Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]#[N:20])([CH2:14][CH:15]([OH:18])CO)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]#[N:20])([CH2:14][CH2:15][OH:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CC(O)CO)CC1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(CCO)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 95.9 %

Procedure:
To a solution of 4-cyano-4-(2,3-dihydroxypropyl)piperidine-1-carboxylic acid tert-butyl ester (3.65 g) in tetrahydrofuran (100 ml) was added 10% aqueous sodium periodate solution (100 ml), and the mixture was stirred at room temperature for 40 min. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue (3.3 g) was dissolved in tetrahydrofuran (100 ml) and sodium borohydride (360 mg) and methanol (20 ml) were added with ice-cooling, and the mixture was stirred at room temperature for 30 min. After completion of the reaction, 10% aqueous citric acid was added and the mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=95:5) and dried under reduced pressure to give the title compound (3.13 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[C:12](Cl)(=[O:16])[CH2:13][CH2:14][CH3:15].C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[C:12]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11])(=[O:16])[CH2:13][CH2:14][CH3:15]
Reactant: NCCc1ccccc1CO
Reactant: CCCC(=O)Cl
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: CCCC(=O)NCCc1ccccc1CO

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and butyryl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-butyrylamino-2-(2-hydroxymethylphenyl)ethane as an oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-n-propylisoquinoline-5-acetonitrile.
Reaction SMILES: [CH3:1][C:2]1([C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[N:14]=3)[N:9]([Si](C(C)C)(C(C)C)C(C)C)[CH:8]=2)=[O:6])[CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1([C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=4)[N:14]=3)[NH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3]1
Reactant: COc1cc(-c2cnc3c(n2)c(C(=O)C2(C)CC2)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C4(C)CC4)c3n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 6.8 %

Procedure:
A solution of (1-methyl-cyclopropyl)-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (20 mg, 0.4 mmol) in anhydrous tetrahydrofuran (2 ml) was treated with tetrabutyl ammonium fluoride (1M in tetrahydrofuran, 0.1 ml, 0.1 mmol) dropwise. The reaction mixture was allowed to stir at room temperature for 10 minutes, and then partitioned between EtOAc/water. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow solid. The residue was purified by preparative thin layer chromatography using 70% EtOAc in hexanes as eluant to provide 10 mg (71%) of (1-methyl-cyclopropyl)-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone as a white solid. M+H=368.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[N:32]1[CH:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[N:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38]([C:36]4[CH:37]=[N:32][CH:33]=[N:34][CH:35]=4)=[O:39])[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: O=C(O)c1cncnc1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6cncnc6)cn5n4)c3)c2)CC1
Yield: 26 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (140 mg, 0.313 mmol), pyrimidine-5-carboxylic acid (58 mg, 0.471 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (90 mg, 0.471 mmol), 1-hydroxybenzotriazole (63 mg, 0.471 mmol), triethylamine (60 μL, 0.471 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (42 mg, 26%) was obtained as a pale-yellow powder.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=[O:28])[CH:6]([S:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.O[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1>>[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][CH2:19][S:18][CH:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[O:16])=[CH:12][CH:13]=2)[C:5]([OH:4])=[O:28])=[CH:26][CH:25]=1
Reactant: CS(=O)(=O)Oc1ccc(CO)cc1
Reactant: O=C(O)Cc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: CS(=O)(=O)Oc1ccc(COC(=O)Cc2ccc(CC(SCCc3ccc(F)cc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-phenyl)-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid 2,2,2-trichloro-ethyl ester (30 mg, 0.01 mmol) and methanesulfonic acid 4-hydroxymethyl-phenyl ester (14 mg, 0.067 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 0.47 mg, 1.4%). Mass Spectrum: M−H+ 545.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[S:14][C:13]([C:15](=[O:17])[CH3:16])=[CH:12][C:11]=1[N+:18]([O-])=O.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:18][C:11]1[CH:12]=[C:13]([C:15](=[O:17])[CH3:16])[S:14][C:10]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(N)c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a two necked 250 mL round bottom flask, charged with 1-[5-(2,4-Dichlorophenylsulfanyl)-4-nitro-2-thienyl]ethanone (7.0 g, 20.2 mmol) prepared as in example 2, 50 mL ethanol and 50 mL of water followed by ammonium chloride (4.32 g, 80.8 mmol) and iron powder (4.53 g, 80.8 mmol). The resulting reaction mixture was heated at 80° C. for 2 hours. After this time, the reaction mixture was cooled to ambient temperature and was passed through a cellite cartridge. The filtrate was concentrated and water was added to the residue and extracted with ethyl acetate. The combined organic layer was separated, dried (Na2SO4), filtered and concentrated to afford the title product (6.4 g, 78% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.64 (1H, s), 7.44 (1H, s), 7.37 (1H, m), 6.68 (1H, m), 2.50 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([Br:14])[CH:10]=[C:9]([F:15])[CH:8]=2)=[O:4].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([Br:14])[CH:10]=[C:9]([F:15])[CH:8]=2)=[O:4]
Reactant: COC(=O)c1cc2c(Br)cc(F)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1cc2c(Br)cc(F)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 34 %

