Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-])=[CH:4][CH:3]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([C:24]#[N:25])[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: [O-][n+]1ccccc1C=Cc1ccc(Cl)cc1
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)O
Product: N#Cc1cccc(C=Cc2ccc(Cl)cc2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(4-chloro-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and crystallization the title compound was obtained as a beige crystalline material. Mp. 113–115° C. (isopropanol), MS: m/e=240 (M+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
3-(4-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol (0.5 mmol, 1 equivalent) was dissolved in CH2Cl2 (5 mL) to which 3 equivalents of triethylamine were then added. Under stream of nitrogen, 2 equivalents of triisopropylsilyl chloride (TIPSCl) were added thereto at 0° C., followed by stirring at room temperature. After 10 minutes, the solution was concentrated by distillation under reduced pressure and hexane was added thereto, followed by washing with a saturated NaHCO3 aqueous solution. After extraction with hexane twice, the organic layer was dried over anhydrous MgSO4, filtered, concentrated and then dried under vacuum to afford the title compound.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[C:8]([CH3:26])=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([C@@H:18]1[CH2:20][C@@H:19]1[F:21])[CH:12]=[C:11]([C:22]([OH:24])=[O:23])[C:10]2=[O:25].Cl.Cl.[N:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[NH:32][CH2:31][CH2:30]2>C(N(CC)CC)C>[N:29]12[CH2:36][CH:33]([CH2:34][CH2:35]1)[N:32]([C:16]1[CH:15]=[C:14]3[C:9]([C:10](=[O:25])[C:11]([C:22]([OH:24])=[O:23])=[CH:12][N:13]3[C@@H:18]3[CH2:20][C@@H:19]3[F:21])=[C:8]([CH3:26])[C:7]=1[F:6])[CH2:31][CH2:30]2
Reactant: C1CN2CCC(C2)N1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1c(F)c(N2CCN3CCC2C3)cc2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To 6 ml of dried N,N-dimethylformamide were added 200 mg of 6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 372 mg of 1,4-diazabicyclo[3.2.1]octane dihydrochloride, and 2 ml of triethylamine, and the mixture was stirred at 100° C. for 1 hour. After allowing to cool, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in a 1N sodium hydroxide aqueous solution under cooling with ice. The solution was neutralized with 1N hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting crude crystals were recrystallized from a mixed solvent of ethanol and 28% aqueous ammonia, and the crystals were collected by filtration, washed with diethyl ether, and dried at 60° C. under reduced pressure overnight to yield 131 mg of the titled compound as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[Br:15][C:16]1[C:17]([NH2:31])=[CH:18][C:19]2[N:20]([CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:31][C:17]1[C:16]([Br:15])=[CH:21][N:20]2[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=[C:19]2[CH:18]=1)=[O:5])[CH3:2]
Reactant: Nc1cc2nc(-c3ccccc3)cn2cc1Br
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A solution of 5-chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (as prepared in Example 14, Step 2, 2.35 g, 10.8 mmol) in dichloromethane (5 ml) was added dropwise over 20 min to a cooled (0° C.) solution of 6-bromo-2-phenyl-imidazo[1,2-a]pyridin-7-ylamine (1.56 g, 5.4 mmol) and triethylamine (877 mg) in dichloromethane (20 ml); the mixture was then stirred for at r.t. (30 min). The mixture was washed (water), and the organic layer was dried (Na2SO4), and evaporated. The title compound (460 mg, 23%) was isolated by filtration over a column of silica gel with dichloromethane as an eluent, and was used without further purification in the next step. MS (m/e)=470.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]([F:12])([F:24])[F:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.6 %

Procedure:
