Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].CN(C)C=O.Br[CH2:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:40]>C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8](=[O:25])[N:7]([CH2:38][C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)=[O:40])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C(CBr)c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nn(CC(=O)c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.4 %

Procedure:
A mixture of 4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile (0.7 g), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 1.75 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 2-bromo-1-(4-fluorophenyl)ethanone (0.35 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.6 g, 88%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][C:26](=[O:47])[C@H:27]([CH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][CH:41]=1)[NH:28][C:29](=[O:38])[C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:37]>COCCOC.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.O.CCOC(C)=O>[CH3:24][O:25][C:26](=[O:47])[C@H:27]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:44][CH:45]=1)[NH:28][C:29](=[O:38])[C:30]1[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 76.5 %

Procedure:
2-[N-(tert-Butyl)sulfamoyl]benzeneboronic acid (0.4 g) was dissolved in DME (10 mL). To this solution was added K2CO3 (0.1 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine methyl ester (0.1 g), Pd(Ph3P)4 (0.1 g) and water (0.2 mL). The mixture was heated at 80° C. overnight. After cooling, EtOAc and water were added to the mixture. The EtOAc phase was dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give 100 mg of the title compound. ESMS: m/z 585 ([M+Na]+).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][Si](C)(C)C)[N:5]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:17]([O:3][C:4]1[NH:5][C:6](=[O:10])[CH:7]=[CH:8][CH:9]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[Si](C)(C)Oc1cccc(O[Si](C)(C)C)n1
Solvent: CC#N
Product: O=C(Oc1cccc(=O)[nH]1)c1ccccc1
Yield: 33 %

Procedure:
A 1.60 g quantity of 2,6-bis(trimethylsilyloxy)pyridine was dissolved in 10 ml of acetonitrile and 5 ml of acetonitrile solution containing 1.30 g of benzoyl chloride was added dropwise to the solution. After the mixture was reacted at room temperature for one day, the reaction mixture was concentrated and subjected to silica gel chromatography using chloroform as an eluent to produce 0.50 g of the title compound in a yield of 33%.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.Cl[CH2:21][C:22]([CH2:24]Cl)=O.C(=O)([O-])[OH:27].[Na+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:24]=[C:22]([CH2:21][OH:27])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 98 °C
Reaction time: 22 h
Yield: 28.2 %