Procedure:
To a solution of 4-bromo-6-fluoro-1H-indole-2-carboxylic acid methyl ester (178 mg, 0.65 mmol) in 5 ml anhydrous dimethylformanide was added sodium hydride (52 mg of a 60% suspension in mineral oil, 1.3 mmol) portionwise at 0° C. The solution was stirred with a magnetic stirrer at 0° C. for 20 minutes. Benzyl bromide (0.17 ml, 1.43 mmol) was added in one portion and the reaction mixture was stirred at 0° C. for 30 minutes. The solution was allowed to warm to room temperature and the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic fractions were washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by Preparative TLC (10% Ethyl acetate/Hexane) to give 80 mg 1-Benzyl-4-bromo-6-fluoro-1H-indole-2-carboxylic acid methyl ester as a yellow solid (34%). 1H NMR (CDCl3, 300 MHz) δ: 3.89 (s, 3H), 5.78 (s, 2H), 7.17 (m, 8H).
Reaction SMILES: CN([Si](C)(C)C)C(=O)C(F)(F)F.[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[OH:24])[C:17]([NH:19][NH2:20])=[O:18].[C:25]1([CH2:31][O:32][C:33]([NH:35][NH:36][C:37](Cl)=[O:38])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([CH2:31][O:32][C:33]([NH:35][NH:36][C:37]([NH:20][NH:19][C:17](=[O:18])[C:16]2[CH:21]=[CH:22][C:23]([OH:24])=[C:14]([OH:13])[CH:15]=2)=[O:38])=[O:34])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: NNC(=O)c1ccc(O)c(O)c1
Reactant: O=C(Cl)NNC(=O)OCc1ccccc1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Product: O=C(NNC(=O)OCc1ccccc1)NNC(=O)c1ccc(O)c(O)c1

Procedure:
19.52 ml (0.10 mol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 4.20 g (0.025 mol) of 3,4-dihydroxybenzoic acid, hydrazide in 25 ml of dry acetonitrile. Stirring was continued at room temperature until a clear solution was formed (40 minutes). After evaporation in vacuo at 30°-40° C., the residue was dissolved in 25 ml of dry dichloromethane. This solution was dropped into a stirred suspension of 5.72 g (25.0 mmol) of [[[(phenylmethoxy)carbonyl]hydrazino]carbonyl]chloride at 5° C. After stirring for 1 hour at 0° C., the mixture was evaporated in vacuo and the oily residue was stirred with ether containing 4 ml of methanol until it became crystalline; yield after washing with ether and drying in vacuo: 8.77 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[O:26])=[CH:4][CH:3]=1>CO.[BH4-].[Na+]>[OH:13][CH:12]1[N:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:9](=[O:26])[C:10]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:11]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(=O)N1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(c2ccccc2)=C(c2ccccc2)C(O)N1c1ccccc1

Procedure:
After the addition of compound 4e (1.00 g, 2.78 mmol) in methanol, NaBH4 was slowly added thereto in acetone-ice bath and the agitation for 3 hours was carried out at room temperature. After the identification of disappearance of compound 4e with TLC, quenching was carried out with in HCL aqueous solution in the ice bath. Then, three times extractions were carried out with EA and three times washings were carried out with brine. Water was removed by using Na2SO4, solvents were removed and then, the column chromatography was carried out with EA/HX (¼). After the distillation under the reduced pressure, vacuum drying was carried out to obtain compound 8
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3(OCC(C)(C)C[O:14]3)[CH2:11]2)[CH2:7]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CC(C)=O.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10](=[O:14])[CH2:11]2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CC2CC3(CC2C1)OCC(C)(C)CO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)CC1CC2CC(=O)CC2C1
Yield: 13.4 %