A mixture of 2-methyl-5-nitrophenol (765 mg, 5.00 mmol), 4-(trifluoromethoxy)benzeneboronic acid (1.24 g, 6.00 mmol), copper(II) acetate (999 mg, 5.50 mmol), triethylamine (3.48 ml, 25.0 mmol), molecular sieves 4A and dichloromethane (20.0 ml) was stirred at room temperature overnight under argon atmosphere. The reaction mixture was filtered through celite. The residue obtained by evaporation of the solvent of the filtrate under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=20:1) to give the title compound (323 mg, 20.6%) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[CH2:10][CH2:9][N:8](C(O)=O)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:15][C:2]([F:1])([F:14])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCNCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of compound 4-(2,2,2-trifluoro-acetyl)-piperazine-1-carboxylic acid tent-butyl ester (15.15 g, 53.69 mmol) in CH2Cl2 (60 mL) was added trifluoroacetic acid (18 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation. Diethyl ether (100 mL) was added to the residue. The white solid was collected by filtration, washed with diethyl ether, and dried under vacuum. The resulting residue, the title compound, was used in the next reaction without further purification. MS m/z (M+H+) 183.1.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:19]=[N:20][NH:21][CH:22]=1)=[CH:13][CH:12]=2.[CH:23]12[O:28][CH:27]1[CH2:26][O:25][CH2:24]2>CN(C=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]1[CH:22]=[N:21][N:20]([CH:27]3[CH2:26][O:25][CH2:24][CH:23]3[OH:28])[CH:19]=1)=[CH:13][CH:12]=2
Reactant: C1OCC2OC12
Reactant: Clc1cc2cc(-c3cn[nH]c3)ccc2cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OC1COCC1n1cc(-c2ccc3cnc(Cl)cc3c2)cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
A mixture of Cs2CO3 (34 mg, 0.105 mmol), 3-chloro-6-(1H-pyrazol-4-yl)isoquinoline (16 mg, 0.070 mmol) and 3,6-dioxabicyclo[3.1.0]hexane (Preparation 37, 24 mg, 0.279 mmol) in DMF (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled, concentrated in vacuo and purified using Biotage silica gel column chromatography eluting with 50-75% EtOAc/cyclohexane to give the title compound as white solid (10 mg, 46%).
Reaction SMILES: N([O-])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[NH:14][NH:15][C:16]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[N:17][N:18]=1>O.C(O)(=O)C>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[C:13]1[N:18]=[N:17][C:16]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])=[N:15][N:14]=1
Reactant: Fc1cccc(F)c1C1=NN=C(c2c(F)cccc2F)NN1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Fc1cccc(F)c1-c1nnc(-c2c(F)cccc2F)nn1
Yield: 85.6 %

Procedure:
A solution of 0.12 g of sodium nitrite in 1 ml of water is added dropwise to the suspension of 0.4 g of 3,6-bis(2,6-difluorophenyl)-1,2-dihydro-1,2,4,5-tetrazine prepared in the preceeding step c.)] in 2.5 ml of glacial acetic acid at room temperature while stirring. The progress of the reaction is followed by thin layer chromatography. After filtration the carmine crystals are washed with water until neutral to give 0.34 g of desired product. This crude product is recrystallized from a mixture of gasoline and acetone to give 0.251 g of pure title product of Example 2, m.p.: 213.5° C.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]([CH3:26])([CH3:25])[NH:5][C:6](=[O:24])[C:7]([CH3:23])([CH3:22])[NH:8][C:9](=[O:21])[C:10]([CH3:20])([CH3:19])[NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].O[Li].O>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C:10]([CH3:20])([CH3:19])[C:9]([NH:8][C:7]([CH3:23])([CH3:22])[C:6]([NH:5][C:4]([CH3:26])([CH3:25])[C:3]([OH:27])=[O:2])=[O:24])=[O:21])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.3 %

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycyl α,α-dimethylglycine methyl ester 6 (2.14 g, 5.52 mmol) was dissolved in THF (60 mL) and a solution of LiOH.H2O (0.695 g, 16.6 mmol) in de-ionized H2O (30 mL) added. The reaction mixture was stirred for 3 h at room temperature before the bulk of solvent was evaporated and the solution diluted with H2O (100 mL). The solution was washed with Et2O (2×40 mL) and acidified to pH 2 by addition of 5 M HCl. A white solid precipitated and was collected by filtration. The residue was washed with icecold H2O (30 mL) and dried under high vacuum affording the title compound as a white solid (1.84 g, 89%). The compound has been prepared before,6 but as far as we have been able to establish has not been appropriately characterised; 1H NMR (200 MHz, DMSO-d6) δ 11.84 (br s, 1H, COOH), 7.59 (s, 1H, NH(Aib)), 7.48 (s, 1H, NH(Aib)), 7.18 (s, 1H, NH(Aib1)), 1.40 (s, 9H, (CH3)3), 1.32 (s, 6H, CH3), 1.28 (s, 6H, CH3), 1.25 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 175.5, 173.5, 173.4, 155.1, 78.7, 55.8, 55.5, 54.8, 28.1, 24.8, 24.7, 24.6; HRMS (m/z): [M+Na]+ calcd. for C17H31N3O6Na, 396.2110. found, 396.2115; Anal. Calcd. for C17H31N3O6: C, 54.68; H, 8.37; N, 11.25. Found: C, 55.0; H, 8.4; N, 11.1.
