Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:4]1=[O:22])[CH3:2].[OH:23]OS([O-])=O.[K+].[OH2:29]>C1COCC1.O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([CH2:13][S:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:23])=[O:29])[C:4]1=[O:22])[CH3:2]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CCn1c(=O)c(CSc2ccc(C)cc2)nc2ccccc21
Agent: [K+]
Solvent: C1CCOC1
Product: CCn1c(=O)c(CS(=O)(=O)c2ccc(C)cc2)nc2ccccc21
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To 280 mg (0,90 mM) of 1-ethyl-3-{[(4-methylphenyl)thio]methyl}quinoxalin-2(1H)-one and 75,8 mg (0,90 mM) in a mixture of 6 ml of THF/water (50/50) were added portion wise 1,1 g (1,8 mM) of oxone. The reaction mixture was maintained under stirring for 30 min and water was added. A precipitate was filtrated and washed thoroughly with water, to give, after drying, 154 mg of 1-ethyl-3-{[(4-methylphenyl)sulfonyl]methyl}quinoxalin-2(1H)-one as a solid. Yield: 50%.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]([NH2:9])[CH2:4]1.C(N(CC)C(C)C)(C)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(#N)C>[CH3:2][C:3]1([CH3:10])[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:21](=[O:22])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4]1
Reactant: CC1(C)CCCC(N)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCCC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3,3-dimethylcyclohexyl)amine hydrochloride (10.0 g, 0.060 mol) and N,N-diisopropylethylamine (15.8 g, 0.12 mol) in acetonitrile (125 mL) at ice bath temperature was added a solution of benzyl chloroformate (11.4 g, 0.067 mol) in acetonitrile (25 mL), dropwise. The mixture was stirred overnight, gradually warming to ambient temperature, and concentrated in vacuo. The residue was partitioned between ethyl acetate/5% citric acid solution and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, adsorbed onto silica gel and purified by flash chromatography (CH2Cl2/hexanes) affording the title compound as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ ppm: 0.85 (s, 6H), 0.92-1.02 (m, 3 H), 1.25 (d, 1 H), 1.36-1.52 (m, 3 H), 1.76 (br. d, 1 H), 3.36-3.44 (m, 1 H), 4.96 (s, 2H), 7.10 (d, 1 H), 7.27-7.36 (m, 5H).
Reaction SMILES: [CH:1](=[N:8][CH:9]([CH2:15][CH2:16][C:17]#[N:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Li+].Cl[CH:26]([F:28])[F:27]>O1CCCC1>[CH:1](=[N:8][C:9]([CH:26]([F:28])[F:27])([CH2:15][CH2:16][C:17]#[N:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCC#N)N=Cc1ccccc1
Reactant: FC(F)Cl
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(N=Cc1ccccc1)C(F)F
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
To the solution of crude ethyl 2-benzylideneamino-4-cyanobutyrate (4) obtained above, was added 0.35 L of tetrahydrofuran (THF) and 28.0 g of lithium t-butoxide (1.6 eq) at 5° C. The mixture was stirred at ˜5° C. for 0.5 h, at 20-25° C. for 2 h, and then warmed to 40° C. Chlorodifluoromethane (34.2 g, 1.8 eq) was slowly bubbled into the reaction mixture, and the temperature maintained at 40-50° C. When the exothern subsided, bubbling was continued for another ˜15 min. and then stopped. The reaction mixture was stirred at 40° C. for 1-2 h. After the reaction was complete, the solvent was removed under reduced pressure. The crude product 5 was ready for use in the next step.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].[CH3:16][N:17]=[C:18]=[O:19]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:16][NH:17][C:18]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:19]
Reactant: COc1cc(OC)c2ccccc2c1O
Reactant: CN=C=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CNC(=O)Oc1c(OC)cc(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.00 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran was added 0.335 g of methyl isocyanate followed by 0.12 g of 4-dimethylaminopyridine. The solution was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate, washed with dilute hydrochloric acid and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue chromatographed on silica gel, eluting with methylene chloride, giving 1-methylcarbamoyloxy-2,4-dimethoxynaphthalene, m.p. 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[NH2:28][C:29]1[C:33](C(N)=O)=[CH:32][NH:31][N:30]=1.NC1[C:42]([C:43]([NH2:45])=[O:44])=CNN=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:28][C:29]4[N:30]([C:14]=2[CH2:15]3)[N:31]=[CH:32][C:33]=4[NH:45][C:43](=[O:44])[CH3:42])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NC(=O)c1c[nH]nc1N
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cnn2c3c(cnc12)C1CCCC(C3)N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-4-pyrazolecarboxamide hemisulfate salt.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH2:18]([OH:25])[C:19]([NH2:24])([CH2:22][OH:23])[CH2:20][OH:21]>CCO.CCOCC>[ClH:1].[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]([CH2:16][NH:24][C:19]([CH2:22][OH:23])([CH2:20][OH:21])[CH2:18][OH:25])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: NC(CO)(CO)CO
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Solvent: CCOCC
Solvent: CCO
Product: Cl
Product: OCC(CO)(CO)NCc1c2ccccc2c(Cl)c2ccccc12

