Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O.O.O.O.O.O.O.O.O.[S-2:21].[Na+].[Na+].[Cl:24][C:25]1[C:33]([CH2:34]Cl)=[CH:32][C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=1>CN(C=O)C.O.C(OCC)(=O)C>[Cl:24][C:25]1[C:33]([CH2:34][S:21][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])=[CH:32][C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: [S-2]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(SCc2cc3c(cc2Cl)OCO3)c([N+](=O)[O-])c1
Reaction time: 48 h

Procedure:
1-bromo-4-methyl-2-nitrobenzene (3 mmol) dissolved in DMF (3 mL) was combined with a solution of sodium sulfide nonahydrate (3 mmol) in water 3 (mL) and stirred for 48 hours. A solution of 5-chloro-6-(chloromethyl)-1,3-benzodioxole (3 mmol) in ethyl acetate (5 mL) was added in and the reaction was agitated for another 24 hours. The reaction was diluted with ethyl acetate and washed sequentially with 0.5 N NaOH solution (7 mL×1), water (7 mL×3) and brine (7 mL×1). The solvent was removed under a stream of nitrogen and the residue crystallized from a mix of dichloromethane and hexane.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH:6]=[C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])[CH:4]=[CH:3]1.Br[C:31]1C=CC=C2C=1C=CN2.CI.BrCCCCC>>[CH3:31][N:7]1[C:2](=[O:1])[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:21]4=[CH:22][C:23]5[O:27][CH2:26][O:25][C:24]=5[CH:28]=[C:20]4[O:19][CH2:18]3)[C:10]2=[O:29])=[CH:6]1
Reactant: Brc1cccc2[nH]ccc12
Reactant: O=C1N(Cc2ccc(=O)[nH]c2)c2ccccc2C12COc1cc3c(cc12)OCO3
Solvent: CCCCCBr
Solvent: CI
Product: Cn1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)ccc1=O

Procedure:
Following the procedure described in PREPARATION 1A, and making non-critical variations using 1′-[(6-oxo-1,6-dihydropyridin-3-yl)methyl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4-bromoindole, and methyl iodide to replace 1-bromopentane, the title compound was obtained (78%): mp 115-118° C.; 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m, 3H), 7.18 (d, 1H), 7.06 (t, 1H), 6.87 (d, 1H), 6.57-6.48 (m, 2H), 6.02 (s, 1H), 5.87-5.83 (m, 2H), 4.90 (d, 1H), 4.75-4.52 (m, 3H), 3.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.8, 162.5, 155.9, 149.1, 142.4, 141.6, 139.7, 137.6, 132.1, 129.1, 124.4, 123.9, 121.3, 119.1, 114.0, 108.6, 102.8, 101.6, 93.7, 80.3, 58.2, 40.8, 38.0; MS (ES+) m/z 403.3 (M+1).
Reaction SMILES: [CH2:1]1[C:15]2[C:6](=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=2)[CH2:5][CH2:4][NH:3][CH2:2]1.[Cl:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[ClH:16].[CH2:20]([O:19][C:17]([N:3]1[CH2:2][CH2:1][C:15]2[C:6](=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH:14]=2)[CH2:5][CH2:4]1)=[O:18])[CH3:21]
Reactant: c1ccc2nc3c(cc2c1)CCNCC3
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2cc3ccccc3nc2CC1
Product: Cl
Yield: 64 %

Procedure:
1,2,4,5-Tetrahydro-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester hydrochloride was prepared from 1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 63.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[CH3:27][S-:28].[Na+].[H-].[Na+].CI>CN(C)C=O.O>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:28][CH3:27])=[CH:11][CH:10]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc12
Reactant: C[S-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(SC)cc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
A suspension of methyl 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.4 g, 6.61 mmol) and sodium thiomethoxide (1.158 g, 16.52 mmol) in N,N-dimethylformamide (40 mL) was stirred at 100° C. overnight. The mixture was cooled to room temperature, treated with NaH (0.264 mg, 6.61 mmol), and stirred for 20 min. Methyl iodide (1.5 g, 9.92 mmol) was added, and the mixture was stirred for 2 h. The mixture was diluted with water and extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 120 g Silica, 0-30% ethyl acetate/hexanes) to afford methyl 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2.54 g, 95% yield). MS (m/z) 392.1 (M+H+).
Reaction SMILES: ClC1C=CC(N(CC)C([C@@H]2C3C(=CC=CC=3)N([C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)=[O:22])[C@@H](C)C2)=O)=CC=1.C1C=C2C=C(C(O)=O)SC2=CC=1.C(Cl)(=O)C([Cl:50])=O.CN(C)C=O>C(Cl)Cl>[S:27]1[C:23]([C:21]([Cl:50])=[O:22])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: CCN(C(=O)[C@H]1C[C@H](C)N(C(=O)c2cc3ccccc3s2)c2ccccc21)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc2ccccc2s1

