Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C1COCC1.[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][NH:18][CH:17]=1)([CH3:11])([CH3:10])[CH3:9].[Br:22][C:23]1[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=1>O>[C:8]([O:12][C:13](=[O:21])/[CH:14]=[CH:15]/[C:16]1[CH:20]=[CH:19][N:18]([S:28]([C:26]2[S:27][C:23]([Br:22])=[CH:24][CH:25]=2)(=[O:30])=[O:29])[CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.53 g NaH (60%) with 40.0 ml THF is cooled down to −30° C. and 3.1 g (E)-3-(1H-pyrrol-3-yl)-acrylic acid tert-butyl ester are added. During the addition it is liberated a gas. The solution is stirred at ambient temperature for 0.5 h. Then 5.0 g of 5-bromothiophene-2-sulfonylchloride is added by -30° C. The mixture is stirred at ambient temperature for 24 h. The NaH is hydrolyzed with water and the solution is extracted with ethyl acetate. The title compound is isolated by flash chromatography. By this method 4.5 g of colorless crystals are obtained.
Reaction SMILES: [C:1](Cl)(=[O:7])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:9][C:10]1([CH3:32])[CH2:15][CH:14]([NH:16][CH2:17][CH2:18][NH:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:13][C:12]([CH3:31])([CH3:30])[NH:11]1>O>[CH2:3]([O:2][C:1]([N:16]([CH:14]1[CH2:15][C:10]([CH3:32])([CH3:9])[NH:11][C:12]([CH3:31])([CH3:30])[CH2:13]1)[CH2:17][CH2:18][N:19]([C:1]([O:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:7])[CH:20]1[CH2:21][C:22]([CH3:29])([CH3:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:7])[CH2:4][CH2:5][CH3:6]
Reactant: CC1(C)CC(NCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CCCCOC(=O)Cl
Solvent: O
Product: CCCCOC(=O)N(CCN(C(=O)OCCCC)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1

Procedure:
120.2 g (0.88 mol) of butyl chlorocarbonate are reacted as described in Example 1 with 135.4 g (0.4 mol) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,2-ethanediamine dissolved in 410 ml of water.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1.CCOCC>O1CCOCC1>[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13]([O:9][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[N:12]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(O)c1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(Oc1cncc(Cl)n1)c1ccccc1
Reaction time: 0.17 h

Procedure:
K-t-BuO (2.1 g, 18.7 mmol) was added to a stirred solution of 1-phenyl-1-ethanol (2.45 g, 20.1 mmol) in dioxane (30 mL) at 0° C. (ice-bath). After 10 min of stirring, 2,6-dichloropyrazine (2.49 g, 16.7 mmol) was added whereupon the reaction mixture turned orange colored. After being stirrred for a further 1.5 h, ether was added and the mixture was filtered. Concentration in vacuo furnished an orange colored oil that was purified by silica gel chromatography (15×5 cm) using n-hexane ethyl acetate (9:1) as eluent. This gave 3.29 g (84%) of the title compound as a colorless oil. HRMS m/z calcd for C12H11ClN2O (M)+ 234.0560, found 234.0551.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[C:7](F)=[CH:6][C:5]=1[Cl:15].Cl.[CH3:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[C:7]([N:19]([CH3:20])[CH3:18])=[CH:6][C:5]=1[Cl:15]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(F)cc1Cl
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1cc(S(C)(=O)=O)c(N(C)C)cc1Cl
Temperature: 65 °C
Reaction time: 15 h
Yield: 59 %

Procedure:
To a stirred solution of 6.00 g (22.5 mmol) 2-Chloro-4-fluoro-5-methanesulfonyl-benzoic acid methyl ester (J. Med. Chem.; 40; 13; 1997; 2017-2034) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 15 h at 65° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 20a was obtained in 59% yield (3.87 g, 13.3 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([NH2:13])=O)=[CH:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[S:23])[NH2:13])=[CH:3]1
Reactant: Cn1cc(C(N)=O)c2ccccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1cc(C(N)=S)c2ccccc21

