Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br-].[C:17]([CH2:20][CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:19])=[O:18].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2(/[CH:14]=[CH:21]/[CH2:20][C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(F)cc2)CCCCC1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)C/C=C/C1(c2ccc(F)cc2)CCCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 18.6 %

Procedure:
To a stirred suspension of 1-(4-fluorophenyl)cyclohexanecarbaldehyde (160 mg, 0.776 mmol) and 2-carboxyethyl triphenylphosphonium bromide (483 mg, 1.164 mmol) in THF (7 mL) at −78° C. was added 1M lithium bis(trimethylsilyl)amide (2.172 mL, 2.172 mmol) in THF dropwise, and the mixture was stirred for 30 mins at −78° C., and 30 mins at a temperatures in the range of from −78° C. to room temperature. Next, the mixture was stirred overnight at room temperature. After addition of 3 mL of 1N HCl, the mixture was extracted with EtOAc (2×), and the combined extracts were washed with brine, dried over Na2SO4 and evaporated to give an oily residue. The residue was purified by Combiflash (24 g silica gel) eluting with 5:95 followed by 3:7 EtOAc-hexane to give (E)-4-(1-(4-fluorophenyl)cyclohexyl)but-3-enoic acid (37.7 mg, 0.144 mmol, 18.53% yield) along with the unreacted starting material (41.5 mg). 1H NMR (400 MHz, CCl3D) δ ppm 7.28-7.33 (2H, m), 6.93-6.99 (2H, m), 5.97 (1H, dt, J=11.64, 1.76 Hz), 5.58 (1H, dt, J=11.64, 7.25 Hz), 2.59 (2H, dd, J=7.25, 1.76 Hz), 1.86-1.96 (2H, m), 1.54-1.76 (8H, m), 1.22-1.33 (2H, m).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][N:9]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])[CH3:3].[CH:23]1(Br)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[C:2]([O:5][C:6](=[O:7])[CH:8]([NH2:9])[CH:23]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: BrC1CCCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(N)C1CCCCCC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
To a soln. of N-(diphenylmethylene)glycerine tert-butyl ester (6.83 mmol) and (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) in 45 mL toluene were sequentially added cycloheptyl bromide (8.2 mmol) and CsOH H2O (34.2 mmol) at −10° C. The reaction mixture was stirred at −10° C. for 10 min and then at RT for 4 days. Another portion of (R)-4,4-dibutyl-2,6-bis(3,4,5-trifluorophenyl)-4,5-dihydro-3H-dinaphthol[7,6,1,2-cde]azepinium bromide (6.84 μmol) was added and stirring was continued at RT for another 24 h. The reaction was quenched with water and extracted 3 times with DCM. The comb. org. layers were combined, conc. and the residue was redissolved in 100 mL THF. A soln. of 100 mL aq. 0.5 M citric acid soln. was added and the mixture was stirred at RT for 4 h. The mixture was concentrated to half of its volume and extracted twice with Et2O. The aqueous layer was basified with solid NaHCO3 and extracted 3 times with DCM. The comb. org. layers were dried over MgSO4 and conc. in vacuo to obtain the desired product as yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3.C1C2NC3C(=CC=CC=3)C=2C=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: COc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: Oc1ccc2c(c1)c1ccccc1n2-c1ccccc1
Yield: 91.8 %

Procedure:
Demethylate 3-methoxy-9-phenylcarbazole (E-4) in the same manner as in Synthesis of Carbazole Derivative 1 to obtain 3-hydroxy-9-phenylcarbazole (E-5) having a colorless needle-like form with a yield of 91.8%; etherify the thus obtained 3-hydroxy-9-phenylcarbazole having a colorless needle-like form with 8-bromooctanol in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 3-(8-hydroxyoctyloxy)-9-phenyl carbazole (E-6) having a colorless needle-like form with a yield of 84.3%; tosylate, thioacetylate, and hydlolyze the thus obtained 3-(8-hydroxyoctyloxy)-9-phenyl carbazole in the same manner as in Synthesis of Carbazole Derivative 2 to obtain 3-(8-meracaptooctyloxy)-9-phenyl carbazole (E-9) (hereinafter referred to as carbazole derivative 3) having a colorless needle-like form represented by the chemical structure 9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: BrCCCBr
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCBr
Yield: 62.1 %

