 2.71 RT (38.30% purity).

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Reference:
Patent; Viamet Pharmaceuticals (NC), Inc.; Sparks, Steven; Yates, Christopher M.; Shaver, Sammy R.; Hoekstra, William J.; (156 pag.)US2018/185362; (2018); A1;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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A solution of cinnoline-4-carboxylic acid (183 mg, 1.02 mmol) in methylene chloride (20 ml) was reacted with EDCI (195 mg, 1.02 mmol) and HOBt (138 mg, 1.02 mmol) for 20 min and then stirred, together with 4b-amino-9b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]-inden-10-one (250 mg, 0.85 mmol), overnight at room temperature. After extraction with methylene chloride and water, the organic layer was dried over MgSO4 and concentrated in a vacuum. Purification by column chromatography (ethylacetate:n-hexane=1:1) afforded the title compound as a white solid (290 mg, 63%). [0846] 1H-NMR (300 MHz, CD3OD) delta 1.15 (d, J=6.8 Hz, 6H, CH3), 2.82 (sep, J=6.8 Hz, 1H, CH), 6.69 (s, 1H, ArH), 6.89 (d, J=7.8 Hz, 1H, ArH), 7.45 (d, J=7.9 Hz, 1H, ArH), 7.65 (m, 1H, ArH), 7.858.03 (m, 5H, ArH) 8.42 (d, J=8.0 Hz, 1H, ArH), 8.51 (d, J=8.4 Hz, 1H, ArH), 9.45 (s, 1H, ArH).

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Reference:
Patent; KATHOLIEKE UNIVERSITEIT LEUVEN K.U. LEUVEN R & D; KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY; Jung, Young Sik; Lee, Chong Kgo; Kim, Hae Soo; Jeong, Hee Chun; Kim, Pil Ho; Han, Soo Bong; Shin, Jin Soo; Neyts, Johan; Thibaut, Hendrik Jan; US2014/114068; (2014); A1;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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(0509) Compound 110 (292 mg, 2.00 mmol) was refluxed in POCl3 overnight. It was cooled to room temperature and poured into ice water, neutralized with Na2C03. The precipitation was filtered out and washed with water, dried by pulling air through. Product was obtained as light yellow solid. (0510) (243mg, 74%). 1H NMR (400 MHz, chloroform-i/) delta 9.35 (s, 1H), 8.57 (ddd, J= 8.5, 1.4, 0.7 Hz, 1H), 8.20 (ddd, J= 8.2, 1.6, 0.7 Hz, 1H), 7.97 – 7.83 (m, 2H).

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Reference:
Patent; THE REGENTS OF THE UNIVERSITY OF COLORADO, A BODY CORPORATE; YIN, Hang Hubert; ZHANG, Shuting; HU, Zhenyi; (114 pag.)WO2019/89648; (2019); A1;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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a. [4-CHLOROCINNOLINE] (9b). A mixture of 4-hydroxycinnoline (2.0 g, 13.7 mmol), phosphorus oxychloride (1.94 mL, 20.5 mmol), and pyridine (0.33 mL, 4.1 mmol) in [CHLOROBENZENE] (50 mL) was refluxed for 1 hour. Then the mixture was cooled and the solvent evaporated under vacuum, water was added, and the mixture was neutralized with solid sodium bicarbonate and extracted with chloroform (3 x 100 mL), washed with water (3 x 100 mL), dried [(MGS04)] and evaporated under vacuum, giving 1.84 g, in 82 % yield; [MP] [76-77 C] (lit mp 78 [C)] [; IH] NMR [(CDC13)] [8] 7.91 (m, 2H), 8.20 (dd, 1H, [J=6.] 2, [J=2.] 1), 8.57 (dd, 1H, J=6. 6, J=1. 8), 9.34 (s, [1H)] ; [13C NMR (CDCL3) No. ] 123.0, 124.9, 130.2, 131.6, 132.3, 133.8, 134.9, 144.4.

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Reference:
Patent; RUTGERS, THE STATE UNIVERSITY; LAVOIE, Edmond, J.; RUCHELMAN, Alexander, L.; LIU, Leroy, F.; WO2004/14906; (2004); A2;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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To a solution OF 4- [ (Z)- (4-BROMOPHENYL) (ethoxyimino) methyl]-1- (4-methyl-4- piperidinyl) piperidine (50 mg, 0.12 MMOL), cinnoline-4-carboxylic acid (25mg, 0.14 mmol), Et3N (0.06 mL, 0.43 MMOL) in DMF (3 mL, anhydrous) was added HATU (60mg, 0. 16MMOL) at room temperature. After 16 h the reaction mixture was poured into ice water, and the solid was collected by filtration. The solid was dissolved in CH2CI2, and dried over NA2SO4. Concentration in vacuo, and purification by preparative TLC (CH2CI2-MEOH, 9: 1) afforded the title compound as a light yellow powder. MS: 564 (M+).

