Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccn1
Reactant: c1ccsc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: c1ccc(-c2cccs2)nc1
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a solution of thiophene (4.7 mL, 59.4 mmole) at 0° C. was added 2.5M n-butyllithium (24 mL, 59.4 mmole) dropwise via syringe. The solution was stirred 3 h and was transferred via cannula into a stirred solution of zinc chloride (8.6 g, 63.4 mmole) in 60 mL THF at room temperature. This solution was stirred for 1 h and was transferred via cannula into a stirred solution of 2-bromopyridine (3.8 mL, 39.6 mmole) and tetrakis-triphenylphosphine palladium (0.22 g, 0.2 mmole) in 100 mL of THF. The solution was stirred overnight at room temperature and was then quenched with saturate ammonium chloride solution (100 mL) and extracted with ether (3×100 mL). The ether extracts were washed with brine (1×100 mL), dried over MgSO4, filtered and concentrated to yield 8.4 g of crude residue. The material was chromatographed (silica gel, 10% ether/hexanes) to yield 5.0 g (78%) of a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([S:14][CH3:15])[N:11]4[N:16]=[CH:17][CH:18]=[C:10]4[CH:9]=3)[CH:3]=2)=[CH:23][CH:22]=1
Reactant: CSc1nc(-c2cccc(Br)c2)cc2ccnn12
Reactant: COc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc(-c3cc4ccnn4c(SC)n3)c2)cc1
Yield: 151.1 %

Procedure:
Under an inert gas atmosphere is dissolved 5-(3bromophenyl)-7-methylsulfanyl-pyrazolo-[1,5-c]pyrimidine (compound D3)(0.25 g) and 4-methoxyphenyl boronic acid (0.45 g) in dimethoxyethane. To this solution are added bis-(triphenylphosphine)palladium(II) chloride (0.13 mmol) and an aqueous sodium carbonate solution (2M, 8 ml). The reaction mixture is heated to reflux for 18 h The mixture is diluted with ethyl acetate and filtered over silica gel. The product is partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic phase is dned over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (0.41 g) in 60% yield is obtained,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)/[CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:49][O:50][C:51](=[O:58])[C@H:52]([CH2:54][CH2:55][S:56][CH3:57])[NH2:53].CN1CCOCC1>CN(C1C=CN=CC=1)C.ClCCl>[F:33][C:30]1[CH:31]=[CH:32][C:27](/[C:20](/[CH2:21][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:19]\[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[C:11]([CH:15]=2)[C:12]([NH:53][C@@H:52]([CH2:54][CH2:55][S:56][CH3:57])[C:51]([O:50][CH3:49])=[O:58])=[O:13])=[CH:28][CH:29]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(O)c1cc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cc(/C=C(/Cn2ccnc2)c2ccc(F)cc2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]-5-[(E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-en-1-yl]benzoic acid (0.3 g; 0.67 mmol), EDC (0.154 g; 0.8 mmol), HOBT (0.108 g; 0.8 mmol), DMAP (0.090 g; 0.74 mmol), L-methionine methyl ester hydrochloride (0.2 g; 1 mmol) and N-Methylmorpholine (110 μl; 1 mmol) in dichloromethane (20 ml) was stirred at room temperature overnight. The organic phase was washed with aqueous sodium bicarbonate, dried and evaporated. The residue was purified by flash chromatography. eluting with a gradient of dichloromethane/ethanol (1-3%) to give methyl (2S)-2-{5-[(E)-2-(4-fluorophenyl)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(2-(4-fluorophenyl)ethyl)benzamido}-4-methylsulfanylbutyrate as a white solid foam Yield=50%.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[C:19]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[ClH:1].[C:19]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=4)=[CH:9][CH:10]=3)[CH:5]=[N:4][N:3]=2)=[CH:28][CH:29]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Cc1cccnc1-c1ccc2c(Cl)nncc2c1
Solvent: C1COCCO1
Product: Cc1cccnc1-c1ccc2c(Nc3ccc(C(C)(C)C)cc3)nncc2c1
Product: Cl
Temperature: 25 °C
Yield: 42.7 %