Procedure:
A suspension of ethyl 5-chloro-1H-indole-2-carboxylate (40 g, 0.18 mol), 1,3-dibromo-propane (181 g, 0.90 mol) and potassium carbonate (49.68 g, 0.36 mol) in 500 mL of acetone was heated under reflux for 16 hours. The mixture was concentrated in vacuo to remove the solvent and the residue was diluted with 1000 mL of water, then extracted with ethyl acetate (300 mL×2). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash silica gel chromatography (EtOAc:PE=1:10) to afford 38.5 g of ethyl 1-(3-bromopropyl)-5-chloro-1H-indole-2-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]([CH2:13][C:14](OC)=[O:15])[C:10](=[O:18])[N:9]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.[Pd]>[O:18]=[C:10]1[N:11]2[CH2:13][C:14](=[O:15])[NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([C:12]=32)[N:9]1[CH2:19][C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cn1c(=O)n(CC(=O)OC)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Reaction time: 2 h

Procedure:
A mixture of dimethyl 2,2′-(4-nitro-2-oxo-1H-benzimidazole-1,3-diyl)diacetate from Step B (270 mg, 0.84 mmol) and 10% Pd/C (50 mg) in MeOH (10 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 2 h, the reaction was filtered through a Celite pad and concentrated in vacuo. The crude solid was dissolved in toluene (3 mL) and p-toluenesulfonic acid monohydrate (2 mg, 0.011 mmol) was added. The mixture was heated at reflux for 30 min and then concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [N+:1]1([O-])[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]([CH3:8])[CH:2]=1.[C:10]([O:13]C(=O)C)(=[O:12])[CH3:11]>O>[C:10]([O:13][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][C:3]=1[CH3:8])(=[O:12])[CH3:11]
Reactant: Cc1cc[n+]([O-])cc1C
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)OCc1ccncc1C
Yield: 30 %

Procedure:
The N-oxide was added portionwise to 60 mL of acetic anhydride and the resulting dark orange solution was heated (water-bath) at about 90° C. for 1 h. The excess acetic anhydride was then distilled off under reduced pressure and the material boiling at 90°-120° C./0.1 torr (39.0 g) was collected. Chromatography of this oil (silica gel/ethyl acetate-pet.ether=2:3) afforded pure 4-acetoxymethyl-3-methylpyridine (19.0 g, 30%) as an oil: ir (neat) 1745 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[CH2:13]([N:15]([CH2:30][CH3:31])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=O)=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:14]>>[CH2:30]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[NH:23][C:24]([CH:28]=[C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:8][C:7]2=[O:12])=[CH:25][C:26]=1[CH3:27])=[O:21])[CH3:31]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: CCN(CC)CCCNC(=O)c1[nH]c(C=O)cc1C
Product: CCN(CC)CCCNC(=O)c1[nH]c(C=C2C(=O)Nc3ccc(OC)cc32)cc1C
Yield: 39 %

Procedure:
5-Methoxy-1,3-dihydroindol-2-one (82.5 mg, 0.5 mmol) was condensed with 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (3-diethylaminopropyl)amide to give 80 mg (39%) of the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:23]O>>[CH3:23][O:21][C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 7.5 °C

