Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=O.[Cl-].[OH:15][NH3+:16].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][CH:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=[N:16][OH:15]
Reactant: [NH3+]O
Reactant: CC(C)C=C(C=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)C=C(C=NO)c1ccccc1
Reaction time: 5 h
Yield: 58.3 %

Procedure:
To a solution of 4-methyl-2-phenyl-2-pentenal (5.0 g, 29 mmol) and hydroxylammonium chloride (2.5 g, 36 mmol) in a mixture of absolute ethanol (15 ml) and water (5 ml) was carefully added a solution of sodium carbonate (7.3 g, 69 mmol) in water (20 ml). After stirring for 5 h a precipitate was filtered off and dried in the air. The crude product was purified by column chromatography on silica gel (50 g, cyclohexane/ethyl acetate 3/1) to give 3.2 g of 4-methyl-2-phenyl-2-pentenal oxime as a solid. M.p. 107°-110° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H][H]>C(O)C.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C=Cc1ccc2ccccc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc2ccccc2c1
Yield: 93.3 %

Procedure:
4.29 g of this ethyl 3-(2-naphthyl)-2-propenoate were dissolved in 60 ml of ethanol. The solution was stirred at room temperature for 3 hours in an atmosphere of hydrogen at atmospheric pressure and in the presence of 500 mg of 5% w/w palladium-on-charcoal. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.04 g (yield 93%) of ethyl 3-(2-naphthyl)propionate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-])=O)=[C:4]([F:13])[CH:3]=1.O.C(OCC)C>C(O)(=O)C.[Fe]>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH2:10])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Fe]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)c(F)cc1Br
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 30.0 g (0.12 mole) of 4-bromo-2-fluoro-5-methoxynitrobenzene in 200 mL of acetic acid was added 40 mL of water, followed by the portionwise addition of 30.0 g (0.54 mole) of iron filings during a 2.5 hour period. Upon complete addition, the reaction mixture was stirred at 25°-35° C. for one hour. Diethyl ether, 200 mL, was added, and the reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was washed with 200 mL of water. The organic layer was separated and neutralized with solid sodium bicarbonate. The mixture was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residual solid. The solid was recrystallized from petroleum ether to give 23.5 g of 4-bromo-2-fluoro-5-methoxyaniline; m.p. 60°-62° C.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CO)c(C)o2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-hydroxymethyl-2-(4-methylphenyl)-5-methyl-1,3-oxazole (3 g) in 30 ml of dichloromethane was cooled to 0° C., and thionyl chloride (1.75 g) added dropwise. The reaction was stirred for 1 hour at room temperature, then washed twice with dilute sodium bicarbonate solution, the organic layer separated, dried over sodium sulfate, and the solvent evaporated under reduced pressure, to yield 4-chloromethyl-2-(4-methylphenyl)-5-methyl-1,3-oxazole, which was used in the next reaction without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][Br:20])=[CH:17][CH:18]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ccc(CCCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(CBr)cc1

Procedure:
To a 50 ml round bottom flask is added 4-(4-methylphenyl)butyl tert-butyldimethylsilyl ether (0.25 g, 0.89 mmol), N-bromosuccinimide (0.158 g, 0.89 mmol), benzoyl peroxide (2.17 mg, 0.0089 mmol) and 10 ml carbon tetrachloride. This mixture is refluxed overnight after which it is cooled and filtered. The filtrate is concentrated and the resulting crude residue is purified by flash chromatography in ethyl acetate-hexanes to afford the product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=3)[N:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[O:23]=[C:24]1[NH:33][C:32]2[N:31]=[CH:30][C:29]([CH:34]=O)=[CH:28][C:27]=2[CH2:26][CH2:25]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>ClC(Cl)C.C(O)C>[OH:10][C@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[N:19]=2)[N:14]=[CH:13][CH:12]=1)[CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:29]2[CH:28]=[C:27]3[C:32](=[N:31][CH:30]=2)[NH:33][C:24](=[O:23])[CH2:25][CH2:26]3)[CH2:3][CH2:4]1
Reactant: COc1ccc2nccc([C@@H](O)CN3CCC(N)CC3)c2n1
Reactant: O=Cc1cnc2c(c1)CCC(=O)N2
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCO
Product: COc1ccc2nccc([C@@H](O)CN3CCC(NCc4cnc5c(c4)CCC(=O)N5)CC3)c2n1
Reaction time: 72 h
Yield: 21 %