Reaction SMILES: [CH:1]1([C:4]2[C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=[C:9]3[C:5]=2[CH2:6][C:7](=[O:23])[N:8]3[CH3:22])[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29](Br)[CH:30]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:24][C:25]1[CH:30]=[C:29]([C:12]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:5]3[C:9](=[CH:10][CH:11]=2)[N:8]([CH3:22])[C:7](=[O:23])[CH2:6]3)[CH:28]=[N:27][CH:26]=1
Reactant: Brc1cncc(Br)c1
Reactant: CN1C(=O)Cc2c1ccc(B1OC(C)(C)C(C)(C)O1)c2C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CN1C(=O)Cc2c1ccc(-c1cncc(Br)c1)c2C1CC1
Temperature: 120 °C

Procedure:
To 4-cyclopropyl-1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 40d (50 mg, 0.16 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 113 mg, 0.479 mmol), 1,2-dimethoxyethane (1.5 mL), and 2 M aqueous sodium carbonate (0.2 mL, 0.4 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (43.5 mg, 4.79 μmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 3 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 75%) to furnish 5-(5-bromo-pyridin-3-yl)-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 343.0451 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.18-0.26 (m, 2H), 0.78-0.88 (m, 2H), 1.87-1.99 (m, 1H), 3.25 (s, 3H), 3.64 (s, 2H), 6.82 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 8.62 (d, J=1.4 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:49])([F:48])[F:47])[CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44][CH3:45])=[C:40]([C:46]([F:47])([F:48])[F:49])[CH:39]=2)[C:35]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][N:52]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2ccc([N+](=O)[O-])cn2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.7 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-propionic acid (332 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200–400 mesh, 90/10 hexane s/ethyl acetate) afforded 3-cyclopentyl-2-(4-methylsulfanyl-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as an off-white solid: mp 109–110° C.; EI-HRMS m/e calcd for C21H22F3N3O3S (M+) 453.1334, found 453.1334.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.N#N.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1>C1COCC1>[OH:26][CH:25]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=1)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)[Mg]Cl
Agent: N#N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 4-iodobenzoate 17a (2.1 g, 8 mmol) in 10 mL of dry THF was added i-propyl magnesium chloride (2M in THF, 4.2 mL, 8.4 mmol) dropwise under N2 at −20° C. The solution was stirred for 30 min. The THF solution was then added slowly to a solution of 4-trifluoromethylbenzaldehyde 17b (1.1 mL, 8 mmol) in THF (20 mL) at −40° C. After 20 min, the reaction mixture was allowed to warm up slowly to room temperature. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/hexanes) to give compound 17c as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:11])[CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CC(N(C)C)=O>[NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([NH:32][CH2:33][CH2:34][OH:35])[N:5]=[C:4]([C:10]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[N:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:11])[CH:3]=1
Reactant: NCCO
Reactant: Nc1cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc(Cl)c1Cl
Solvent: CC(=O)N(C)C
Product: Nc1cc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)nc(NCCO)c1Cl
Temperature: 160 °C
Yield: 56.3 %

Procedure:
The compound prepared in Example 407 (0.065 g) and 2-aminoethanol (0.008 g) were suspended in dimethyl acetamide (3 mL) and heated at 160° C. for 30 minutes. The reaction mixture was heated at 200° C. for 1 hour. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material. The crude material was purified by flash column chromatography (eluant: 1-4% (9:1=methanol:ammonium hydroxide)/ethyl acetate) to furnish the title compound (0.037 g), possessing the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[I-].[K+]>CC(C)=O.O>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of 2-fluoro-4-hydroxy-benzonitrile (80 g, 0.58 mol), potassium carbonate (162 g, 1.17 mol) and benzyl bromide (76.4 mL, 0.64 mol) and potassium iodide (9.6 g, 0.058 mol) in acetone (600 mL) was stirred at RT and a significant exothermic reaction was observed. Stirring continued for 18 h without cooling. Reaction progress was monitored by TLC analysis. The reaction mixture was diluted with H2O (600 mL) and extracted with EtOAc (500 mL×2). The combined organic extracts were washed with saturated aqueous NaCl solution (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was triturated in cyclohexane (300 mL) and the crystalline solid was filtered off and washed to afford 4-Benzyloxy-2-fluoro-benzonitrile (118.2 g, 90%). 1H NMR (400 MHz, CDCl3): 7.51 (1H, dd, J=8.70, 7.48 Hz), 7.40 (5H, m), 6.86-6.76 (2H, m), 5.11 (2H, s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:10]1[CH:42]=[CH:41][C:13]([CH2:14][N:15]([C:30]2[N:31]=[CH:32][C:33]3[C:38]([C:39]=2[CH3:40])=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:16]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[C:5]([F:8])([F:7])[F:6])[CH3:2].[OH-].[Na+].Cl>C(O)C.O1CCCC1>[CH2:1]([O:3][C:4]([C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:30]2[N:31]=[CH:32][C:33]3[C:38]([C:39]=2[CH3:40])=[CH:37][CH:36]=[CH:35][CH:34]=3)[S:16]([C:19]2[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)(=[O:17])=[O:18])=[CH:41][CH:42]=1)([CH3:9])[C:5]([F:6])([F:7])[F:8])[CH3:2]
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(C(C)(OCC)C(F)(F)F)cc2)c2ncc3ccccc3c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(C)(c1ccc(CN(c2ncc3ccccc3c2C)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a mixed solution of ethyl 4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (102 mg, 0.17 mmol) prepared in Example 13 in ethanol (1 mL) and tetrahydrofuran (1 mL) was added 2 mol/L aqueous sodium hydroxide solution (340 μL, 0.68 mmol) at room temperature. The reaction solution was stirred at room temperature overnight, and then to the reaction solution was added 2 mol/L hydrochloric acid solution (1 ml). The mixture was extracted with chloroform three times. The organic layer was combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→10:1) to give 4-{[[4-(1-ethoxy-2,2,2-trifluoro-1-methylethyl)benzyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic acid (82 mg, 85%) as a colorless powder.
Reaction SMILES: C1COCC1.[CH:6]1([C:9](=[O:12])[CH2:10][CH3:11])[CH2:8][CH2:7]1.[C:13]([O:20][CH2:21][CH3:22])(=[O:19])[C:14]([O:16]CC)=O>C(OCC)C>[CH:6]1([C:9](=[O:12])[CH:10]([CH3:11])[C:14](=[O:16])[C:13]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][CH2:7]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)C1CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=O)C1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
165 mL of an 1 M solution of bis(trimethylsilyl)lithiumamid in THF (166 mmol, 1.10 eq.) were brought forward in 500 mL of diethyl ether and cooled down to −78° C. 14.8 g of 1-cyclopropylpropan-1-one 1-12-1 was dissolved in 100 mL of diethyl ether and added dropwise at −78° C. The mixture was stirred for one hour at −78° C. and then 24.5 mL of diethyl oxalate was added dropwise. The cooling bath was removed and the mixture was stirred for 24 hours at rt. 500 mL of aqueous 1M hydrogen chloride solution was added and the mixture was extracted with DCM, dried over a silicone filter sulfate and concentrated in vacuo to provide 27.2 g (137 mmol, 91%) of the target compound as crude product. The crude product was used for the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Cl)[CH:20]=1.CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1cccnc1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCc3cccnc3)c12
Yield: 90 %

Procedure:
To a round bottom flask with stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), 3-picolyl chloride (1.1 equiv.) potassium carbonate (5 equiv.) and 10 mL DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of solvent afforded 3-methyl-4-(pyridin-3-ylmethoxy)-benzofuran-2-carboxylic acid t-butyl ester as a thick oil in 90% yield.