Procedure:
Thionyl chloride (60 ml; 0.83 mol) was added drop-wise to a mixture of (4-benzyloxy-phenyl)acetic acid (100 gm; 0.4132 mol) and methanol (300 ml) under constant stirring while maintaining the temperature at 5-10° C. After complete addition, the reaction mixture was stirred for 5-6 hours at room temperature. After completion of the reaction, white crystalline solid was isolated by filtration to yield (4-benzyloxy-phenyl)-acetic acid methyl ester. Yield: 104 g, Efficiency: 98.31%.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:11](=[O:13])[O:10][CH2:9][C:8]=2[CH:14]=1.Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]2[N:12]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:11](=[O:13])[O:10][CH2:9][C:8]=2[CH:14]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2ccc(Br)cc2CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)OCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of sodium hydride (55 wt % in mineral oil, 1.36 g, 31.2 mmol) in N,N-dimethylformamide (37 ml) was added 6-bromo-1,4-dihydro-2H-3,1-benzoxazin-2-one (5.93 g, 26.0 mmol) in N,N-dimethylformamide (37 ml) at 0° C. The mixture was stirred at room temperature for one hour, then 2-(chloromethoxy)ethyltrimethylsilane (4.77 g, 28.6 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with water (four times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=90/10 to 60/40) to afford 6-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4-dihydro-2H-3,1-benzoxazin-2-one as a pale yellow solid (7.96 g, 22.2 mmol, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)([Cl:14])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: O=S(Cl)Cl
Product: Cc1cc(C(=O)Cl)ccc1Br
Yield: 101.3 %

Procedure:
1 g 4-bromo-3-methyl-benzoic acid in 20 g thionylchloride was refluxed 1 h. The reaction was evaporated to give 1.1 g desired product.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].CO[C:7](=N)[CH:8]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[C:13]=1[Cl:20])[CH2:9][CH3:10].Cl>C(O)C>[Cl:20][C:13]1[C:14]([C:18]#[CH:19])=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH:8]([C:7]1[NH:3][CH2:2][CH2:1][N:4]=1)[CH2:9][CH3:10]
Reactant: C#Cc1cccc(OC(CC)C(=N)OC)c1Cl
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: C#Cc1cccc(OC(CC)C2=NCCN2)c1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ethylene diamine (30 mg, 0.5 mmol) was dissolved in dry ethanol (1.9 ml). The solution was cooled to 0° C. and 2-(2-chloro-3-ethynyl-phenoxy)-butyrimidic acid methyl ester (100 mg, 0.4 mmol) was added. After 1 h a solution of concentrated HCl (few drops) in ethanol (0.9 ml) was added and the reaction mixture was stored overnight at 0° C. The reaction mixture was then diluted with a further portion of ethanol (1.6 ml) and heated to 75° C. for 5 h. After cooling to room temperature a precipitate was formed that was filtered and discarded. The filtrate was evaporated and treated with CHCl3. Another precipitate was formed, which was filtered again. Finally, the CHCl3 phase was evaporated to yield 2-[1-(2-chloro-3-ethynyl-phenoxy)-propyl]-4,5-dihydro-1H-imidazole; 1H-NMR (CDCl3) 1.08 t, 3H, 1.9-2.1 m, 2H, 3.10-3.9, vbr s, 4H, 3.39, s, 1H, 4.85 dd, 1H, 7.05 d, 1H, 7.1-7.2, m, 2H.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21]C(C)C)=[CH:15][CH:14]=2)=[CH:9]1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[S:8]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[CH2:20][NH:21][C:33]([NH:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:34])=[CH:15][CH:14]=2)=[CH:9]1
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)NCC(C)c1ccc(-c2ccsc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(CNC(=O)NC1CCCCC1)c1ccc(-c2ccsc2)cc1

Procedure:
The title compound was prepared from 2-(4-(3-thienyl)phenyl)propyl-2-propyl amine trifluoroacetate (prepared in example 1) and cyclohexyl isocyanate in a manner analogous to the procedure described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[CH:7]=[C:6]1[CH2:18][CH2:19][CH3:20].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(C1C2C(=CC(C(OC)=O)=CC=2)N(CC2C=CC=CC=2OC)C=1CCC)(=O)C(C)C>>[Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[C:7]([C:32](=[O:33])[CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:6]1[CH2:18][CH2:19][CH3:20]
Reactant: CCCc1cc2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Reactant: O=C(Cl)Cc1ccccc1
Agent: CCCc1c(C(=O)C(C)C)c2ccc(C(=O)OC)cc2n1Cc1ccccc1OC
Product: CCCc1c(C(=O)Cc2ccccc2)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Yield: 45 %