Procedure:
A solution of 10.9 g of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (K. Meguro, H. Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262) and 5.2 g of 1,3-dichloroacetone in 200 ml of dioxan was treated with 3.13 g of anhydrous sodium hydrogen carbonate and stirred at 98° C. for 22 h. After cooling the inorganic salts were filtered off, the filtrate was treated with 0.93 g of p-toluenesulphonic acid and stirred at 98° C. for 1.5 h. 74.5 ml of 1N aqueous sodium hydroxide solution and 2.5 g of active charcoal were added to this solution and the mixture was stirred at 80° C. for 2 h. After cooling the mixture was filtered over Dicalite and the filtrate was concentrated in a vacuum. The residue was taken up in dichloromethane and water and the aqueous phase was extracted four times with chloroform. The chloroform was evaporated in a vacuum. The residue (about 8 g) was crystallized from ethyl acetate. The crystals (7.3 g) were filtered off, dissolved in dichloromethane and chromatographed over 180 g of silica gel. The desired product was eluted with dichloromethane containing 2 to 4% ethanol and was recrystallized from ethyl acetate/ethanol 2:1. There were obtained 3.4 g of 8-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 203-204° C., which was converted into the hydrochloride, m.p. 252-254° C.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[NH:15][NH2:16].C(N(CC)CC)C.[C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>C1COCC1.O>[CH3:34][C:31]([CH3:32])([CH3:33])[O:30][C:28](=[O:29])[NH:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:2](=[O:3])[NH:16][NH:15][C:14]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)NN
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NNC(=O)NCCCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To 4-nitrophenyl chloroformate (1.008 g, 5.00 mmol) in THF (25.00 mL) at 0° C. was added ethyl carbazate (0.521 g, 5 mmol) and triethylamine (1.525 mL, 11.00 mmol). The mixture was stirred at 0° C. for 1 hour. Then N-Boc-1,4-butanediamine (1.148 mL, 6.00 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water was then added, extracted twice with ethyl acetate, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) giving ethyl 13,13-dimethyl-4,11-dioxo-12-oxa-2,3,5,10-tetraazatetradecan-1-oate (I-8a: 1.045 g, 66%) as a white solid. LC-MS (M+1) 319.1, t=0.92 minute.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH2:18]C)=[O:16])=[CH:14][N:8]3[NH:7][CH2:6][CH2:5]2)[CH:11]=1.[CH3:22]OS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:3]([F:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:20])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:22])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: CCOC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cn2c3c(c(F)c(Cl)cc3c1=O)CCN2C
Temperature: 120 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
To 1.69 g (5.5 mmol) of the compound (132) obtained in Example 24, 10 ml (109 mmol) of dimethylsulfate was added, and the solution was heated at 120° C. for 4.5 hours. After air-cooling, the solution was added to 90 ml of ice/water to which 15 g (109 mmol) of anhydrous potassium carbonate was added, and the solution was stirred for 1 hour. The solution was extracted with 200 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 60g, eluent solvent; chloroform: methanol=100:1) to obtain 600 mg of the subject compound (133) in a 36% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([NH:40][S:41]([C:44]1[S:48][C:47](Br)=[CH:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])[CH3:38].CCCCCC>C1(C)C=CC=CC=1>[C:37]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[N:11]=3)[CH:22]=2)=[CH:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:36])[CH3:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
A stirred mixture of 4-(4-fluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.14) (0.34 g, 0.57 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.19 g, 0.63 mmol), tetrakis(triphenyl-phosphine)palladium (0.039 g, 0.033 mmol) in toluene (5 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(4-fluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.37 g) as a white solid.
Reaction SMILES: [H-].[Na+].I[CH3:4].O.[N+:6]([C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1)([O-:8])=[O:7]>O1CCCC1>[CH3:4][O:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
16 g (60%) of sodium hydride was dispersed in 20 ml of tetrahydrofuran. To this, 100 ml of a solution in which 50 g of p-nitrobenzyl alcohol was dissolved in tetrahydrofuran, was added in drops while cooling with ice. The mixture was stirred for one hour at room temperature, and thereafter 56 g of iodomethane was added in drops while cooling with ice, and the mixture was further stirred for 3 hours at room temperature. To the reaction solution was added water, and a mixture was extracted with ethyl acetate. The extracted solvent was distilled off under reduced pressure, and the resulting product was purified by silica gel chromatography to obtain 40 g of p-methoxymethylnitrobenzene.
Reaction SMILES: C[O-].[Na+:3].[NH2:4][C:5]([NH2:7])=[S:6].C([O:10][C:11](=O)[CH:12]([NH:18][C:19](=[O:30])[C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=1)[C:13](OCC)=[O:14])C>C(O)C>[OH:10][C:11]1[C:12]([NH:18][C:19](=[O:30])[C:20]2[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=2)=[C:13]([OH:14])[N:7]=[C:5]([S-:6])[N:4]=1.[Na+:3]
Reactant: CCOC(=O)C(NC(=O)c1cc(C)c(OC)c(C)c1)C(=O)OCC
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1c(C)cc(C(=O)Nc2c(O)nc([S-])nc2O)cc1C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
1.5 equivalents of sodium methoxide (30% solution in methanol) were added to 20.6 g of thiourea in 900 ml of absolute ethanol. 91 g of 2-(4-methoxy-3,5-dimethyl-benzoylamino)-malonic acid diethyl ester were added in small portions, and then the mixture was stirred at 60° C. for 3 h. Then the mixture was cooled to room temperature, and the precipitate was filtered off with suction, washed with 100 ml ethanol and 100 ml diethyl ether and dried in vacuo. 78.2 g of the crude title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH2:23])=[C:21]([O:28][CH3:29])[CH:20]=1>>[ClH:1].[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][C:22]([NH:23][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)=[C:21]([O:28][CH3:29])[CH:20]=1
Reactant: COc1cc(Cl)c(OC)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c(OC)cc1Cl
Product: Cl

