Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].[O:24]1CCCC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([OH:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH4-]
Agent: [Li+]
Product: O=C(OCc1ccccc1)N1CCN(O)CC1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a mixture of oil 1-benzyloxycarbonyl-4-ethoxycarbonyl-piperazine (30 g) in tetrahydrofuran (200 ml) was added lithiumborohydride (2.7 g) and stirred at 60° C. for 5 hours. To quench thc mixture, added methanol, dilute hydrochloric acid and then concentrated hydrochloric acid. Diluted with diethylether and resulting suspension washed with water (×2) dilute sodiumbicarbonate then brine, dried (MgSO4) and evaporated to give as a colourless oil oil 1-benzyloxycarbonyl-4-hydroxy-piperazine (23 g) which was used directly in the next step without further purification or characterisation.
Reaction SMILES: O[C@@:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH2:3][CH2:4]O.C(N(C(C)C)C(C)C)C.CS(Cl)(=O)=[O:55].C(=O)([O-])[O-].[Na+].[Na+]>O.C1COCC1>[OH:55][C:10]1[N:9]=[CH:8][N:7]2[CH2:4][CH2:3][C@@H:2]([C:30]3[CH:31]=[C:32]4[C:37](=[CH:38][CH:39]=3)[CH:36]=[C:35]([C:40]([NH:42][CH3:43])=[O:41])[CH:34]=[CH:33]4)[C:6]=12
Reactant: CS(=O)(=O)Cl
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 10 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To THF (100 mL) and water (63 μg, 3.5 mmol) was added 6-[(1S)-1,3-dihydroxy-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (10.0 g, 17.6 mmol). The reaction mixture was cooled to 10° C., and ethyldiisopropylamine (3.41 g, 26.4 mmol) and methanesulfonyl chloride (3.03 g, 26.4 mmol) were successively added thereto, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of sodium carbonate (3.73 g, 35.2 mmol) in water (40 mL), and the mixture was warmed to 57° C., and stirred for 5 hr. The mixture was concentrated under reduced pressure to adjust the volume of the residue to 45 mL. Ethyl acetate (50 mL) was added thereto at 45° C., and the mixture was stirred. The reaction mixture was stirred with cooling to room temperature and then cooling to 5° C. The crystals were collected by filtration, and washed with ethyl acetate (40 mL) cooled to 5° C. The obtained wet crystals were dried under reduced pressure to give crude 6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (5.3 g, 17.3 mmol). yield 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[C:14](Cl)=[O:15].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24]>>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:15]
Reactant: COCCOCCO
Reactant: O=C(Cl)c1cnoc1-c1ccc(Cl)cc1Cl
Product: COCCOCCOC(=O)c1cnoc1-c1ccc(Cl)cc1Cl
Yield: 96 %

Procedure:
5-(2',4'-Dichlorophenyl)-4-isoxazolecarbonyl chloride (2.0 g.; 0.007 mol.) was covered with 2-(2'-methoxyethoxy) ethanol and the solution was heated on a steam cone for 2 hours. After esterification, the excess 2-(2'-methoxyethoxy) ethanol was extracted into water. The insoluble oil was dissolved in ether, dried with anhydrous magnesium sulfate and concentrated to yield 2-(2'-methoxyethoxy)ethyl-5-(2',4'-dichlorophenyl)-4-isoxazolecarboxylate (2.4 g.; 96% yield) as an oil having the following analysis:
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[N+:11]([O-])=O.[OH-].[Na+].O>CCOC(C)=O>[NH2:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[N:2]([CH3:1])[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:24])([CH3:25])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:7]#[N:8]
Reactant: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(c1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C#N)cc1N
Temperature: 80 °C

Procedure:
SnCl2-2H2O (0.17 mol) is added to a solution of 4-[methyl-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]-3-nitrobenzonitrile (31) (R4=CH3, 34.0 mmol) in EtOAc (125 mL) and the mixture is heated at 80° C. for 1 h. After cooling, to the reaction mixture are successively added 6N NaOH (120 mL), H2O (150 mL), and EtOAc (150 mL). The reaction mixture is filtered through Celite (25 g) and washed with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with hexane to give (32) (R4=CH3).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([C:16]4[O:17][CH2:18]C(C)(C)N=4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=[CH:2]1.S(=O)(=O)(O)[OH:24].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=3)[C:16]([O:17][CH3:18])=[O:24])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)COC(c2cccc(-c3cccc4occc34)c2)=N1
Solvent: O
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc3occc23)c1