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Reference:
Patent; SCHERING AKTIENGESELLSCHAFT; WO2004/113323; (2004); A1;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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A solution of cinnoline-4-carboxylic acid (183 mg, 1.02 mmol) in methylene chloride (20 ml) was reacted with EDCI (195 mg, 1.02 mmol) and HOBt (138 mg, 1.02 mmol) for 20 min and then stirred, together with 4b-amino-9b-hydroxy-7-isopropyl-4b,9b-dihydro-5-oxa-indeno[2,1-a]-inden-10-one (250 mg, 0.85 mmol), overnight at room temperature. After extraction with methylene chloride and water, the organic layer was dried over MgSO4 and concentrated in a vacuum. Purification by column chromatography (ethylacetate:n-hexane=1:1) afforded the title compound as a white solid (290 mg, 63%). [0846] 1H-NMR (300 MHz, CD3OD) delta 1.15 (d, J=6.8 Hz, 6H, CH3), 2.82 (sep, J=6.8 Hz, 1H, CH), 6.69 (s, 1H, ArH), 6.89 (d, J=7.8 Hz, 1H, ArH), 7.45 (d, J=7.9 Hz, 1H, ArH), 7.65 (m, 1H, ArH), 7.858.03 (m, 5H, ArH) 8.42 (d, J=8.0 Hz, 1H, ArH), 8.51 (d, J=8.4 Hz, 1H, ArH), 9.45 (s, 1H, ArH).

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Reference:
Patent; KATHOLIEKE UNIVERSITEIT LEUVEN K.U. LEUVEN R & D; KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY; Jung, Young Sik; Lee, Chong Kgo; Kim, Hae Soo; Jeong, Hee Chun; Kim, Pil Ho; Han, Soo Bong; Shin, Jin Soo; Neyts, Johan; Thibaut, Hendrik Jan; US2014/114068; (2014); A1;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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a. 4-Chloro-8-nitroquinoline (6a). This intermediate was prepared from 4-chloroquinoline (obtained by treating 4-hydroxyquinoline with [POC13] as [ DESCRIBED BY GOULEY, R. W., ET AL. , J. AMER. CHEM. SOC., 1947, 69, 303-306.4-] Chloroquinoline (10.0 g, 61.3 mmol) was added in small portions to sulfuric acid (45 mL) taking care to maintain the temperature at or below 15 C. Then the solution was cooled and maintained at-15 C during the addition of fuming nitric acid (9 mL). The mixture was allowed to warm to room temperature and stirred for an additional 3 hours. The reaction mix was poured on ice and basified (pH 9) with NH40H. The resulting precipitate was filtered, washed well with water, dried, and recrystallized from methanol to provide 7.5 g of 6a, in 59 % yield; m. p. = [128-129 C] (lit. m. p. = [129-130 C) ; IH] NMR [(CDC13)] [8] 7.67 (d, [1H,] J=4. 5), 7.75 (dd, 1H, J=8. 6 [HZ,] J=7. 6), 8.10 (dd, 1H, J=7. 6, J=1. 3), 8. 48 (dd, 1H,. [J=8.] [6,] J=1.3), 8.94 (d, 1H, J=4. 5); [13C] NMR [(CDC13)] [8] 123.0, 124.4, 126.5, 127.5, 128.3, 140.6, 143.2, 148.7, 152.1.

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Reference:
Patent; RUTGERS, THE STATE UNIVERSITY; LAVOIE, Edmond, J.; RUCHELMAN, Alexander, L.; LIU, Leroy, F.; WO2004/14906; (2004); A2;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics

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875-66-1, a. [4-CHLOROCINNOLINE] (9b). A mixture of 4-hydroxycinnoline (2.0 g, 13.7 mmol), phosphorus oxychloride (1.94 mL, 20.5 mmol), and pyridine (0.33 mL, 4.1 mmol) in [CHLOROBENZENE] (50 mL) was refluxed for 1 hour. Then the mixture was cooled and the solvent evaporated under vacuum, water was added, and the mixture was neutralized with solid sodium bicarbonate and extracted with chloroform (3 x 100 mL), washed with water (3 x 100 mL), dried [(MGS04)] and evaporated under vacuum, giving 1.84 g, in 82 % yield; [MP] [76-77 C] (lit mp 78 [C)] [; IH] NMR [(CDC13)] [8] 7.91 (m, 2H), 8.20 (dd, 1H, [J=6.] 2, [J=2.] 1), 8.57 (dd, 1H, J=6. 6, J=1. 8), 9.34 (s, [1H)] ; [13C NMR (CDCL3) No. ] 123.0, 124.9, 130.2, 131.6, 132.3, 133.8, 134.9, 144.4.

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Reference:
Patent; RUTGERS, THE STATE UNIVERSITY; LAVOIE, Edmond, J.; RUCHELMAN, Alexander, L.; LIU, Leroy, F.; WO2004/14906; (2004); A2;,
Cinnoline – Wikipedia
Cinnoline – an overview | ScienceDirect Topics