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-chloro-2,5-dimethoxyaniline (54 mg, 0.290 mmol) similar to Example 117 and isolated as a brown solid (58 mg, 73%). 1H NMR (CDCl3): 8.84-8.82 (m, 1H), 8.61-8.57 (m, 1H), 7.93-7.87 (m, 1H), 8.50 (bs, 1H), 7.66 (s, 1H), 7.49-7.45 (m, 1H), 7.02 (s, 1H), 7.01 (s, 1H), 4.07 (s, 3H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([CH2:40][CH2:41][C:42]([NH:44][NH2:45])=[O:43])[CH:33]=4)[N:16]3[C:15](=[O:46])[O:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[C:58](Cl)(Cl)=[O:59]>C(Cl)Cl>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@@H:13]2[C@@H:17]3[CH2:18][CH2:19][CH2:20][C@@H:21]([C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[C:32]4[CH:33]=[C:34]([CH2:40][CH2:41][C:42]5[O:43][C:58](=[O:59])[NH:45][N:44]=5)[CH:35]=[CH:36][C:37]=4[O:38][CH3:39])[N:16]3[C:15](=[O:46])[O:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:48])[CH:8]=1
Reactant: COc1ccc(CCC(=O)NN)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CCc2n[nH]c(=O)o2)cc1-c1ccc(C(F)(F)F)cc1[C@@H]1CCC[C@H]2[C@@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)OC(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46600 %

Procedure:
To 3-[2′-{(1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-3-oxohexahydro[1,3]oxazolo[3,4-a]pyridin-5-yl}-6-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]propanehydrazide (10 mg, 0.015 mmol) in DCM (2 mL) was added DIPEA (5.6 mg, 0.044 mmol) and phosgene (4.30 mg, 0.44 mmol). The reaction was stirred at room temperature for 30 minutes before the reaction was directly purified by column chromatography to yield (1R,5S,8aS)-1-[3,5-bis(trifluoromethyl)phenyl]-5-{2′-methoxy-5′-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-4-(trifluoromethyl)biphenyl-2-yl}hexahydro[1,3]oxazolo[3,4-a]pyridin-3-one (5 mg, 6.99 mmol). 1H NMR indicated that this compound exists as a pair of rotamers at 3:1 ratio: 1H NMR (500 MHz, CDCl3) δ9.23 (s, 1H), 7.88 (s, 1H), 7.80 (s, 2H), 7.79 (s, 1H, minor rotamer), 7.65 (s, 2H, major rotamer) 7.62 (m, 1H) 7.4 (d, J=7.8 Hz, 1H, major rotamer), 7.25 (d, J=7.8 Hz, 1H, minor rotamer), 7.09 (s, 1H), 7.02 (m, 2H), 5.58 (m, 1H, minor rotamer) 5.42 (m, 1H, major rotamer), 4.19 (m, 1H), 3.85 (s, 3H, minor rotamer), 3.80 (s, 3H, major rotamer), 3.0-2.85 (m, 4H), 1.98 (m, 2H), 1.5-1.6 (m, 4H). MS ESI calc'd. for C33H27F9N3O5 [M+H]+ 716.2. found 716.3. RTA (95% HS): 942 nM
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1)([O-:3])=[O:2].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C.O1CCCC1>[CH3:16][C:15]1([CH3:20])[O:13][C@@H:10]([CH2:9][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH2:11][O:12]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Solvent: C1CCOC1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC[C@H](Cn2ccc([N+](=O)[O-])n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 269.1 %

Procedure:
A solution of (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (1 g, 5.34 mmol) in 2,2-dimethoxypropane (8.5 mL, 0.63M) and tetrahydrofuran (10 mL, 0.53 M) was treated with para-toluenesulfonic acid monohydrate (0.11 g, 0.57 mmol). The reaction was stirred under nitrogen at 25° C. overnight. After this time, the reaction was concentrated in vacuo. Silica gel column chromatography (Aspire 40 g, 20-45% ethyl acetate/hexanes) afforded 1-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-3-nitro-1H-pyrazole (348.5 mg, 29%) as a viscous yellow/orange oil. The material was used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]>>[CH2:28]([O:30][C:31]([C:33]1[CH:34]=[C:35]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:22][C:21](=[O:23])[N:20]([CH3:24])[C:19]=4[CH:25]=3)[C:10]([F:11])([F:12])[F:13])=[C:4]([Cl:27])[CH:3]=2)[CH:36]=[CH:37][C:38]=1[F:39])=[O:32])[CH3:29]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Product: CCOC(=O)c1cc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
The title compound was prepared in analogy to Example 117 from 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 116, step 8) by Suzuki coupling with 3-ethoxycarbonyl-4-fluoro-phenylboronic acid [CAS Reg. No. 874219-36-0]. MS (m/e)=552.3 [M+H+], MS (m/e)=506.1 [(M-CH3CH2O−)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:14]([Zn]CC)C.ICI.[Cl-].[NH4+]>C(Cl)(Cl)Cl.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:14][CH:9]2[CH:10]([NH2:13])[CH2:11][CH2:12]3)=[CH:6][CH:7]=1
Reactant: NC1C=C(c2ccc(F)cc2)CC1
Reactant: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: ICI
Product: NC1CCC2(c3ccc(F)cc3)CC12

