Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15](C)[N:16]1[C:25]2[C:20](=[CH:21][C:22]([I:27])=[CH:23][C:24]=2[F:26])[C:19](=[O:28])[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:17]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[F:26][C:24]1[CH:23]=[C:22]([I:27])[CH:21]=[C:20]2[C:25]=1[N:16]([NH:15][CH3:13])[CH:17]=[C:18]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:19]2=[O:28]
Reactant: CCOC(=O)c1cn(N(C)C(=O)OC(C)(C)C)c2c(F)cc(I)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cn(NC)c2c(F)cc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.9 %

Procedure:
A solution of trifluroacetic acid (6.40 g) in methylene chloride (5 mL) is added dropwise over a 4 minute period to a solution of ethyl 1-((tert-butoxycarbonyl)(methyl)amino)-8-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Preparation 34, 1.10 g) in methylene chloride (20 mL) at room temperature. After 3.5 h, the mixture is poured into a mixture of saturated sodium bicarbonate solution (125 mL) and water (50 mL), and extracted two times with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated at reduced pressure. The resulting gummy solid is stirred with diethyl ether at room temperature to afford 0.857 g (98%) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[CH:20]=[N:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[N:12]=1>CN(C=O)C>[CH:3]1([O:9][C:11]2[CH:20]=[N:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH:24]4[CH2:7][CH2:8][CH2:3][CH2:4][CH2:5]4)=[C:16]([O:21][CH3:22])[CH:17]=3)[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(OC3CCCCC3)nc2cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a DMF solution (5 mL) of NaH (0.32 g 8 mmol) under argon, cyclohexanol (0.7 mL, 6.7 mmol) is added dropwise. The mixture is stirred at room temperature for 25 minutes, then 2-chloro-6,7-dimethoxyquinoxaline is added portionwise. The reaction is stirred for 15 minutes at room temperature, at 90° C. for 2 hours, and at 110° C. for 1 hour. The mixture is cooled, quenched with H2O, and partitioned between EtOAc/H2O. The organic layer is washed with H2O and brine, dried (MgSO4), and chromatographed (10% EtOAc/hexanes) to provide a waxy white solid (m.p. 75-78° C.). Anal. Calcd. for C21H28N2O3: C, 70.76; H, 7.92. N, 7.86; Found: C, 70.81; H, 7.79; N, 7.70.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1.N1C=CN=C1.[CH:20]([Si:23](Cl)([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([O:14][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:20]([CH3:22])[CH3:21])[CH:6]=1
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=Cc1ccc([N+](=O)[O-])c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To a solution of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime (5.0 g, 25 mmol) in N,N-dimethylformamide (40 mL) is added imidazole (1.8 g, 27 mmol), followed by triisopropylsilyl chloride (6.0 mL, 28 mmol), and 4-(dimethylamino)pyridine (catalytic amount). After stirring overnight at room temperature, the reaction mixture is diluted with diethyl ether (200 mL) and then washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude solid is purified by flash chromatography (hexanes/ethyl acetate) to give 4-nitro-3-[(triisopropylsilyl)oxy]benzaldehyde O-methyloxime as a white solid (6.2 g, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][CH2:16][CH3:17])=[N:8][C:9](S(C)=O)=[N:10][CH:11]=1)=[O:5])[CH3:2].CCCCCC.C(OCC)(=O)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:15][CH2:16][CH3:17])=[N:8][C:9]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCNc1nc(S(C)=O)ncc1C(=O)OCC
Reactant: Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNc1nc(Nc2ccccc2)ncc1C(=O)OCC
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of 4-ethylamino-2-methanesulfinyl-pyrimidine-5-carboxylic acid ethyl ester (5.38 g, 20.9 mmol) in 4 mL of aniline was heated at 130° C. for 1 hour. The solution was cooled to room temperature, and 20 mL of 1:1 hexane:ethyl acetate was added. The resultant white solid was collected by filtration to give 1.96 g (33%) of the title product. The filtrate was concentrated in vacuo and purified by flash chromatography eluting with 3:1 hexane:ethyl acetate to provide an additional 257 mg (4%) of pure 4-ethylamino-2-phenylamino-pyrimidine-5-carboxylic acid ethyl ester, mp 145-147° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:10]1[C:11]([Cl:18])=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)[OH:9]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Cl:18][C:11]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[CH:15][N:14]=[C:13]([S:16][CH3:17])[N:12]=1
Reactant: CSc1ncc(C(O)c2ccccc2Cl)c(Cl)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CSc1ncc(C(=O)c2ccccc2Cl)c(Cl)n1
Reaction time: 2.5 h