Procedure:
(±)-trans-1-(Benzo[b]thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was made following general procedure A, substituting benzo[b]thiophene-2-carbonyl chloride for 4-trifluoromethyl-benzoyl chlorided. Benzo[b]thiophene-2-carbonyl chloride was prepared by reaction of thianaphthene-2-carboxylic acid with oxalyl chloride and dimethylformamide in methylene chloride. The crude 1-(benzo[b]thiophene-2-carbonyl)-2-methyl-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide was isolated as a mixture of cis and trans isomers. Purification by silica gel chromatography (1% methanol/methylene chloride) followed by purification via HPLC yielded (±)-trans-2-methyl-1-(pyrimidine-5-carbonyl)-1,2,3,4-tetrahydro-quinoline-4-carboxylic acid (4-chloro-phenyl)-ethyl-amide (34%). 1H-NMR (CDCl3) δ: 1.02-1.18 (m, 6H), 1.65-1.75 (m, 1H), 2.55-2.65 (m, 1H), 3.60-3.70 (m, 1H), 3.80 (q, 2H), 5.05-5.15 (m, 1H), 6.70 (d, 1H), 6.80-7.00 (m, 3H), 7.20-7.40 (m, 4H), 7.45 (s, 1H), 7.50 (d, 2H), 7.70 (d, 1H), 7.80 (d, 1H). MS m/z: 489/491 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16](O)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C@@H:40]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:41]([O:43][CH3:44])=[O:42].CN1CCOCC1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>C(Cl)Cl.O>[C:31]([O:30][C:28]([NH:27][C:9]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16](=[O:17])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][C@@H:40]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:41]([O:43][CH3:44])=[O:42])=[N:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])([CH3:32])([CH3:33])[CH3:34]
Reactant: COC(=O)[C@@H](CCCCN)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N=C(NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCNC(=O)[C@@H](CCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A stirred solution of acid 8 (1.95 g, 4.00 mmol) and amine 14 (1.04 g, 4.00 mmol) in CH2Cl2 (60 mL) was charged with NMM (2.64 mL, 24.0 mmol) and EEDQ (1.97 g, 8.00 mmol). The resulting mixture was stirred at room temperature for 16 h. Water (20 mL) was added to the reaction mixture and extracted with CH2Cl2 (3×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography (silica gel, 20% to 40% EtOAc in hexanes) to afford amide 15 (2.15 g, 73% over two steps) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.10-4.02 (m, 1H), 4.01-3.92 (m, 1H), 3.70 (s, 3H), 3.35 (t, J=6.8 Hz, 2H), 3.24-3.10 (m, 2H), 1.83-1.67 (m, 2H), 1.66-1.55 (m, 4H), 1.52 (s, 9H), 1.46 (s, 9H), 1.45-1.35 (m, 6H), 1.438 (s, 9H), 1.431 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[NH:5][CH2:4][C:3]1=[O:14].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][N:5]=1
Reactant: CN1C(=O)CNC(=O)c2ccccc21
Reactant: O=P(Cl)(Cl)Cl
Product: CN1C(=O)CN=C(Cl)c2ccccc21

Procedure:
The title compound 467 (1.54 g, 8.10 mmol) was heated in phosphorus oxychloride (15 mL) at 95° C. for 2 hours. The reaction mixture was then cooled to room temperature and excess of phosphorus oxychloride was removed under reduced pressure. The black oil was dissolved in ethyl acetate and the organic phase was washed with sodium bicarbonate (saturated solution) and brine, dried over sodium sulfate, filtered and concentrated to afford crude title compound 468 that was used as such for the next step. MS (ESI): 209.12 (MH)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>CO.C(OCC)(=O)C.[Zn]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=1[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Cc1ccc(C(C)(C)C)c(N)c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
5.52 g (84.4 mmol) of zinc powder were added to a suspension of 1.06 g (4.21 mmol) of methyl 2-(4-t-butyl-3-nitrophenyl)acetate [prepared as described in step (i) above] in 30 ml of methanol, and subsequently acetic acid was added to the mixture in four 0.8 ml portions over a period of 1 hour. The reaction mixture was stirred for 2 hours, after which it was diluted with ethyl acetate. It was then filtered using a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and the concentrate was again dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of ammonium chloride, with a saturated aqueous solution of sodium hydrogencarbonate, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 870 mg (yield 94%) of the title compound as an oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8](=[O:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[I-].[CH3:19][S+](C)(C)=O.[OH-].[K+].[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>C(O)(C)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([OH:15])([CH2:19][N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:16][CH:17]=1
Reactant: c1nc[nH]n1
Reactant: C[S+](C)(C)=O
Reactant: O=C(COc1ccc(Cl)cc1)Cn1cncn1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: OC(COc1ccc(Cl)cc1)(Cn1cncn1)Cn1cncn1