Procedure:
A mixture of 2-[3-(benzofuran-4-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.4 g), concentrated sulfuric acid (0.8 ml) and water (1 ml) in methanol (20 ml) was refluxed for 48 hours. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was successively washed with 10% sodium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired products were collected and evaporated in vacuo to afford methyl 3-(benzofuran-4-yl)benzoate (0.77 g).
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.[C:26]([NH:34][NH2:35])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:11][C:10]1[C:9]([N:8]=[N:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([NH2:13])[N:34]([C:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:33])[N:35]=1
Reactant: NNC(=O)c1ccccc1
Reactant: N#CC(C#N)=NNc1ccccc1
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(C(=O)c2ccccc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
(3,5-diamino-4-phenylazopyrazol-1-yl)phenylmethanone was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and benzoic hydrazide (68 mg, 0.5 mmol). Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in methanol and then precipitated by the addition of water. The resulting solid was isolated by filtration and dried to yield 20 mg (13%) of the compound as an orange coloured solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[N:19]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:20]3[C:25]([N:26]=2)=[CH:24][N:23]=[CH:22][N:21]=3)[CH2:13][CH2:12]1.C(=O)([O-])O.[Na+]>C(O)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:19]2[C:18]([NH:17][CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][NH:8][C:2]4[N:7]=[CH:6][CH:5]=[CH:4][N:3]=4)[CH2:16][CH2:15]3)=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:33][CH:32]=1
Reactant: NCCN1CCC(Nc2nc3cncnc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(Cn2c(NC3CCN(CCNc4ncccn4)CC3)nc3cncnc32)cc1
Yield: 67 %

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 5.5 parts of N-[1-(2 aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 160 parts of ethanol was stirred and refluxed for 20 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4.5 parts (67%) of 9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-9H-purin-8-amine; mp. 164.1° C. (compound 164).
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]([CH3:24])([CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)C.B(Br)(Br)Br.O>C(Cl)Cl>[CH2:16]([NH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C:5]([CH3:23])([CH3:24])[C:4]([OH:25])=[O:3])=[CH:12][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)OCC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the impure 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid ethyl ester (100 mg of the mixture) dissolved in methylene chloride (5 mL) cooled to −78° C. under a nitrogen atmosphere was added boron tribromide (1M in dichloromethane, 0.432 mL). The mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to −78° C. and an additional 0.432 mL of the 1M boron tribromide in dichloromethane was added. The mixture was warmed to room temperature and stirred for 20 minutes. The mixture was poured over H2O (10 mL) and extracted with dichloromethane (3×). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to a clear film. This was dissolved in dioxane/2M HCl (10 mL/10 mL) and was refluxed for 20 minutes. The mixture was cooled and brought to pH 10 with 2 N NaOH. The basic solution was washed with diethyl ether (3×) and brought to pH 4 with 2N HCL. The acidic solution was extracted with diethyl ether (3×), washed with brine (2×), dried over anhydrous sodium sulfate and concentrated to give 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid as a clear film (23 mg, 46%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[CH3:11][O:12][CH2:13]/[CH:14]=[CH:15]/B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2](/[CH:15]=[CH:14]/[CH2:13][O:12][CH3:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: O=Cc1cc(O)cc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(O)cc(C=O)c1
Temperature: 80 °C

Procedure:
3-Bromo-5-hydroxybenzaldehyde from the previous step (1 eq.) and 2-[(1E)-3-methoxyprop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 eq.) were combined in DMF (0.05 M). To this solution was then added palladium acetate (10% loading), triphenylphosphine (20% loading) and sodium carbonate (2 M aqueous solution, 4 eq.). The resulting suspension was heated at 80° C. for 16 h. The reaction mixture was quenched with 10% aq. HCl and extracted with ether. The combined organic extracts were washed with water, sat. aq. NaHCO3 and brine. Drying over MgSO4, filtration and concentration of the filtrate in vacuo afforded the crude product as a brown tar. Purification by way of column chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→2:1 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][NH:7][CH3:8])[CH3:2].Cl[C:11]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]>N1C=CC=CC=1>[O:12]=[C:11]([N:7]([CH3:8])[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])[C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCNC
Reactant: CCOC(=O)C(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCN(C)C(=O)C(C)(C)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a solution of 61 g of N-methyl-β-alanine ethyl ester in 600 ml of dry pyridine there is added 82 g of ethyl 2-chloroformyl-2-methylpropionate. During the addition, which takes 30 minutes, the mixture is mechanically stirred and cooled with ice. Stirring is continued at 10° C for 30 minutes and then at 30° - 40° C for 1 hour. Next the pyridine is evaporated in vacuo, leaving a residue to which a small quantity of water is added, whereafter the mixture is extracted with ether. The extract is dried over magnesium sulphate and evaporated leaving the above-mentioned product as a liquid which is purified by distillation at reduced pressure. Yield 97 g (75%). Boiling point 134° - 136° C (1 mm). nD22 1.4565.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][Si](C(C)C)(C(C)C)C(C)C)[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C@@H:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)(=[O:3])[CH3:2].F>N1C=CC=CC=1.O1CCCC1>[C:1]([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][OH:15])[O:7][C@H:6]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[NH:35][C@@H:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:38][CH2:37]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO[Si](C(C)C)(C(C)C)C(C)C)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Temperature: 25 °C
Yield: 82.1 %