Procedure:
To a dichloromethane solution (0.28 mL) of 3-(4-fluorophenyl)cyclopent-2-enamine (55.8 mg, 0.315 mmol) synthesized in Reference Synthesis Example 223, diethylzinc (15% solution in toluene) (162 μL, 1.78 mmol) was added and then diiodomethane (127 μL, 1.58 mmol) was added at 0° C. with stirring and the resultant mixture was stirred at room temperature for 1 day. After completion of the reaction, saturated ammonium chloride aqueous solution was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was concentrated under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7].[I-].[Na+].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[ClH:1].[Cl:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:15]4[C:10](=[C:11]([O:16][CH3:17])[CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8][C:6]3=[O:7])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: COc1cccc2c1CCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cccc2c1CCC(=O)N2CCCN1CCN(c2cccc(Cl)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.2 %

Procedure:
A solution composed of 1-(3-chloropropyl)-5-methoxy-3,4-dihydrocarbostyril (39.1 g, 0.15 mole), sodium iodide (33.5 g, 0.23 mole) and acetonitrile (200 ml) was heated under reflux for 1 hour and then cooled to room temperature. To this solution was further added 1-(3-chlorophenyl)-piperazine (39.3 g, 0.2 mole) and sodium carbonate (21 g, 0,2 mole). The mixture was further stirred for 4 hours and then filtered while it was hot. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, made acidic with hydrochloric acid and then recrystallized from ethanol to give 31.2 g of 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-5-methoxy-3,4-dihydrocarbostyril hydrochloride as colorless flakes.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:26]2)(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)CC1CCc2cc(O)ccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.1 %

Procedure:
To a solution of pyridine (820 μL, 10.1 mmol) in dichloromethane (10 mL) cooled to 0° C. trifluoromethanesulfonic anhydride (1.56 mL, 9.28 mmol) was added. The resulting mixture was stirred for 5 min, and methyl (R/S)-(5-hydroxy-indan-1-yl)acetate (1.74 g, 8.44 mmol, from Step C) was added. The reaction mixture was warmed to ambient temperature, stirred for 1 hr and diluted with dichloromethane. The organic layer was washed with H2O, brine and dried over MgSO4. The mixture was filtered and concentrated in vacuo. Purification by flash chromatography (10% EtOAc/hexanes) on SiO2 gave 2.63 g of the title compound as a pale yellow liquid: 1H NMR (CDCl3) δ 1.83-1.88 (m, 1H), 2.47-2.55 (m, 2H), 2.78 (dd, 1H, J=6.0, 15.8 Hz), 2.92-3.01 (m, 2H), 3.62-3.65 (m, 1H), 3.76 (s, 3H), 7.09 (dd, 1H, J=2.3, 8.3 Hz), 7.16 (s, 1H), 7.25 (d, 1H, J=8.2 Hz).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:15]=1C#N.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:3]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:11]=[C:1]([C:15]2[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:14]=2[O:13][CH3:12])[N:2]=1
Reactant: COc1cc(OC)c(OC)cc1C#N
Reactant: O=P(Cl)(Cl)Cl
Reactant: CNC(=O)c1ccccc1C
Product: COc1cc(OC)c(-c2cc3ccccc3c(Cl)n2)cc1OC

Procedure:
3-(2,4,5-Trimethoxyphenyl)isoquinolin-1-one obtained by reacting N-methyl-o-toluamide (1.50 g) and 2,4,5-trimethoxybenzonitrile (1.93 g) according to Example 10-1 was reacted with phosphorous oxychloride (10 ml) according to Example 10-2, to give 1-chloro-3-(2,4,5-trimethoxyphenyl)isoquinoline, which was then reacted with N-ethylpiperazine (15 ml) at 120° C. for 5 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give the free compound of the title compound as a pale yellow oil.