Procedure:
A mixture of 1-(4-chlorophenoxy)3-(1,2,4-triazol-1-yl)propan-2-one (0.7g), trimethylsulphoxonium iodide (0.74g), potassium hydroxide (0.38g) and 1,2,4-triazole (0.23g) in tert butyl alcohol (15ml) was heated at 80° for 2.5h, then cooled and partitioned between ethyl acetate and water. The organic phase was separated, washed with water and then brine, dried and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a Lobar silica column, using 2% methanol in chloroform as eluent, to give 2(4-chlorophenoxymethyl)1,3-di(1,2,4-triazol-1-yl)propan-2-ol as a gum. NMR in deuteriochloroform: δ 3.6(2H,s); 4.45(4H,q): 6.75(2H,d); 7.21(2H,d); 7.95(2H,s); 8.2(2H,s).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(Cl)Cl>O>[CH:1]([C:4]1[CH:10]=[CH:9][C:7](/[N:8]=[CH:17]/[C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:11])([F:21])[F:22])=[CH:20][CH:19]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)c1ccc(N)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)c1ccc(/N=C/c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 2 h
Yield: 99.1 %

Procedure:
4-Isopropylaniline (5.5 ml, 40.2 mmol) was added to a vigorously stirred mixture of 4-(trifluoromethyl)benzaldehyde (5.5 ml, 40.2 mmol) in H2O (60 ml) at room temperature. After 2 hours, DCM (100 ml) was added and the mixture was stirred for 20 minutes. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated to give the imine (11.6 g, 99%) as a beige solid. 1H NMR (360 MHz, CDCl3) δ: 1.28 (6H, d, J 6.9), 2.95 (1H, septet, J 6.9), 7.18-7.21 (2H, m), 7.25-7.29 (2H, m), 7.71-7.73 (2H, m), 8.00-8.02 (2H, m), 8.52 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[CH2:42][C:5]2[C:6]3[CH2:11][CH2:10][NH:9][CH:8]([C:12]4[C:13]([CH2:39][OH:40])=[C:14]([C:19]5[CH:20]=[C:21]([NH:27][C:28]6[CH:37]=[CH:36][C:35]7[CH2:34][N:33]([CH3:38])[CH2:32][CH2:31][C:30]=7[N:29]=6)[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=5)[CH:15]=[C:16]([F:18])[CH:17]=4)[C:7]=3[S:41][C:4]=2[CH2:3]1.Br[C:45]1C=C(NC2C=CC3CN(CC)CCC=3N=2)C(=O)N(C)C=1>>[CH3:1][C:2]1([CH3:43])[CH2:42][C:5]2[C:6]3[CH2:11][CH2:10][NH:9][CH:8]([C:12]4[C:13]([CH2:39][OH:40])=[C:14]([C:19]5[CH:20]=[C:21]([NH:27][C:28]6[CH:37]=[CH:36][C:35]7[CH2:34][N:33]([CH2:38][CH3:45])[CH2:32][CH2:31][C:30]=7[N:29]=6)[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=5)[CH:15]=[C:16]([F:18])[CH:17]=4)[C:7]=3[S:41][C:4]=2[CH2:3]1
Reactant: CCN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Reactant: CN1CCc2nc(Nc3cc(-c4cc(F)cc(C5NCCc6c5sc5c6CC(C)(C)C5)c4CO)cn(C)c3=O)ccc2C1
Product: CCN1CCc2nc(Nc3cc(-c4cc(F)cc(C5NCCc6c5sc5c6CC(C)(C)C5)c4CO)cn(C)c3=O)ccc2C1
Yield: 28 %