Procedure:
(2R,3S,4R,5R)-2-{6-[(1S)-2,3-Dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}-5-{[(triisopropylsilyl)oxy]methyl}tetrahydrofuran-3,4-diyl diacetate (0.305 g, 0.49 mmol) was stirred in pyridine (2 mL) and tetrahydrofuran (2 mL). Hydrofluoric acid in pyridine (2.0 M) was added (15 drops) and the reaction was stirred at room temperature for thirty minutes. The reaction was quenched using saturated sodium bicarbonate then extracted using ethyl acetate (3×10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The brown residue was purified by column chromatography (30-50% ethyl acetate/hexanes followed by ethyl acetate) to give the title compound as a white solid (0.188 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[CH:12]([CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:6][CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[N:13]2[C:17]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:16]=3[N:15]=[C:14]2[C:24]2[C:25]([O:32][CH3:33])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=C/C(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CCC(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)cc1
Reaction time: 1 h

Procedure:
To a solution of 210 mg (0.383 mmol) 4-{(E)-3-cyclohexyl-3-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-propenyl}-benzoic acid methyl ester in 4 ml methanol was added 30 mg Pd on carbon 5%. The reaction mixture was hydrogenated at 1.5 bar under vigorous stirring for 1 hour, then filtered over dicalite and concentrated under vacuum. Colorless oil (90%). MS (Turbo Spray): m/z=550.4 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[OH:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCC(NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CO)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
2-(R/S)-[(tert-butoxycarbonyl)amino]tetradecanoic acid 41 (1.00 g, 2.92 mmol) in abs. THF (3 ml) was added slowly dropwise to BH3-THF complex (1.0M, 5.8 ml, 5.80 mmol) at 0° C. After stirring for 2 hours, the reaction mixture was quenched with 10% acetic acid in methanol (v/v) and evaporated. The residue was taken up in CH2Cl2 (10 ml) and washed with 1M KHSO4(aq) (1×20 ml) and brine (2×20 ml). The solution was then dried over MgSO4, filtered and evaporated. Purification by column chromatography gave 44 (821 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:5]2=1.[H-].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:24]=1[CH2:25]Cl>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:25][C:24]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:23]=1[Cl:22])[C:10]1[CH:9]=[N:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][C:5]2=1
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c3cc(N)ccc3n(Cc3cc(Cl)ccc3Cl)c2cn1
Yield: 53.8 %