Procedure:
1-Chloro-6-(3-methyl-2-pyridinyl)phthalazine (200 mg; 0.78 mmol) and 4-tert-butylaniline (117 mg, 0.125 mL; 0.78 mmol) in 1,4-dioxane were heated at reflux for 2 h. After allowing to cool down to room temperature the precipitate was collected by filtration washed with 1,4-dioxane and dried to give the title compound (135 mg) (43%). 1H NMR (500 MHz, DMSO-d6) δ: 1.35 (9H, s), 7.48 (1H, dd, J 4.9 and 7.6 Hz), 7.55-7.61 (4H, m), 7.90 (1H, dd, J 0.8 and 7.8 Hz), 8.47 (1H, dd, J 1.6 and 8.6 Hz), 8.52 (1H, d, J 2.0 Hz), 8.63 (1H, dd, J 1.2 and 4.7 Hz), 9.09 (1H, d, J 8.6), 9.32 (1H, s); MS (ES M+1) 369.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[CH:12]1([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:16]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[CH:19]=[N:18][N:17]=3)[N:25]=2)=[O:11])[CH:3]=1
Reactant: Nc1cccc(-c2nncn2C2CC2)n1
Reactant: Cc1cnc(C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(-c3nncn3C3CC3)n2)cc1Cl
Yield: 47 %

Procedure:
A solution of 4-chloro-5-methylpicolinic acid (159 mg, 0.924 mmol), 6-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine (169 mg, 0.840 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (383 mg, 1.01 mmol), and N-methylmorpholine (11 μL, 1.01 mmol) in N,N-dimethylformamide was stirred at 65° C. for 12 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile, and the solid product was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL), diethyl ether (80 mL), and dried under vacuum to afford 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methylpicolinamide as a white powder (140 mg, 47% yield).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].CS[C:15]1[S:19][CH:18]=[CH:17][S+:16]=1>CC(C)=O.C(OCC)C>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[S:16]1[CH:17]=[CH:18][S:19][C:15]1=[N+:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSc1scc[s+]1
Reactant: C1CCCNCC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: CCOCC
Product: c1csc(=[N+]2CCCCCC2)s1

Procedure:
0.25 g of hexahydroazepine and 0.5 g of 2-methylthio-1,3-dithiolium perchlorate were teated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 0.31 g (yield: 52.0%) of 1-(1,3-dithiol-2-ylidene)hexahydroazepinium perchlorate (Compound No. 37) was obtained as crystals having a melting point of from 86° to 88° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([CH3:3])[CH3:2].[F-:14].[K+].O>O1CCOCC1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([F:14])(=[O:12])=[O:11])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1S(=O)(=O)Cl
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccccc1S(=O)(=O)F
Reaction time: 45 h
Yield: 96.1 %