Procedure:
Using the same general procedure as described for the preparation of 240, reaction of 5-bromo-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methylpyridin-2(1H)-one (143 mg, 0.394 mmol) with 182c (300 mg, 0.513 mmol) gave a 28% yield (70 mg) of 241 as a yellow solid: mp 134-135° C.; 1H NMR (500 MHz, DMSO-d6) d 8.78 (d, 1H, J=2.0 Hz), 8.43 (s, 1H), 7.44 (d, 1H, J=2.0 Hz), 7.31 (dd, 1H, J=9.5, 2.5 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.18 (dd, 1H, J=9.5, 2.5 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.86 (m, 1H), 4.38 (m, 2H), 4.04 (m, 1H), 3.84 (m, 1H), 3.59 (s, 3H), 3.43 (s, 2H), 3.03 (m, 1H), 2.89 (m, 1H), 2.75 (s, 4H), 2.62 (m, 2H), 2.53 (m, 2H), 2.50 (m, 2H), 1.23 (s, 6H), 1.08 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 628 (M+H).
Reaction SMILES: [Cl:1][CH:2]([Cl:9])[C:3](=O)[CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][NH2:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(O)(=O)CC>>[Cl:1][CH:2]([Cl:9])/[C:3](=[N:21]/[NH:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:19])/[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCC(=O)O
Product: CCCC/C(=N\NS(=O)(=O)c1ccc(C)cc1)C(Cl)Cl
Temperature: 60 °C
Yield: 43.4 %

Procedure:
1,1-Dichlorohexan-2-one (Intermediate 5) (45.3 mg, 0.27 mmol) and 4-methylbenzenesulfonohydrazide (50 mg, 0.27 mmol) were added to propionic acid (0.5 ml) and then heated to 60° C. for 4 hours. The reaction mixture was then heated to 100° C. for 5 minutes and allowed to cool to room temperature overnight. Hexanes (20 ml) were added and the precipitate was filtered under nitrogen to yield the title compound (39.5 mg).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][NH2:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=O)=[CH:17][CH:16]=1.CC(C)=O.C(#N)C>C(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:23]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)=[CH:22][C:21]([C:18]3[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=3)=[N:13]2)=[CH:10][CH:11]=1)(=[O:5])=[O:4]
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(CC(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CC(C)=O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nc(-c3ccc(Cl)cc3)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
4-(Methylsulphonyl)phenylhydrazine hydrochloride (1.4 g, 6.2 mmol) is added to a stirred solution of 1,3-bis[4-chlorophenyl]propane-1,3-dione (1.6 g, 5.4 mmol) in a mixture of ethanol (50 mL), acetone and acetonitrile. The reaction is heated to reflux and stirred. After cooling to room temperature, the reaction mixture is concentrated in vacuo. The residue is taken up in ethyl acetate and washed with water and brine and dried over MgSO4, filtered, and concentrated in vacuo to give 1-[4-(methylsulfonyl)phenyl]-3,5-bis(4-chlorophenyl)-1H-pyrazole.
Reaction SMILES: [F:1][C:2]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[S:14]([NH2:17])(=[O:16])=[O:15])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5].C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([O:33][CH3:34])[N:30]=[C:29]([O:35][CH3:36])[N:28]=2)C=CC=CC=1.O.Cl>C(#N)C>[CH3:34][O:33][C:31]1[N:30]=[C:29]([O:35][CH3:36])[N:28]=[C:27]([NH:26][C:25]([NH:17][S:14]([C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:2]([F:1])=[C:3]([F:8])[C:4]([F:7])([F:6])[F:5])(=[O:16])=[O:15])=[O:24])[N:32]=1
Reactant: COc1nc(NC(=O)Oc2ccccc2)nc(OC)n1
Reactant: NS(=O)(=O)c1sccc1C(F)=C(F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COc1nc(NC(=O)NS(=O)(=O)c2sccc2C(F)=C(F)C(F)(F)F)nc(OC)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
According to steps (1) to (4) in Preparation Examples 1, 3-(1,2,3,3,3-pentafluoropropen-1-yl)-2-thiophenesulfonamide was prepared. A portion (0.3 g) of this substance and 0.311 g of phenyl-N-(4,6-dimethoxy-1,3,5-triazin-2-yl)carbamate were dissolved in 4 ml of dry acetonitrile. To the solution, 0.175 g of 1,8-diazabicyclo-(5,4,0)-7-undecene was added dropwise, and the mixture was subjected to reaction under stirring for 2.5 hours at room temperature. After completion of the reaction, the resulting product was poured into water and acidified with hydrochloric acid. The precipitated crystals were filtered, washed with water and dried to obtain 0.47 g of the object compound having a melting point of 149° to 153° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12]Br)=[CH:10][C:5]=2[O:4][C:3]1=[O:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[O:16][CH3:15])[CH2:28][CH2:27]3)=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: Cn1c(=O)oc2cc(CCBr)ccc21
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CCc2ccc3c(c2)oc(=O)n3C)CC1
Yield: 65.1 %