Procedure:
To a solution of (2-chlorophenyl)-(4-chloro-2-methylsulfanylpyrimidin-5-yl)methanol (10.8 g, 35.75 mol) in toluene (150 mL) was added manganese (IV) oxide (Aldrich) (31.2 g, 10 eq). The resulting mixture was heated to reflux with stirring for a total of 2.5 hours. The reaction was then filtered hot through a 3.5 cm pad of Celite. The pad of Celite was rinsed with hot ethyl acetate, and the filtrate was concentrated to give a crude oil. Purification by Flash Column Chromatography on Silica Gel eluting with a gradient of 2%-10% ethyl acetate in hexanes gave the title compound as a yellow viscous semi-solid (5.3 g, (M+H)+=299.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([Cl:23])=[CH:15][C:16]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:11]=[CH:10]2)=[N:6][CH:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].[NH:72]1[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:23][C:14]1[CH:13]=[C:12]2[C:17](=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)[N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([N:72]3[CH2:77][CH2:76][CH2:75][CH2:74][CH2:73]3)=[CH:7][N:6]=1)[CH:10]=[CH:11]2
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc(Cl)cc2ccn(Cc3ccc(Br)cn3)c12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)cc2ccn(Cc3ccc(N4CCCCC4)cn3)c12
Temperature: 110 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
A mixture of ethyl 1-[(5-bromopyridin-2-yl)methyl]-5-chloro-1H-indole-7-carboxylate (0.30 g), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (88 mg), sodium tert-butoxide (0.12 g), piperidine (84 mg), tris(dibenzylideneacetone)dipalladium (0) (70 mg), and dehydrated toluene (6.0 mL) was bubbled with argon for 10 minutes, followed by stirring at 110° C. for 2 hours. The reaction mixture was filtered through Celite and washed with diethyl ether. To this filtrate was added saturated aqueous sodium bicarbonate, followed by extraction with diethyl ether, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, filtering and concentrating under reduced pressure, the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain ethyl 5-chloro-1-[(5-piperidin-1-ylpyridin-2-yl)methyl]-1H-indole-7-carboxylate (0.23 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[N+:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2c(Cl)ccnc12
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Temperature: 100 °C
Yield: 37.4 %

Procedure:
A suspension of 4-chloro-8-nitroquinoline (200 mg, 0.96 mmol), 3-(trifluoromethyl)phenol (250 mg, 1.54 mmol), K2CO3 (414 mg, 2.99 mmol) in CH3CN (2 mL) was heated in a sealed tube at 100° C. for 8 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 120 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.83 (d, J=5.4 Hz, 1H), 8.60-8.57 (d, J=8.4 Hz, 1H), 8.36 (d, J=6.9 Hz, 1H), 7.85-7.73 (m, 5H), 6.87 (d, J=5.4 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)O)[C:5]([F:8])=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:10]([C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[O:26][C:20](=[O:21])[NH:19]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)cnc1F)[C@H](O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2cc(Br)cnc2F)[C@@H](c2ccc(F)cc2)O1
Temperature: 25 °C
Yield: 15 %