Procedure:
A solution of the product of Step 3 (400 mg, 1.350 mmol) in acetone (8.0 mL) and water (8.00 mL) was stirred at room temperature 16 hrs with p-toluenesulfonic acid monohydrate (257 mg, 1.35 mmol). The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and brine. The separated organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. Flash chromatography (10 to 60% EtOAc in hexanes) afforded ethyl[5-oxooctahydropentalen-2-yl]acetate (38 mg, 0.181 mmol, 13.4% yield) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 4.14-4.09 (m, 2H), 2.73-2.71 (m, 2H), 2.53-2.47 (m, 2H), 2.37-2.32 (m, 3H), 2.29-2.25 (m, 2H), 2.08-2.02 (m, 2H), 1.27-1.24 (m, 3H).
Reaction SMILES: [CH:1]([O:4][CH:5]([CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14](COC)[CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:3])[CH3:2].Cl.O.C(=O)([O-])O.[Na+]>CC(C)=O>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([CH2:11][CH:5]([O:4][CH:1]([CH3:2])[CH3:3])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:13]1
Reactant: CCOC(=O)C(Cc1cn(COC)c2ccccc12)OC(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cc1c[nH]c2ccccc12)OC(C)C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2.3 g of Ethyl 2-isopropoxy-3-(1-methoxymethyl-1H-indol-3-yl)propionate was dissolved in 25 ml of acetone, and 15 ml of 5N hydrochloric acid was added, and the mixture was stirred for 2 hours. The reaction solution was cooled with ice, treated with water and sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 20 ml of ethanol, and an aqueous solution containing 2 g of potassium carbonate was added, and the mixture was stirred at 50° C. for 3 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was subjected to silica gel column chromatography (50% ethyl acetate-hexane), to give 0.75 g of the title compound.
Reaction SMILES: [C:1]1([CH3:39])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(O)C=CC=CC=1>Br.C(O)(=O)C>[C:1]1([CH3:39])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)N2CCNCCNCC2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
1,4,7-Tris(p-toluenesulfonyl)-1,4,7-triazacyclononane (17.56 g, 29.7 mmol) and phenol (21 g, 223.0 mmol) are dissolved in 240 ml of a solution of HBr (33%) in glacial acetic acid. The solution is heated at 90° C. for 30 h. A solid appears after 3 h. After returning to ambient temperature, the mixture is filtered and the solid is washed with diethyl ether (2×80 ml). The hydrobromide salt is dissolved in a 1M sodium hydroxide solution until the pH is of the order of 12 units. The aqueous solution is extracted with chloroform (8×50 ml). The combined organic phases are dried over Na2SO4 and the solvent is evaporated under vacuum. Finally, a white solid is obtained (7.36 g, yield 88%).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.[F:32][C:33]1[CH:34]=[C:35]([S:42](Cl)(=[O:44])=[O:43])[CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40]>C(Cl)Cl>[F:32][C:33]1[CH:34]=[C:35]([S:42]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:43])=[O:44])[CH:36]=[CH:37][C:38]=1[N+:39]([O-:41])=[O:40]
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 0 °C
Yield: 52.7 %

Procedure:
A 25-mL round-bottomed flask was cooled to 0° C. and charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydro chloride (500 mg, 1.25 mmol, Example 91, Step 1), CH2Cl2 (10 mL) and triethylamine (0.52 mL, 3.74 mmol). 3-Fluoro-4-nitrobenzenesulfonyl chloride (328 mg, 1.371 mmol, Matrix Scientific, Columbia, S.C.) was added and after 10 min the reaction was concentrated onto silica gel and purified via column chromatography (40 g silica gel, 0 to 100% hexanes in EtOAc) to give 2-(4-(4-((3-fluoro-4-nitrophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (350 mg).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:30]C(=O)C)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[S:17][C:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)=[CH:12][CH:11]=2)[CH2:4][O:3]1.Cl>C(O)C>[NH2:30][C:5]([CH2:4][OH:3])([CH2:6][OH:7])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][C:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[O:29])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(C(=O)c4ccc(C)cc4)s3)cc2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C(=O)c2ccc(-c3ccc(CCC(N)(CO)CO)cc3)s2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
N-[2,2-Dimethyl-5-(2-{4-[5-(4-methylbenzoyl)-2-thienyl]phenyl}ethyl)-1,3-dioxan-5-yl]acetamide (0.22 g) was dissolved in ethanol (4 mL), concentrated hydrochloric acid (2 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was concentrated, aqueous potassium carbonate solution was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (163 mg) as brown crystals.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>CC(C)=O>[F:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:4](=[O:5])[C:3]1[CH2:7][CH2:8][CH2:9][CH2:10][C:2]=1[C:1]([OH:6])=[O:11]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccc(Cl)cc1F
Solvent: CC(C)=O
Product: O=C(O)C1=C(C(=O)Nc2ccc(Cl)cc2F)CCCC1
Reaction time: 0.08 h