Procedure:
Methyl 1-(2-chlorobenzyl)-3-phenylacetyl-2-propylindole-6-carboxylate (230 mg) was prepared from methyl 1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (380 mg) and phenylacetyl chloride (189 mg) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH2:14][CH2:15][CH3:16])[CH3:6].O.C(OCC)C>ClC(Cl)(Cl)Cl>[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([Br:2])[CH2:14][CH2:15][CH3:16])[CH3:6]
Reactant: CCCC(O)CCCCC(=S)OCC
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCC(Br)CCCCC(=S)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 200 %

Procedure:
64.8 grams (0.24 mole) of phosphorus tribromide at 0° C were dropped into a solution of 140.0 grams (0.6 mole) of 6-hydroxy-8-methylthiooctanoic acid ethyl ester (VIb) in 150 ml of tetrachloromethane, the mixture stirred for 2 hours at 0° C. and allowed to stand for 10 hours at room temperature. There were dropped into the reaction mixture, cooled to 0° C., 150 ml of water and subsequently 600 ml of diethyl ether. The organic phase was separated off, washed with saturated aqueous sodium bicarbonate solution, dried with sodium sulfate and the solvent removed in a vacuum. After vacuum distillation of the residue there were obtained 135.0 grams (76% of theory) of 6-bromo-8-methylthiooctanoic acid ethyl ester as a yellowish oil having a boiling point of 140° C. to 145° C. at 1 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:26])(=[O:25])[N:20]=CN(C)C)=[CH:15][CH:14]=3)[C:11]([CH3:27])=[C:10]([C:28](N(OC)C)=[O:29])[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]([Mg]Br)[CH3:36]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:20])(=[O:26])=[O:25])=[CH:17][CH:18]=3)[C:11]([CH3:27])=[C:10]([C:28](=[O:29])[CH2:35][CH3:36])[C:9]=2[CH3:34])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1c(C)c(-c2ccc(Cl)cc2)n(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c1C
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1c(C)c(-c2ccc(Cl)cc2)n(-c2ccc(S(N)(=O)=O)cc2)c1C

Procedure:
To a stirred solution of 5-(4-Chlorophenyl)-1-(4-(N-((dimethylamino)methylene) sulfamoyl)phenyl)-N-methoxy-N,2,4-trimethyl-1H-pyrrole-3-carboxamide (step 3, 0.750 g, 1.49 mmol) in anhydrous THF (50 ml) at 0° C., ethyl magnesium bromide (Grignard reagent, 0.994 g, 7.4 ml, 7.46 mmol) was added dropwise and reaction mixture was heated to reflux for 1 h. The completion of reaction was monitored by TLC. After cooling, reaction mixture was quenched by addition of solution of saturated ammonium chloride (10 ml) and extracted with ethyl acetate (1×50 ml). Combined organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 0.4% methanol in dichloromethane as an eluent to yield the title compound which was finally purified by preparative HPLC (0.062 g, 10%)
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9]1.[C:15]1([C:21](Cl)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:21]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[CH:9]1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.7 %

Procedure:
Triethylamine (3.05 ml, 21.86 mmol) was added to a solution of 1H-imidazole-4-carbaldehyde (2 g, 20.82 mmol) and triphenylmethyl chloride (5.80 g, 20.82 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase was washed dried over sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallised from dichloromethane and hexanes to afford the title compound as a cream solid (4.7 g, 67% yield).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.Br[CH2:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>>[CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:19]=[N:18][N:17]([CH2:22][C:23]5[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=5[C:25]#[N:26])[CH:16]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Reactant: N#Cc1ccccc1CBr
Product: Cc1nnc(-c2ccc3occ(-c4cnn(Cc5ccccc5C#N)c4)c3c2)o1
Yield: 91 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using 2-(bromomethyl)benzonitrile instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 91%) was obtained as colorless crystals.
Reaction SMILES: O([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])=[O:9])C1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][NH:27][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[O:9])=[CH:20][CH:19]=1
Reactant: COc1ccc(NCCN)cc1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(NCCNC(=O)N2CCCC2=O)cc1
Yield: 91.4 %