Procedure:
To a 25 mL round bottom flask was added tert-butyl (1R,2R)-1-(5-bromo-2-fluoropyridin-3-yl)-2-(4-fluorophenyl)-2-hydroxyethylcarbamate (1450 mg, 3.38 mmol) in dichloromethane (12 mL). To this solution was added trifluoroacetic acid (2.60 mL, 33.8 mmol) and the reaction was allowed to stir over night at room temperature. The reaction solvent was evaporated in vacuo and the crude oil was diluted with diethylether and washed with saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and the solvent was then evaporated in vacuo and the crude residue was diluted with dry tetrahydrofuran. The solution was cooled to 0° C. and carbonyldiimidazole (282 mg, 1.74 mmol) was added and the reaction was allowed to stir overnight. The reaction solvent was then evaporated in vacuo and the crude residue was diluted with 2N ammonia in methanol and stirred for 15 min. The solvent was then evaporated in vacuo and the crude solid was purified by silica gel chromatography 15% EtOAc/85% Hexanes to 50% EtOAc/50% Hexanes affording the desired product and its regioisomer as an inseparable mixture. The inseparable mixture was further purified by reverse phase chromatography using a sunfire col 30×100 45%-55% MeOH/H2O 0.1% TFA over a 20 minute run time affording (4R,5R)-4-(5-bromo-2-fluoropyridin-3-yl)-5-(4-fluorophenyl)oxazolidin-2-one (180 mg, 0.507 mmol, 10.99% yield). 1H-NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.10 (d, J=8.0), 7.42-7.38 (m, 2H), 7.19-7.15 (m, 2H), 5.81 (brs, 1H), 5.36 (d, J=4.0, 1H), 5.01 (d, J=4.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.17 min. Mass=356.96 (MH)+.
Reaction SMILES: [CH2:1]([C@H:8]1[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](Cl)(=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23].C(OCC)(=O)C>O1CCCC1>[CH3:23][C:22]([CH3:25])([CH3:24])[C:21]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]([CH3:13])([CH3:14])[O:11][C:10]1=[O:15])=[O:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)OC(=O)N[C@H]1Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)N1C(=O)OC(C)(C)[C@@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Reaction of the auxiliary (10) (0.085 g, 0.415 mmol) in solution in tetrahydrofuran (2 ml) at -78° C. with butyllithium (1.6M, 0.262 ml, 0.419 mmol) and pivaloyl chloride (0.056 ml, 0.456 mmol) for 30 minutes and then at room temperature for 2 hours with work-up and flash column chromatography using 30% ethyl acetate/40-60 petroleum ether furnished the title compound (19) as an oil (0.104 g, 87%); νmax (CDCl3) 1742 cm-1 ; δH (CDCl3 ; 300 MHz) 1.30 (3H, s, C(CH3)2), 1.34 (6H, s, C(CH3)3), 1.35 (3H, s, C(CH3)2), 2.86 (1H, dd, J=9.3 and 14.2, CH2Ph), 3.05 (1H, dd, J=4.1 and 14.2, CH2Ph), 4.53 (1H, dd, J=4.2 and 9.3, CHCH2), 7.18-7.28 (5H, m, ArCH); δC (125 MHz; CDCl3) 22.10 (CH3), 26.29 (CH3), 28.07 (CH3), 35.24 (CH2), 41.68 (C), 65.47 (CH), 81.80 (C), 126.94 (CH), 128.76 (CH), 129.38 (CH), 137.19 (C), 152.03 (CO), 179.49 (CO); m/z (CI+, NH3) 290 (M+ +1).
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Yield: 49.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.0 g), triethylamine (0.54 mL), 2,4-difluorocinnamic acid (0.72 g), WSC.HCl (0.75 g), and methylene chloride (40 mL), to give the captioned compound (0.73 g, 49%) as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[C:5]2[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][O:20][C:21]=1[CH3:22]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:19][O:20][C:21]=1[CH3:22])=[O:14]
Reactant: O=C(Cl)c1cc(Cl)nc2ccc(Br)cc12
Reactant: Cc1onc(-c2ccccc2)c1N
Solvent: c1ccncc1
Product: Cc1onc(-c2ccccc2)c1NC(=O)c1cc(Cl)nc2ccc(Br)cc12
Temperature: 70 °C
Yield: 71.6 %