Procedure:
Using the reductive amination procedure described in 1, 10 -chloroanthracene-9-carbaldehyde (Aldrich) and tris(hydroxymethyl)aminomethane (Aldrich) gave 2-((10-chloro-9-anthracenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol hydrochloride, mp 251°-254° (dec), (EtOH/Et2O), (C,H,Cl,N).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].O.[Sn](Cl)(Cl)(Cl)[Cl:16]>Cl.O>[ClH:16].[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: Cc1ccc(N)c(Br)c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)c(Br)c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
To a stirred, cooled (-5° C.) solution of 2-bromo-4-methylaniline (50.54 g, 0.272 mol.) in concentrated HCl solution (200 mL) was added sodium nitrite (18.9 g, 0.274 mol.) in water (200 mL) dropwise at such a rate as to maintain temperature below 5° C. After complete addition, the mixture was further stirred at 5° C. for 30 minutes. A solution of tin chloride monohydrate (185.4 g, 0.822 mol.) in concentrated HCl (total volume 400 mL) was added dropwise again maintaining temperature below 5° C. After complete addition and 30 minutes of further stirring, the mixture was placed in the freezer overnight. The light brown solid which precipitated was isolated by filtration and washed with cold brine followed by a solution of petroleum ether/diethyl ether (2/1 by volume). This solid was slowly added to an ice cooled mixture of 50% sodium hydroxide solution/ethyl acetate. The mixture was extracted with ethyl acetate and the organic phase dried over magnesium sulfate. After filtration, the solution was concentrated to 400 mL total volume, diluted with diethyl ether (1.5 L) and treated with dry HCl. The product, 2-bromo-4-methylphenylhydrazine hydrochloride (52.4 g) was isolated as a light brown solid and used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=1[CH3:12])[CH3:3].[CH3:13][C:14]([CH3:17])([O-])C.[K+].Cl.ClC(C)C[NH2:23]>CN(C)C=O>[NH2:23][CH:14]([CH3:17])[CH2:13][O:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[C:6]([CH3:12])[CH:7]=1
Reactant: Cc1cc(CO)oc1CN(C)C
Reactant: CC(Cl)CN
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(COCC(C)N)oc1CN(C)C
Reaction time: 0.33 h
Yield: 14.4 %