Procedure:
3,4,5,6-tetrahydrophthalic anhydride (7.7 g) and 2-fluoro-4-chloroaniline (7.2 g) were added to acetone (50 ml) and, after stirring at 50°-55° C. for 5 minutes, the reaction mixture was concentrated under reduced pressure. The resultant crystals were washed with n-hexane. Yield 13.2 g; m.p. 92°-94° C.
Reaction SMILES: CC(C)([O:4][C:5]1[N:10]=[C:9]([O:11]C(C)(C)C)[C:8]([C:16]2([OH:32])[C:25]3[S:24][C:23]([CH3:26])=[N:22][C:21]=3[CH2:20][CH2:19][C:18]3[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:17]2=3)=[CH:7][N:6]=1)C>C(O)(=O)C>[OH:32][C:16]1([C:8]2[C:9](=[O:11])[NH:10][C:5](=[O:4])[NH:6][CH:7]=2)[C:25]2[S:24][C:23]([CH3:26])=[N:22][C:21]=2[CH2:20][CH2:19][C:18]2[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:17]1=2
Reactant: Cc1ccc2c(c1)CCc1nc(C)sc1C2(O)c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)CCc1nc(C)sc1C2(O)c1c[nH]c(=O)[nH]c1=O

Procedure:
A solution of the product from step (iv) in acetic acid was stirred overnight. The solvent was removed under reduced pressure and the residue purified by chromatography eluting with 5-6% methanol in dichloromethane.
Reaction SMILES: [Mg].BrCCBr.Cl[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH3:14].[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>O1CCCC1>[Cl:13][C:9]1[C:8]([CH3:14])=[C:7]([C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCCC1
Reactant: Cc1c(Cl)cccc1Cl
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1C1(O)CCCCC1
Temperature: 25 °C

Procedure:
Under a nitrogen blanket, 96 g (4 moles) of magnesium shavings in 60 ml of absolute THF (tetrahydrofuran) are placed in a receiver. At 65° C., 1 ml of 1,2-dibromoethane is added and then a solution of 644 g (4 moles) of 2,6-dichlorotoluene in 1.5 liters of absolute THF is dripped in over a period of 21/4 hours. The mixture is then stirred under reflux for 4 hours and cooled to room temperature, and 352.8 g (3.6 moles) of cyclohexanone in 250 ml of absolute THF is added under a nitrogen blanket. After the reaction the Grignard reaction mixture is worked up as usual and the solvent is substantially removed by distillation under reduced pressure. The residue is subjected to incipient distillation (30° to 107° C./0.27 mbar). The crude product remaining (676 g), which already consists to the extent of 90% of 1-(3'-chloro-2'-methylphenyl)-cyclohexanol, can be purified further by column chromatography using toluene as eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](O)([CH3:13])[CH2:9][CH:10]1[CH2:12][CH2:11]1.S(=O)(=O)(O)O.[H][H]>CO.[Pd]>[CH:10]1([CH2:9][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH2:1])[CH3:13])[CH2:12][CH2:11]1
Reactant: [H][H]
Reactant: CC(O)(CC1CC1)c1ccccc1N
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(CC1CC1)c1ccccc1N

Procedure:
To a solution of 2.96 g (15.5 mmol) of 2-(2-aminophenyl)-1-cyclopropyl-propan-2-ol in 70 ml methanol is added 4.43 g (43.4 mmol) conc. sulfuric acid (96%). The resulting mixture is hydrogenated over 600 mg Pd/C(10%) for 20 hours at 30–35° C. After that time no more hydrogen uptake is detected. The catalyst is filtered off and the solvent removed in a water-jet vacuum. The residue is taken up in ethylacetate/water and the water phase is neutralised by the addition of sodium carbonate. The water phase is extracted twice with ethylacetate, then the combined organic phase is dried over sodium sulfate. After removal of the solvent in a water-jet vacuum, the crude amine is obtained. The obtained raw material is purified by column chromagraphy over silica gel (eluant: hexane/ether=5:1). Yield: 2.1 g 2-(2-cyclopropyl-1-methyl-ethyl)phenylamine in the form of a brown oil (1H-NMR).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][N:11]2[C:12](=[O:28])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:15][C:14]=3[C:24]([F:27])([F:26])[F:25])=O)(C)(C)C.[ClH:31]>CCOCC.O>[ClH:31].[CH3:23][CH2:22][CH:19]([C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:28])[N:11]3[CH2:29][CH2:30][NH:8][CH2:9][C@H:10]32)=[C:14]([C:24]([F:26])([F:27])[F:25])[CH:15]=1)[CH2:20][CH3:21]
Reactant: CCC(CC)c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCC(CC)c1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-(3-pentyl)-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (35 mg, 0.08 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 25 mg of a white solid. MS (ESI) 327 (M−Cl).