Procedure:
1-Methylindole-3-carboxamide (0.6 g) was suspended in toluene (20 ml); Lawesson's Reagent (0.7 g) was added and the mixture was heated at reflux under nitrogen for 30 min until dissolution occurred. The solution was cooled and toluene was removed under reduced pressure. The orange residue was purified by column chromatography on alumina using CH2Cl2 as eluant. This afforded an orange crystalline material, (0.5 g). δH (360 MHz, DMSO-d6) 3.82 (3H, s, NCH3), 7.18 and 7.23 (2H, 2×dt, J=7.1, 1.1 Hz, H-5 and H-6), 7.49 (1H, d, J=7.5 Hz, H-7), 8.08 (1H, s, H-2), 8.59 (1H, d, J=7.5 Hz, H-4), 8.76 (2H, brs, NH2); m/z 190 (M+, 100%), 174 (20), 157 (80).
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][Si:37]([CH3:44])([CH3:43])[CH2:38][CH2:39][O:40][CH2:41]Cl>>[Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[N:29]([CH2:41][O:40][CH2:39][CH2:38][Si:37]([CH3:44])([CH3:43])[CH3:36])[C:28](=[O:33])[CH2:27]4)=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (592 mg, 1 mmol) was treated as described in general procedure L using 2-(trimethylsilyl)ethoxymethyl chloride (354 μL, 2 mmol) to give 5-{4-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: [CH:1]1([NH:5][S:6](Cl)(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[CH2:10]([N:12]1[C:16]([C:17]2[CH:18]=[C:19]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([O:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:13]1)[CH3:11].C(N(CC)CC)C>ClCCl>[CH:1]1([NH:5][S:6]([NH:26][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]3[N:12]([CH2:10][CH3:11])[N:13]=[C:14]([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=4)[CH:15]=3)[CH:18]=2)([CH3:25])[CH3:24])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)NC1CCC1
Reactant: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C(C)(C)N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C(C)(C)NS(=O)(=O)NC2CCC2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 39.7 %

Procedure:
A solution of cyclobutylsulfamoyl chloride (0.65 M in CH2Cl2, 3.0 mL, 1.9 mmol, 1.5 equiv) was added to a solution of 2-(3-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}phenyl)propan-2-amine (0.50 g, 1.3 mmol, 1 equiv) and triethylamine (1.1 mL, 7.7 mmol, 6.0 equiv) in dichloromethane at −78° C. The reaction mixture was stirred for 10 minutes at −78° C., then cooling bath was removed. Stirred an additional 20 minutes, then partitioned between dichloromethane and aqueous citric acid solution (1 M). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-cyclobutyl-N′-[1-(3-{1-ethyl-3-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-5-yl}phenyl)-1-methylethyl]sulfamide (270 mg, 40%) as a white solid. Calcd (M+1)+: 523.2. Found: 523.1. 1H NMR (600 MHz, cdcl3) δ 7.60-7.49 (m, 4H), 7.42 (t, J=7.7, 1H), 7.29 (d, J=7.6, 1H), 7.23 (d, J=8.7, 2H), 5.86 (s, 1H), 4.75 (s, 1H), 4.33 (d, J=8.5, 1H), 4.08 (q, J=7.2, 3H), 2.24 (dd, J=16.8, 7.8, 2H), 1.89-1.80 (m, 3H), 1.72 (s, 6H), 1.70-1.54 (m, 3H), 1.41 (t, J=7.2, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[CH:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]#[C:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCI
Reactant: C#Cc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCCCC#Cc1cccc(OC)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
3-Methoxyphenylacetylene [5.00 g, 0.032M, prepared by the method of E. Negishi et al, J. Org. Chem. 45 2526-8, (1980)] was dissolved in dry tetrahydrofuran (15 ml), cooled to -70° C. under nitrogen, and n-butyl lithium, 1.6M in hexane, (24.40 ml, 0.038M), added dropwise. After stirring for 0.5 h, iodohexane (8.00 g, 0.038M), dissolved in dry tetrahydrofuran, (15 ml) was added dropwise. The rection was warmed slowly to room temperature, refluxed overnight, then cooled. The solution was then quenched with water, acidified with dilute hydrochloric acid and extracted with diethyl ether (twice). The organic phases were combined, washed with water and dried, (MgSO4). Evaporation in vacuo affored 7.71 g of product as an orange oil.
Reaction SMILES: O[CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[O:25]=[C:23]1[C:22]2[C:21](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20](=[O:30])[N:24]1[CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(O)COc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(COc1ccccc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At RT, 1.5 g of rac-tert-butyl (2-hydroxy-3-phenoxypropyl)carbamate (5.6 mmol, 1 equivalent), 0.99 g of phthalimide (6.73 mmol, 1.2 equivalents) and 2.21 g of triphenylphosphine (8.4 mmol, 1.5 equivalents) were initially charged in 23 ml of dry tetrahydrofuran. 1.70 ml of diisopropyl azodicarboxylate (8.4 mmol, 1.5 equivalents) were added dropwise, and the mixture was stirred at RT for 2 h. LC/MS showed complete conversion of the reaction. The reaction mixture was concentrated and purified by chromatography on silica gel (Biotage Isolera; cyclohexane/ethyl acetate gradient as mobile phase). This gave 1.08 g of the title compound (48% of theory).
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.C(OCC)(=O)C>[S:1]1[C:5]([C@H:6]([O:25][Si:26]([C:39]([CH3:41])([CH3:42])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH:7]=[CH:8]/[C@H:9]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C@@H:10]2[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:4][C:3]2[CH:43]=[CH:44][CH:45]=[CH:46][C:2]1=2
Reactant: C=C1C[C@H](O)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1=CC(=O)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1cc2ccccc2s1
Temperature: -25 °C