Procedure:
6-Bromo-2-chloroquinoline-4-carbonyl chloride (500 mg) and 4-amino-5-methyl-3-phenylisoxazole (400 mg) were dissolved in dichlorormethane (15 mL) and pyridine (1 mL). The reaction solution was heated at 70° C. overnight. The white precipitation was collected by filtration, washed with ethyl acetate and dried to give 6-bromo-2-chloro-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (520 mg) as a white solid. 1H NMR (DMSO-d6): δ 2.52 (s, 3H), 7.52 (m, 3H), 7.72 (m, 2H), 8.02 (m, 4H), 10.58 (s, 1H); LCMS: ret. time: 32.23 min.; purity: 100%; MS (m/e): 441.82 (M+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=[N:20]3)[CH2:14][CH:15]=2)=[CH:2]1.I[CH3:31]>>[CH3:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[N:21]=[N:20]3)[CH2:12][CH:11]=2)=[CH:2]1
Reactant: CI
Reactant: O=c1c2ccccc2nnn1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Product: Cn1cc(C2=CCN(CCCn3nnc4ccccc4c3=O)CC2)c2ccccc21
Yield: 35.3 %

Procedure:
Starting from 3-[3-(4-(1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one (0.83 g, 2.2 mmol) and iodomethane (0.14 mL, 2.2 mmol), and following the same procedure as in example 21, 0.31 g of 3-[3-(4-(1-methyl-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl)propyl]-1,2,3-benzotriazin-4(3H)-one was isolated as an orange solid. Yield 35%; mp 70° C.; MS: 400.3 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 2.20 (m, 2H), 2.54 (m, 2H), 2.66 (t, 2H), 2.72 (t, 2H), 3.21 (m, 2H), 3.75 (s, 3H), 4.60 (t, J=5.34 Hz, 2H), 6.11 (t, 1H), 6.99 (s, 1H), 7.16 (t, 1H), 7.22 (t, 1H), 7.27 (m, 2H), 7.75 (t, 1H), 7.87 (m, 1H), 8.12 (d, 1H), 8.36 (d, 1H).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([OH:14])=[O:13].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:13]
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Agent: [Na]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cc2ccccc2)c1
Temperature: 60 °C

Procedure:
24.4 g of the sodium salt of 2-chloro-5-nitrobenzenesulphinic acid are dissolved in 150 ml of ethanol under reflux conditions, and 35 g of benzyl chloride are gradually added. After 10 to 12 hours under reflux conditions the solution is cooled down to 60° C., and the precipitated salt is separated off by filtration. The solution, on cooling down to 0° C., yields 24.1 g of colourless crystals of benzyl 2-chloro-5-nitrophenyl sulphone.
Reaction SMILES: C(O[C:4]([NH:6][CH2:7][C:8]([C:10]1[N:17]2[C:13]([S:14][CH:15]=[CH:16]2)=[N:12][C:11]=1[CH3:18])=O)=[O:5])C.O.[NH2:20][NH2:21]>C(O)C>[CH3:18][C:11]1[N:12]=[C:13]2[N:17]([C:10]=1[C:8]1[CH2:7][NH:6][C:4](=[O:5])[NH:20][N:21]=1)[CH:16]=[CH:15][S:14]2
Reactant: NN
Reactant: CCOC(=O)NCC(=O)c1c(C)nc2sccn12
Solvent: CCO
Solvent: O
Product: Cc1nc2sccn2c1C1=NNC(=O)NC1