Procedure:
By following the procedure indicated in Example 1, but starting from 5.12 g of 3-methyl-6-(2-bromoethyl)-benzoxazolinone and 4.82 g of 1-(2-methoxyphenyl)-piperazine, 4.78 g of the title product having a melting point of 137°-137.5° C. were obtained after crystallisation from cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: CC(=O)N(C)C
Reactant: COc1ccnc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccnc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 2-methyl-4-methoxypyridine (2.03 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 12.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.99 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(4-methoxypyridin-2-yl)propan-2-one (2.35 g).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.C([N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])C.[C:25](Cl)(=[O:32])[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30].Cl>C1(C)C=CC=CC=1>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[O:8][C:4]3[CH:3]=[C:2]([O:1][C:25]([CH2:26][CH2:27][CH2:28][C:29]([O:8][C:4]4[CH:5]=[CH:24][C:23]5[N:20]=[C:21]([C:22]6[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=6)[O:1][C:2]=5[CH:3]=4)=[O:30])=[O:32])[CH:17]=[CH:16][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc2nc(-c3ccc(F)cc3)oc2c1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)CCCC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(CCCC(=O)Oc1ccc2nc(-c3ccc(F)cc3)oc2c1)Oc1ccc2nc(-c3ccc(F)cc3)oc2c1
Yield: 88 %

Procedure:
6-Hydroxy-2-(p-fluorophenyl)benzoxazole (20.00 g, 0.087 mole) from Example 7 is mixed with 300 ml of toluene and 12 g (0.12 mole) of triethylamine under nitrogen atmosphere. Glutaryl chloride (7.10 g, 0.042 mole) is added and the mixture is stirred and heated at reflux for 5 hours. After cooling to room temperature 300 ml of 1N hydrogen chloride is added and stirring is continued for a few minutes. The resulting precipitate is filtered and recrystallized from DMF. The title compound (20.5 g, 88 percent yield), illustrated in Formula 16, is recovered and has a melting point of 189° C.-190° C. ##STR19##
Reaction SMILES: C[O:2][C:3](=[O:52])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][S:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[C:20]([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O:33]C)=[O:32])(=[O:26])=[O:25])=[CH:19][C:18]([S:38]([NH:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O:47]C)=[O:46])(=[O:40])=[O:39])=[CH:17]3)(=[O:13])=[O:12])[CH:5]=1.[OH-].[Na+:54].C(O)(=O)C>C(O)C>[Na+:54].[Na+:54].[Na+:54].[C:20]1([S:24]([NH:27][C:28]2[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=2)[C:31]([O-:33])=[O:32])(=[O:26])=[O:25])[C:21]2[C:16](=[CH:15][C:14]([S:11]([NH:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([O-:52])=[O:2])(=[O:12])=[O:13])=[CH:23][CH:22]=2)[CH:17]=[C:18]([S:38]([NH:41][C:42]2[CH:43]=[C:44]([CH:49]=[CH:50][CH:51]=2)[C:45]([O-:47])=[O:46])(=[O:40])=[O:39])[CH:19]=1
Reactant: COC(=O)c1cccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cccc(C(=O)OC)c4)cc(S(=O)(=O)Nc4cccc(C(=O)OC)c4)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C([O-])c1cccc(NS(=O)(=O)c2ccc3c(S(=O)(=O)Nc4cccc(C(=O)[O-])c4)cc(S(=O)(=O)Nc4cccc(C(=O)[O-])c4)cc3c2)c1
Reaction time: 0.75 h

Procedure:
A mixture of 12.0 g of the product of Example 11 and 62.0 ml of 2N sodium hydroxide is stirred for 45 minutes. The solution is neutralized with 3.6 ml of glacial acetic acid and diluted with 400 ml of ethanol. The solvent is concentrated in vacuo to a small volume. Then it is diluted again with ethanol with the separation of an oil. The solvent is decanted off, and the oil is triturated with fresh ethanol to produce a yellow solid. The solid is separated, washed with ethanol and ether, and dried at 70° C. to yield 7.3 g of the product of the Example.