Procedure:
(Z)-7-((1R,2R,5S)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-(tert-butyldiphenylsilyloxy)prop-1-enyl)-5-hydroxy-3-methylenecyclopentyl)hept-5-enoic acid (23a) is dissolved in acetone (0.1 M) and cooled to −25° C. Jones reagent (1 molar equivalent) is added dropwise with stirring. Upon completion, as judged by TLC, the reaction is quenched with isopropyl alcohol and the crude reaction mixture is diluted with ethyl acetate, washed three times with brine, and dried over magnesium sulfate. After filtration and solvent evaporation, the product is purified by flash chromatography using hexanes-ethyl acetate as eluent to afford the title intermediate.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][N:24](CC3C=CC=CC=3)[CH2:25][CH3:26])[CH:16]=2)=[C:7]([NH:34][C:35]([NH:37][C:38]2[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=2[CH:47]([CH3:49])[CH3:48])=[O:36])[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4].Cl>C(O)C.[C].[Pd]>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][NH:24][CH2:25][CH3:26])[CH:16]=2)=[C:7]([NH:34][C:35]([NH:37][C:38]2[C:43]([CH:44]([CH3:46])[CH3:45])=[CH:42][CH:41]=[CH:40][C:39]=2[CH:47]([CH3:48])[CH3:49])=[O:36])[C:6]1=[O:50])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCN(CC)Cc3ccccc3)c2)c2cccnc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCNCC)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
To a solution of N-[1-butyl-4-[3-{2-(N-benzyl-N-ethylamino)ethoxy)-phenyl]-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (129 mg, 0.191 mmol) in ethanol (10 ml) were added 12N aqueous hydrochloric acid solution (1 ml) and 10% palladium-carbon (210 mg), and the mixture was stirred at room temperature under hydrogen atmosphere for five hours. The mixture was filtered through a cerite pad, and the filtrate was concentrated. To the concentrated resultant was added aqueous ammonia, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The reside was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (10% methanol in chloroform) to give the title compound (63 mg, 0.10 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:38])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH3:37])[N:32]=[CH:31]2)[C:18]([O:20][CH3:21])=[O:19])[CH3:14]>>[Cl:8][C:7]1[C:2]([N:26]([CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH3:37])[N:32]=[CH:31]3)[S:25]([C:24]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=2[CH2:13][CH3:14])(=[O:39])=[O:38])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: CCc1cc(C(=O)OC)ccc1S(=O)(=O)NCc1ccc2c(cnn2C)c1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: CCc1cc(C(=O)OC)ccc1S(=O)(=O)N(Cc1ccc2c(cnn2C)c1)c1ncc(C(F)(F)F)cc1Cl