Procedure:
27 g of 2-isopropylbenzenesulfonyl chloride and 22 g of KF are stirred in 75 ml of dioxane and 20 ml of water at 45° C. for 27 h and at RT for 45 h. 800 ml of water are then added, and the mixture is extracted with 3×300 ml of EA. The combined organic phases are dried over Na2SO4 and the solvent is removed in vacuo. 24 g of a colorless oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[N+]([C:21]1[CH:22]=[C:23]([S:27](Cl)(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)([O-])=O.[CH2:31]([N:33](CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][N:9]([S:27]([C:23]2[CH:24]=[CH:25][C:26]([C:31]#[N:33])=[CH:21][CH:22]=2)(=[O:29])=[O:28])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCNCCc1ccc(OC)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A mixture of methyl acrylate (6.0 g, 69.7 mmol) and p-methoxyphenethyl amine (10.5 g, 69.7 mmol) in anhydrous methanol (88 mL) was refluxed for 3 days and then was concentrated to give methyl 3-[(4-methoxyphenethyl)amino]-propionate (16.2 g). To a solution of methyl 3-[(4-methoxyphenethyl)amino]-propionate (3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added 3-nitrobenzenesulfonyl chloride (2.8 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at room temperature, the mixture was quenched with 1 N HCl solution (150 mL) and extracted with methylene chloride (100 mL). Combined organic layers was washed successively with 1 N HCl solution (100 mL) and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (2.5/1 to 2/1: hexanes/EtOAc) to provide methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.28 g, 7.8 mmol).
Reaction SMILES: [CH3:1][NH2:2].Cl[CH2:4][C:5]([NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])=[O:6].Cl>C1COCC1.CCOC(C)=O>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[NH:7][C:5](=[O:6])[CH2:4][NH:2][CH3:1]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNCC(=O)Nc1c(C)cccc1C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, methylamine (600 mmols) in 300 mL THF was cooled to 0° C. A solution of 2-chloro-N-(2′,6′-dimethylphenyl)acetamide (100 mmols) was dissolved in 200 mL THF, and slowly dripped into the cold methylamine solution. The reaction was stirred overnight. The reaction was filtered, and the filtrate evaporated to yield an oily residue. This was dissolved in EtOAc (100 mL) and treated with 1N HCl (200 mL). The aqueous layer was washed with EtOAc, then basified to Ph 10-12 with 6 N NaOH. The product was extracted into EtOAc (2×50 mL), the organic phase was dried, and the solvent was evaporated to yield N-(2,6-dimethyl-phenyl)-2-methylamino-acetamide (compound (23)) as an oil (12.8 gm; 67% yield).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].N[C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>C(O)(=O)C>[CH3:9][C:6]1[CH:7]=[CH:8][C:3]2[C:1]([NH:2][C:18]3[CH:19]=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=[CH:16][C:17]=3[S:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)=[N:12][CH:11]=[N:10][C:4]=2[N:5]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: Nc1cc([N+](=O)[O-])ccc1Sc1ccc(O)cc1
Solvent: CC(=O)O
Product: Cc1ccc2c(Nc3cc([N+](=O)[O-])ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
A solution of the product from Example 10B (340 mg, 1.80 mmol), and the product of Example 85A (480 mg, 1.80 mmol) in acetic acid (10 mL) was stirred in an oil bath preheated to 130° C. for 30 minutes. The mixture was then cooled to room temperature, the acetic acid removed under vacuum leaving a brown oil as the title compound (0.65 g, 89%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][O:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:34])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1.[OH-].[NH4+:42].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][C:16]1[N:17]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)=[O:34])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:42])[C:19]=2[N:28]=1
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
mCPBA (6.60 g, 28.7 mmol) was added to a solution of 2-(2-methoxyethyl)-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinoline (6.5 g, 17 mmol) in chloroform (100 mL); the reaction was stirred for two hours at ambient temperature. The reaction was cooled to 0° C., and ammonium hydroxide (50 mL) was added. A solution of benzenesulfonyl chloride (4.11 mL, 33.0 mmol) in chloroform (20 mL) was added over a period of 20 minutes, and the reaction was allowed to warm to ambient temperature and stirred for two hours. The work-up procedure and chromatographic purification was carried out as described in Part D of Example 8. The resulting product was triturated with 10% aqueous sodium hydroxide, isolated by filtration, washed with water, and dried overnight in a vacuum oven to provide 2-(2-methoxyethyl)-1-(5-morpholin-4-yl-5-oxopentyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white powder, mp 128-129° C.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]2[N:21]=[CH:20][C:19]3[CH2:18][CH2:17][C:16]4[C:22]([C:26]([NH:28][C:29]5[C:34]([CH2:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:30]=5[CH2:37][CH3:38])=[O:27])=[N:23][N:24]([CH3:25])[C:15]=4[C:14]=3[N:13]=2)[CH2:7][CH2:6]1)(=[O:4])[CH:2]=[CH2:3].[CH3:39][NH2:40]>O1CCCC1.ClCCl.CO.[OH-].[NH4+]>[CH2:37]([C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][CH3:36])[C:29]=1[NH:28][C:26]([C:22]1[C:16]2[CH2:17][CH2:18][C:19]3[CH:20]=[N:21][C:12]([NH:11][CH:8]4[CH2:7][CH2:6][N:5]([C:1](=[O:4])[CH2:2][CH2:3][NH:40][CH3:39])[CH2:10][CH2:9]4)=[N:13][C:14]=3[C:15]=2[N:24]([CH3:25])[N:23]=1)=[O:27])[CH3:38]
Reactant: CN
Reactant: C=CC(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)CCNC)CC3)nc1-2
Temperature: 60 °C
Yield: 77 %

Procedure:
To a solution 8-[(1-acryloylpiperidin-4-yl)amino]-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (30 mg, 0.058 mmol) in tetrahydrofurane (1 mL) in a sealed tube, methylamine (2M in tetrahydrofurane) (0.3 mL) was added. The mixture was then heated at 60° C. for 2 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol/30% ammonium hydroxide: 8/2/0.2) to 27 mg of the title compound (77% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:10]=[CH:9][NH:8][N:7]=1.[H-].[Na+].[CH:13](I)([CH3:15])[CH3:14].O>CN(C)C=O.CC(OC)(C)C>[CH:13]([N:8]1[CH:9]=[CH:10][C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[N:7]1)([CH3:15])[CH3:14].[CH:13]([N:7]1[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:9]=[N:8]1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: c1csc(-c2cc[nH]n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)n1ccc(-c2cccs2)n1
Product: CC(C)n1nccc1-c1cccs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88 %
Yield: 1 %