Procedure:
A mixture of 5-(dimethylaminomethyl)-4-methyl-2-furanmethanol (1.35 g) and potassium tert-butoxide (0.9 g) in dry dimethylformamide (3 ml) at 0° was treated with a solution of 2-chloropropylamine, hydrochloride (0.4 g) in dry dimethylformamide (2 ml). After 20 minutes at ambient temperature, the mixture was quenched with oxalic acid (2 g) and the solvent removed in vacuo. Excess anhydrous sodium carbonate was added and the product extracted into chloroform. The chloroform extract was purified by filtration and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica, methanol: 0.88 ammonia 19:1) affording the title compound (0.1 g).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([O:12]CCCCC)=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].Cl>[OH-].[Na+]>[CH2:1]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1cc(C(=O)OCCCCC)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of n-pentyl 3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoate (4.5 g) and 1N sodium hydroxide (70 ml) was heated on a steam bath for 1 hour. After cooling, the reaction mixture was adjusted to a pH of 2.5 by addition of 4N hydrochloric acid. The precipitated 3-n-pentylamino-4-phenoxy-5-sulphamyl-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. After drying in vacuo, the compound was obtained with a melting point of 223°-224° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:32])=[O:31]
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 3 ml of dichloromethane with 69 mg (0.6 mmol) of methanesulfonic acid chloride and 61 mg (0.6 mmol) of triethylamine and stirred together for 1.5 hours at room temperature. Then, it is washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue is chromatographed via flash chromatography (5 g of Isolute) with a gradient of cyclohexane:ethyl acetate=100:0 to 50:50 as an eluant. 80 mg (30% of theory) of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is obtained as a resin. (MS: m/e 542)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1CCN)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)[CH3:19].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH2:19][CH2:18][NH:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Cc1ccccc1CCN
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1cccc(CCNS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
A mixture of [2-(2-amino-ethyl)-phenyl]-acetic acid tert-butyl ester (422.5 mg, 1.795 mmol), triethylamine (908 mg, 8.977 mmol), and methanesulfonyl chloride (226.2 mg, 1.975 mmol) in CH2Cl2 (20 mL) was combined and stirred at 0° C. for 18 h. The organic solution was washed consecutively with dilute HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title sulfonamide (535 mg). MS 331 (M+18).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:26]=[CH:25][CH:24]=[CH:23][C:5]=2[NH:6][CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:27]I>CN(C)C=O.C(OCC)(=O)C>[CH3:27][N:6]1[C:5]2[CH:23]=[CH:24][CH:25]=[CH:26][C:4]=2[NH:3][C:2]([CH3:1])=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: CCOC(=O)C1=C(C)Nc2ccccc2NC1c1cccc([N+](=O)[O-])c1
Reactant: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(C)Nc2ccccc2N(C)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A reaction mixture containing 2,5-dihydro-4-methyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester (1,5 g., 4.25 mmole) in dry dimethylformamide (5 ml.) is treated with methyl iodide (581 mg., 5.5 mmole) and then allowed to stir at room temperature for 24 hours. The reaction mixture is diluted with ethyl acetate and is washed with sodium bicarbonate, water, and brine. After drying over magnesium sulfate, the solvent is evaporated and the residue is purified by flash chromatography on silica gel (30% ethyl acetate in hexanes). The yellow foam obtained (701 mg.) is crystallized from ether-hexanes to provide yellow crystalline 2,5-dihydro-1,4-dimethyl-2-(3-nitrophenyl)-1H-1,5-benzodiazepine-3-carboxylic acid, ethyl ester; m.p. 113°-115.5°. TLC (silica gel; ethyl acetate:hexanes, 1:1) Rf =0.5.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[N+:9]([C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH:14]=[CH:15][NH:16]2)([O-:11])=[O:10].C(#N)C>C(Cl)Cl>[Cl:1][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[CH:20][C:12]=2[N+:9]([O-:11])=[O:10])[NH:16][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Solvent: CC#N
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
N-Chlorosuccinimide (1.23 g, 9.25 mmol) is added to a solution of 4-nitroindole (1.5 g, 9.25 mmol, Aldrich) in methylene chloride (75 mL). The resulting mixture is heated to reflux for 16 hours. Acetonitrile (10 mL) is added to the mixture and heating is continued for another 16 hours. The reaction is cooled to room temperature and the methylene chloride is removed by rotary evaporation. The residue is taken up in ethyl acetate and washed with water. The ethyl acetate layer is dried over magnesium sulfate, filtered and the solvents removed by rotary evaporation. The crude material is purified via silica gel column chromatography using 30% ethyl acetate/hexane as the eluent. The product containing fractions are combined and the solvents removed by rotary evaporation to yield 1.35 g of 3-chloro-4-nitroindole as an orange solid (74%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br.FC(F)(F)C1C=CC(C2(C#N)CCCC2)=CC=1>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C:13]2([C:14]#[N:15])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: BrCCCCBr
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: N#CC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: N#CC1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCC1