Procedure:
A mixture of ethyl 6-amino-9H-β-carboline-3-carboxylate (100 mg, 0.39 mmol), NaH (0.58 mmol, 24 mg of 60 wt. % suspension in mineral oil) and 2,5-dichlorobenzyl chloride (115 mg, 0.59 mmol) in DMF (2 mL), was treated according to Method A. Purification of the crude product by column chromatography on silica with hexane/ethyl acetate (7:3) as eluent furnished the desired product (87 mg, 54% yield) as a yellow solid. 1H NMR (DMSO-d6) δ8.96 (s, 1H), 8.74 (s,1H), 7.60 (d,J=8.6 Hz, 1H), 7.48 (d, 1H), 7.41 (dd, J=8.4 Hz, 2.1Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.01 (d,J=8.6 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 5.80 (s, 2H), 5.10 (br s, 1H), 4.37 (q,J=7.0 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H); MS (APCI; (M+H)+) m/z 414.
Reaction SMILES: [Br:1][CH2:2][Br:3].[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:26])([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[CH:27]1[CH:32]([CH3:33])[CH:31]([CH3:34])[CH2:30][C:29](=[O:35])[CH2:28]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C1([N-]C2CCCCC2)CCCCC1.[Li+]>O1CCCC1.O.CCOCC>[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:25])([CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:13]=1[CH:27]1[CH:32]([CH3:33])[CH:31]([CH3:34])[CH2:30][C:29]([CH:2]([Br:3])[Br:1])([OH:35])[CH2:28]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: BrCBr
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(=O)CC(C)C2C)c(OCc2ccccc2)c1
Agent: C1CCC([N-]C2CCCCC2)CC1
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CC(O)(C(Br)Br)CC(C)C2C)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a -78° C. solution of 17.4 g (0.10 mole) of dibromomethane and 21.7 g (0.050 mole) of 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4,5-dimethylcyclohexanone in 100 ml of tetrahydrofuran is added dropwise over a period of 2 hours a solution of lithium dicyclohexylamide (0.10 mole) in 100 ml of tetrahydrofuran. The reaction is stirred one hour longer at -78° C. and quenched by addition of 2 ml (0.11 mole) of water. The reaction is added to 300 ml ether and 200 ml water. The ether extract is dried over magnesium sulfate and evaporated. The crude product is purified via column chromatography on 500 g of silica gel eluted with ether-pentane to give pure 3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-1-dibromomethyl-4,5-dimethylcyclohexanol.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:17])[CH:13]=[C:14]([CH:15]=[CH2:16])[C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:12]1[CH:13]=[C:14]([CH:15]=[CH2:16])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([C:3]#[N:4])[CH3:18])[N:7]=2
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: C=Cc1cc(Cl)cc2nn(CC(C)(N)C#N)nc12
Product: C=Cc1cc(Cl)cc2nn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-vinyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (50 mg) described in Example 59 above and 4-trifluoromethylthiobenzoyl chloride (0.05 mL), the title compound was isolated as a white solid (65 mg, 73%). Rf=0.5 (1:1 EA/heptane). MS (ES): M/Z [M+H]=466. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.41 (d, J=13.4 Hz, 1H), 5.50 (d, J=11.5 Hz, 1H), 5.57 (d, J=13.4 Hz, 1H), 6.45 (d, J=17.6 Hz, 1H), 6.91 (dd, J=17.6, 11.3 Hz, 1H), 7.51 (s, 1H), 7.84 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.3 Hz, 2H), 8.03 (s, 1H) and 8.96 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH:20]([OH:32])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[C:20](=[O:32])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccccc1C1CCN(Cc2ccccc2)CC1O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1C1CCN(Cc2ccccc2)CC1=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
To a cooled (−78° C.) solution of oxalyl chloride (0.839 g, 6.73 mmol) in dry DCM (5 mL) was added dimethylsulfoxide (1.05 g, 13.46 mmol) dropwise. The mixture was stirred for 10 min at −78° C., 1-benzyl-4-(2-methoxyphenyl)piperidin-3-ol (1.0 g, 3.367 mmol) in DCM (10 mL) was added and stirring continued for a further 20 min at −78° C. Triethylamine (3.3 ml, 23.56 mmol) was added, the reaction mixture was stirred for 15 min at −78° C., warmed to room temperature and diluted with water. The organic layer washed with 2N HCl (50 mL), 10% aqueous sodium bicarbonate solution, brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 1-benzyl-4-(2-methoxyphenyl)piperidin-3-one (0.7 g, 70%) which was used in the next step without further purification. 1H NMR (200 MHz, CDCl3): δ 2.72 (m, 2H) 2.91-3.045 (m, 2H), 3.71 (m, 2H), 3.80 (s, 2H), 6.87-6.99 (m, 2H), 7.12 (dd, J=7.5, 1.7 Hz, 1H), 7.18-7.45 (m, 6H); m/e=295 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:18]=2[C:19](O)=[O:20])=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:19](=[O:20])[C:18]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(Cl)cc3c(=O)o2)CC1
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a stirring solution of 2-[(4-Boc-piperazin-1-ylcarbonyl)amino]-5-chlorobenzoic acid (1.6 g, 4.17 mmol) in DMF (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.4 g, 12.51 mmol). After 30 min, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic phase was washed consecutively with 1 M citric acid, brine, sat. aq sodium bicarbonate, and brine, then dried with MgSO4, filtered and concentrated in vacuo. The residue was then suspended in diethyl ether, sonicated, filtered and dried in vacuo to give 0.86 g (58%) of the title compound as a white solid.