Procedure:
3-(2-thienyl)-1H-pyrazole (31.6 mmol) was dissolved in 150 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (37.9 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, isopropyl iodide (47.4 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 14 h. Isopropyl iodide (5.9 mmol) was added and the mixture was stirred at room temperature overnight. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 5.40 g 1-isopropyl-3-(2-thienyl)-1H-pyrazole (88% yield) and 50 mg of 1-isopropyl-5-(2-thienyl)-1H-pyrazole (1% yield).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[C:14]([CH:16]=1)[NH2:15].CCCCCC>C1(C)C=CC=CC=1>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[C:14]([NH:15][C:1](=[O:3])[CH3:2])[CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cc(NC(C)=O)cc(C(F)(F)F)c1
Reaction time: 1.5 h

Procedure:
Acetic anhydride (1.22 ml, 12.8 mmol) is added during 10 min to a solution of 5-methoxy-3-trifluoromethyl-aniline (2.29 g, 12.0 mmol) in toluene (10 ml) at a temperature of 25-33° C. After 90 min at RT, hexane (10 ml) is added und the suspension is stirred for 20 min. Filtration, washing with toluene/hexane 2:1 and hexane gives the title compound: mp: 123-124° C.; API-MS: 234 [MH]+; TLC: Rf=0.27 (Hex/EtOAc, 1:1).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:22])[F:23])[CH:12]=2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (prepared as in Example 89A, 2.92 g, 7.72 mmol) in tetrahydrofuran/water (88 mL, 3:1) was treated with lithium hydroxide (647 mg, 15.43 mmol). The reaction was stirred at 25° C. for 3 d. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (50 mL) and extracted with ether (25 mL). The aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric acid solution. The product was extracted into ethyl acetate (3×75 mL) and ether (1×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×100 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (2.37 g, 84.5%) as a pale-yellow semi-solid: EI-HRMS m/e calcd for C16H19F3O4S (M+) 364.0956, found 364.0958.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:15]([Br:16])=[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][N:9]3[N:8]=2)[N:5]=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccnn1-c1nn2c(c1Br)CCCC2
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1c([N+](=O)[O-])cnn1-c1nn2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.6 g (12.7 mmol) 5-Amino-1-(3-bromo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl)pyrazole was suspended in 15 ml acetic acid and treated with 1.23 ml (13.0 mmol) acetic anhydride. The mixture was stirred for 5 hours at room temperature. 1.5 ml (15.9 mmol) acetic anhydride was added and then, with ice-bath cooling, 0.66 ml (15.5 mmol) fuming nitric acid was added, dropwise. After stirring for 12 hours at room temperature, the mixture was concentrated. The residue was dissolved in 30 ml ethanol and treated with 11.2 ml concentrated hydrochloric acid. After heating for 3 hours under reflux, the mixture was concentrated and the residue taken up in water and ethyl acetate. It was made basic with 2N aqueous sodium hydroxide and the organic phase separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with water and once with saturated aqueous sodium chloride. The organic phase was dried and concentrated. The residue was recrystallised from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[F:17][C:18]([F:32])([F:31])[O:19][C:20]1[CH:21]=[C:22](/[CH:26]=[CH:27]/[C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][C:13]([NH:16][C:28](=[O:29])/[CH:27]=[CH:26]/[C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][C:18]([F:31])([F:32])[F:17])[CH:21]=2)=[N:12]1
Reactant: O=C(O)/C=C/c1cccc(OC(F)(F)F)c1
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2cccc(OC(F)(F)F)c2)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(3-trifluoromethoxy-phenyl)-acrylic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCCC=Cc1cccc(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCCc1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
In a reaction vessel were placed 0.53 g of 4-(3-fluorophenyl)-3-buten-1-ol and 50 ml of ethyl acetate, and the air in the vessel was exchanged for nitrogen. Then, 0.1 g of 10% palladium carbon was added thereto, and the nitrogen in the vessel was exchanged for hydrogen, followed by vigorous stirring at room temperature for 24 hours. After the hydrogen in the vessel was exchanged for nitrogen, the reaction solution was filtered through a celite bed, and the filtrate was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.48 g of 4-(3-fluorophenyl)-1-butanol.