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 3-ethyl-4-(N-((1-methyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-2 of Example 4).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4](O)([C:21]([F:24])([F:23])[F:22])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:7][C:6]=1[C:17]([F:20])([F:19])[F:18].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=[C:6]1[C:17]([F:19])([F:20])[F:18])[C:21]([F:24])([F:23])[F:22]
Reactant: COC(=O)C(O)(c1c(C(F)(F)F)[nH]n(-c2ccccc2)c1=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(=C1C(=O)N(c2ccccc2)N=C1C(F)(F)F)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of α-hydroxy-2,5-dihydro-5-oxo-1-phenyl-α-trifluoromethyl-3-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (192 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (183 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.N([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[N:30]=[CH:29][NH:28][C:26]3=2)[N:21]=[C:20]([CH3:31])[CH:19]=1)C1C=CC=CC=1>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]3[N:30]=[CH:29][NH:28][C:26]3=2)[N:21]=[C:20]([CH3:31])[CH:19]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2ccc(F)c(Cl)c2)c2c(ccc3nc[nH]c32)n1

Procedure:
A mixture of 14.5 g. (0.1 m.) of 3-chloro-4-fluoroaniline, 21.7 g. (0.1 m.) of the compound of Example I, C. and 500 ml. of ethanol was refluxed overnight with stirring. It was then chilled, filtered and the product washed with ether and air-dried to give 25 g. The crude product was recrystallized from 1500 ml. of MeOH to yield 17 g.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.O.[NH2:21][NH2:22].O>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:21][NH2:22])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[CH3:11])=[CH:14][CH:15]=1
Reactant: NN
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21
Solvent: C1CCOC1
Solvent: O
Product: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Yield: 90.1 %

Procedure:
(2-Chloro-9-methyl-9H-purin-6-yl)-(4-chloro-phenyl)-amine (3.58 g, 12.1 mmol) was dissolved in tetrahydrofuran (50 mL). Hydrazine monohydrate (26 mL, 536 mmol) was added and the reaction mixture was heated to reflux over night. The next day water was added and the resulting solid was collected by filtration, washed with water and dried to give (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine (3.16 g, 90%) as a white crystalline compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[CH:11][N:12]=[C:13](Cl)[C:8]2=[N:7][C:6]=1[CH2:15][CH3:16])=[O:4].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[CH:11][N:12]=[C:13]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][C:22]=3[Cl:24])[C:8]2=[N:7][C:6]=1[CH2:15][CH3:16])=[O:4]
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: CCc1nc2c(Cl)nccn2c1C(=O)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nccn2c1C(=O)OC
Yield: 77.4 %

Procedure:
8-Chloro-2-ethylimidazo[1,2-a]pyrazine-3-carboxylic methyl ester (0.92 g, 3.8 mmol) synthesized in Reference Example 1 was dissolved in a mixed solvent of toluene (32 mL) and methanol (8 mL), then 2,4-dichlorobenzeneboronic acid (1.49 g, 7.8 mmol) and tetrakistriphenylphosphine palladium complex (230 mg, 0.2 mmol) were added thereto, and the mixture was heated under reflux for 2 hours under nitrogen atmosphere. The reaction mixture was allowed to cool, and purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give the title compound (1.03 g) as a pale yellow crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O:27][CH2:28][CH2:29]Br)(=[O:26])[CH3:25]>CN(C=O)C.O>[C:7]1([C:13]([CH2:29][CH2:28][O:27][C:24](=[O:26])[CH3:25])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)OCCBr
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CCOC(C)=O)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
A solution of potassium tert.butoxide (448 g, 4M) in DMF (2 l) under nitrogen at room temperature was treated dropwise with diethyl phenylmalonate (945 g, 4M). 1-Acetoxy-2-bromoethane (668 g, 4M) was added. The reaction was allowed to cool to room temperature after 45 mins and was diluted with water (5 l) then extracted with IPE (2 l, 500 ml). The extracts were washed, dried and evaporated to give the title compound (1300 g). Bp 130°/0.05 mm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:26])[CH:3]=1.Cl[CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[N:7][C:2]([N:1]5[CH2:28][CH2:29][CH2:30][S:31]5(=[O:33])=[O:32])=[CH:3][C:4]=4[CH3:26])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Cc1cc(N)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Product: Cc1cc(N2CCCS2(=O)=O)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1

Procedure:
Using (6-amino-4-methylpyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.0 g) described in Preparation Example 141 and 3-chloropropane-1-sulfonyl chloride (0.69 mL) and by the reaction and treatment in the same manner as in Example 78, the title compound (636 mg) was obtained.