Procedure:
A mixture of 7 g of 5-ethoxycarbonylaminoacetyl-6-methylimidazo[2,1-b]thiazole, 100 ml of ethanol and 8 ml of 100% hydrazine hydrate is refluxed under heating for 2 days. After cooling, crystals are collected by filtration and recrystallized from a mixed solvent of chloroform and methanol to give 3.4 g of 6-(6-methylimidazo[2,1-b]thiazol-5-yl)-4,5-dihydro-2H-1,2,4 triazin-3-one as white crystals, melting at 293°-295° C. with decomposition.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl.S(Cl)(Cl)=O.[C:38]([O-])(O)=O.[Na+]>CO.C1COCC1>[CH2:1]([O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1)[CH3:38]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(C)=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To {2′-[(acetyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid methyl ester (0.292 g, 0.69 mmol) in MeOH (2.3 mL) and THF (2.9 mL) was added aqueous 1N NaOH (1.7 mL), and the solution was stirred at room temperature for 2 hours. The mixture was neutralized with aqueous 1N HCl, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was dissolved in EtOH, and thionyl chloride (0.11 mL, 1.51 mmol) was added. The reaction was stirred for 30 minutes, until no starting material was seen by analytical LCMS. The solution was neutralized with saturated aqueous NaHCO3, and the aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].CC1(C)O[C:16](=O)[CH2:15][C:13](=O)[O:12]1>>[O:12]=[C:13]1[C:3]2[C:4](=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])[NH:5][CH:16]=[CH:15]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=c1cc[nH]c2cc(Cl)cc(Cl)c12

Procedure:
Kokai Pat. No. Hei 1(1989)-246263 describes a method for producing 5,7-dichloro-4-(2-fluorophenoxy)-quinoline whereby a mixture of 3,5-dichloroaniline and Meldrum's acid is heated to give 4-oxo-5,7-dichloro-1,4-dihydroquinoline, which is reacted with phosphorus oxychloride to give 4,5,7-trichloroquinoline, which is then reacted with 2-fluorophenol to give the final compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:24]4[O:23][CH:27]=[CH:26][CH:25]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1ccco1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccco4)c3)cnc2c1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and furan-2-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(fur-2-yl)phenyl]imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (6 mg, 4%): m/z (ES+) 355 [MH+].
Reaction SMILES: O=[C:2]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:10]([O:12]C)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Br:25])[C:18]([O:20][CH3:21])=[O:19].C(O)C.O=S(Cl)Cl>CO.C(OCC)(=O)C.C(O)(=O)C>[Br:25][C:24]1[C:15]2[NH:14][C:2]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[C:10](=[O:12])[C:16]=2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(Br)c(N)c1
Reactant: COC(=O)C1CCCCCCC1=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CCCCCC3
Temperature: 130 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
A mixture of methyl 2-oxocyclooctanecarboxylate (32.0 g, 174 mmol), methyl 3-amino-4-bromobenzoate (20.0 g, 87 mmol) and ethanol (120 mL) was heated to reflux, at an oil bath of 130° C., acetic acid (1.5 mL) was added and the mixture was reflux for 1.5 hours. Hot PPA (200 g, 120° C.) was added to the reaction mixture carefully. The reaction mixture was heated at an oil bath of 130° C. for 3 hours. After cooling for a while, ice (200 g), ethyl acetate (60 mL) and petroleum ether (60 mL) were added to the reaction mixture, the mixture was concentrated until 200 mL solvent was removed. Then water (600 mL) and ethyl acetate (60 mL) were added, the resulting mixture was stayed at room temperature overnight. A light brown solid was slowly formed. The mixture was filtered and the filtered cake was dried to give a light brown solid, which was placed into methanol (90 mL). SOCl2 (30 mL) was added dropwise with cooling with an ice-bath. The resulting mixture was heated to reflux for 4 hours, concentrated and treated with saturated NaHCO3 solution (60 mL) and ethyl acetate (30 mL), filtered and the filtered cake was dried to give desired product (6.6 g) as a pale white solid (21%). 1H NMR (DMSO-d6) δ10.25 (s, 1H), 7.96-7.98 (d, 1H, J=7.6 Hz), 7.09-7.11 (d, 1H, J=7.6 Hz), 3.02-3.06 (m, 2H), 2.63-2.66 (m, 2H), 1.75-1.77 (m, 2H), 1.53-1.55 (m, 2H), and 1.36-1.39 (m, 4H). MS (ESI) m/e [M+1]+ 364/366.