Procedure:
1-(3,5-bis(trifluoromethyl)phenyl)cyclopentanecarbonitrile (455) was synthesized from 2-(3,5-bis(trifluoromethyl)phenyl)acetonitrile (454) and 1,4-dibromobutane following the procedure described for 1-(4-trifluoromethyl-phenyl)-cyclopentanecarbonitrile (237).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[CH2:26]=O>CC(O)C>[OH:8][C:6]1[C:5]([CH2:26][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: C=O
Reactant: C1COCCN1
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Solvent: CC(C)O
Product: COC(=O)Cc1c(CN2CCOCC2)c(O)cc(O)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
Compound 1 (0.19 g, 0.74 mmol) obtained in Example 1 was dissolved in 2-propanol (3.0 mL), and morpholine (0.065 mL, 0.75 mmol) and aqueous 37% formalin solution (0.063 mL, 0.78 mmol) were added thereto and stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and then purified through preparative thin-layer chromatography (methanol/chloroform=1/9) to obtain Compound 14 (0.091 g, 35%) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](O)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[NH:37]([CH2:41][CH2:42][OH:43])[CH2:38][CH2:39][OH:40].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:40][CH2:39][CH2:38][N:37]([CH2:41][CH2:42][OH:43])[C:24]([C:21]1[N:13]2[C:12]([CH2:11][N:10]([C:8]([C:6]3[CH:5]=[CH:4][C:3]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:34])[F:35])=[C:2]([CH3:1])[CH:7]=3)=[O:9])[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14]2)=[CH:23][CH:22]=1)=[O:25]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reactant: OCCNCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(CCO)CCO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step F (0.50 g, 1.02 mmol) and diethanolamine (0.13 g, 1.24 mmol) in N,N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole (0.15 g, 1.11 mmol) and 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (0.22 g, 1.15 mmol) followed by N,N-diisopropylethyl amine (0.27 mL, 1.55 mmol). The reaction mixture was stirred overnight, then diluted with ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. Purification by flash chromatography on silica gel using a solvent system of 5% methanol in chloroform provided the title compound (0.46 g) as a white foam.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(N(CC)CC)C.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]([O:14][C:12]([N:19]1[CH2:23][CH2:22][C@@H:21]([O:24][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:20]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 8 h

Procedure:
A round-bottomed flask was charged with p-toluenesulfonyl chloride (16.01 g, 83.98 mmol, 1.5 equiv.) and 150 ml of anhydrous DCM. The solution was cooled to an ice-water bath and evacuated and purged with nitrogen. To this solution was added a solution of (3R)-(−)-N—BOC-3-hydroxypyrrolidine (purchased from Aldrich) (10.47 g, 55.99 mmol) in 50 mL of DCM, followed by DMAP (0.66 g) and triethylamine (16.2 mL). The solution was stirred under nitrogen overnight from 0° C. to rt. TLC (5% MeOH in DCM) showed the completion of the reaction. The reaction was quenched by addition of polymer-supported amine (8 g), stirred 30 min. 100 mL of DCM was added. The organic layer was washed with H3PO4 (1M, 2×50 mL), followed by NaHCO3 (50 mL), brine (50 mL), dried (K2CO3), filtered through a silica gel pad, and concentrated to obtain the title compound as a liquid, 15.82 g (82.8%). MS: 363 (M+Na+); TLC (DCM) Rf=0.3.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCc1ccc(Br)cc1
Product: Clc1ccc(-c2nn(Cc3ccc(Br)cc3)c3c2CCNCC3)cc1
Yield: 25.6 %

Procedure:
The title compound (0.032 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05. found, m/z 418.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.40 (m, 6H), 6.92 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 3.32-3.30 (br m, 4H), 3.03-3.01 (br m, 4H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([F:17])[CH:11]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][NH2:1])[O:9][N:8]=2)=[CH:11][C:12]=1[F:17]
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.3 %

Procedure:
5-(Azidomethyl)-3-(4-bromo-3-fluorophenyl)-4,5-dihydroisoxazole (8.046 g, 26.9 mmol) was dissolved in a mixture of acetonitrile (40 ml) and water (4 ml). Triphenylphosphine (8.48 g, 32.3 mmol) was added and the reaction mixture stirred at room temperature for 48 hours. The reaction mixture was then poured onto a silica gel chromatography column (400 ml). The product was eluted with 10% to 20% water/acetonitrile, then freeze dried to yield 2.67 g of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>C(#N)C.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Fc1ccc(Br)c(OCC(F)(F)F)c1
Temperature: 150 °C
Yield: 186.6 %

Procedure:
To a stirred solution of 2-bromo-5-fluorophenol (1.5 g) in acetonitrile (0.5 mL) and DMF (8.5 mL) in a microwave tube was added potassium carbonate (2.1 g) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.37 g). The mixture was heated to 150° C. in a microwave oven for 30 minutes. In a second microwave tube the same reaction was repeated. Both mixtures were combined. The solvent was removed in vacuum, ethyl acetate and hexane (1:1) was added and the mixture was washed with water. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 4.0 g of the title compound.