Procedure:
A mixture of 4.0 g (19.5 mmol) of 1-phenoxycarbonyl-2-oxopyrrolidine and 3.4 g (20.4 mmol) of 2-(4-methoxyphenylamino)ethylamine was heated at 115°-120° C. for 4 hr. The reaction solution was refined by silica gel column chromatography, whereby 4.94 g (87.0%) of the objective product (Ia-1) was obtained from the eluate with toluene-ethyl acetate (3/1 v/v). The needles melting at 83.5°-84.5° C. were obtained by recrystallizing from ethanol.
Reaction SMILES: [N].N1C2C(=CC=CC=2)C=N1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[N:15][NH:16]2.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Cl:11][C:12]1[C:13]2[C:17]([CH:18]=[CH:19][CH:20]=1)=[N:16][N:15]([CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1)[CH:14]=2
Reactant: Clc1cccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [N]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Clc1cccc2nn(C3CCCCO3)cc12

Procedure:
Scheme 3 shows the synthesis of 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 10 starting by cyclization of 3-chloro-2-methylaniline 11 with potassium acetate, acetic anhydride, and isoamyl nitrite to yield 4-chloro-1H-indazole 12. The indazole nitrogen of 4-chloro-1H-indazole 12 was protected as tetrahydropyranyl (THP) with 3,4-dihydro-2H-pyran, and pyridinium p-toluenesulfonate in dichloromethane to yield 4-chloro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole 13 and a minor amount (about 10%) of the THP regioisomer, 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. The mixture was reacted with PdCl2(PPh3)2, tricyclohexylphosphine, bis(pinacolato)diboron, and potassium acetate in DMSO and heated to 130° C. for 16 hours to give 10, containing a minor amount (about 10%) of the THP regioisomer, 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:13]([N:14]([CH3:23])[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO>[F:3][C:4]1[C:13]([N:14]([CH3:23])[C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(N(C)C(=O)c2ccccc2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)c1ccccc1)c1cccc(C(=O)O)c1F
Temperature: 60 °C
Yield: 92.6 %

Procedure:
Sodium hydroxide (0.26 g, 6.50 mmol) was dissolved in methanol (30 ml), and methyl 2-fluoro-3-(N-methylbenzamido)benzoate (1.42 g, 4.94 mmol) was added thereto. The mixture was heated for 3 hours at 60° C. The mixture was cooled to room temperature, and then the solvent was concentrated under reduced pressure. The concentration residue was dissolved in water, and washed with methylene chloride. While the aqueous layer was cooled, the pH thereof was adjusted to 2 to 3 with a 1N hydrochloric acid, and a solid precipitated during continued agitation. The resultant solid was filtered, washed with water, and dried at 50° C., as a result of which 1.25 g (yield: 94%) of the indicated compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:12][CH2:11][CH2:10][O:7]2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Brc1ccc(C2OCCO2)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-bromobenzaldehyde (1 Scheme 18, 9.5 g, 51.4 mmol) and ethylene glycol (6.4 g, 113 mmol) and p-toluenesulfonic acid (120 mg) in benzene (200 mL) was refluxed in a Dean Stark apparatus for 4 h. The reaction mixture was cooled to room temperature, and the solution was extracted with cold water/ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), and concentrated to give a colorless oil (11.4, 95%); 1H NMR (300 MHz, CDCl3) δ 4.01-4.14 (4 H), 5.78 (s, 1 H), 7.37 (d, J=8.34 Hz, 2 H), 7.53 (d, J=8.34 Hz, 2 H); HRMS (EI) calcd for C9H9BrO2 227.9786, 229.9766, found 227.9771, 229.9754.