Procedure:
To a stirred solution of (R)-2-(4-aminopiperidin-1-yl)-1-(6-methoxy-[1,5]naphthyridin-4-yl)ethanol (2f) (0.34 g, 1.13 mmole) in dichloroethane (10 mL) and dry ethanol (5 mL) at RT was added 7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridine-3-carboxaldehyde (113 g) (0.20 g, 1.13 mmole) and granular Na2SO4 (approximately 100 mg). After 72 h, the reaction was concentrated. The remaining residue was dissolved in dry ethanol and reacted with NaBH4 (0.043 g, 1.13 mmole). After 12 h at RT, the reaction was concentrated under vacuum and the residue was dissolved in a mixture of H2O (10 mL) and saturated aqueous NaHCO3 (50 mL). The aqueous solution was extracted with EtOAc (2×75 mL) and the combined organic phases were washed with brine then were dried over Na2SO4. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) afforded the title compound (0.11 g, 21%) as a white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.43 (br s, 1H), 8.77 (d, J=4.5 Hz, 1H), 8.23 (d, J=9.0 Hz, 1H), 8.01 (s, 1H), 7.75 (d, J=4.5 Hz, 1H), 7.58 (s, 1H), 7.24 (d, J=9.0 Hz, 1H), 5.77 (m, 1H), 5.23 (br s, 1H), 4.02 (s, 3H), 3.63 (s, 2H), 3.38 (m, 2H), 3.11 (m, 1H), 2.83 (m, 2H), 2.65 (m, 1H), 2.47 (m, 2H), 2.32 (m, 1H), 2.17 (m, 1H), 1.79 (m, 2H), 1.27 (m, 2H); MS (ES) m/e 463 M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH3:18])[CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)=[N:4][N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[C:22]([O:29][CH3:30])[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.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>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[S:6][C:5]([N:7]([CH3:18])[CH:8]3[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]3)=[N:4][N:3]=2)=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Reactant: COc1cc(Cl)ccc1B(O)O
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(Cl)ccc1-c1nnc(N(C)C2CC(C)(C)NC(C)(C)C2)s1
Temperature: 80 °C
Yield: 88.7 %

Procedure:
Nitrogen was bubbled through a stirred solution of 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine [Intermediate 4] (1 g, 3.00 mmol) and (4-chloro-2-methoxyphenyl)boronic acid (0.615 g, 3.30 mmol) in dioxane (20 mL). To this mixture was added Pd(PPh3)4 (0.173 g, 0.150 mmol) followed by a solution of Na2CO3 (0.954 g, 9.00 mmol) in water (5 mL). The reaction was heated at 80° C. for 18 hours. The reaction mixture was cooled to RT, diluted with EtOAc (150 mL) and washed with water (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to afford the crude product as a dark red/brown oil which solidified on standing. The crude material was purified by flash chromatography using an 80 g silica cartridge running a gradient of [2M NH3 in MeOH]/DCM to afford the title compound as an off-white solid (1.051 g, 89% yield). LC-MS: Rt 1.04 min; MS m/z 395.2 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=8.59 Hz, 1H), 7.32 (d, J=2.02 Hz, 1H), 7.15 (dd, J=8.59, 2.02 Hz, 1H), 4.35 (tt, J=12.38, 3.54 Hz, 1H), 3.97 (s, 3H), 2.98 (s, 3H), 1.60 (dd, J=11.87, 3.28 Hz, 2H), 1.41 (t, J=12.13 Hz, 2H), 1.27 (s, 1H), 1.21 (s, 6H), 1.08 (s, 6H).
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH2:6][NH:7][CH2:8][C@@H:4]2[CH2:3][N:2]1[C:9]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[CH:17][C:16]=2[OH:26])=[CH:11][CH:10]=1.[Si:27]([O:34][CH2:35][CH:36]=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].[Na].C(O)(=O)C>C(Cl)Cl>[Si:27]([O:34][CH2:35][CH2:36][N:7]1[CH2:6][C@@H:5]2[CH2:1][N:2]([C:9]3[N:14]=[N:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[N:23][NH:24][CH:25]=5)=[CH:17][C:16]=4[OH:26])=[CH:11][CH:10]=3)[CH2:3][C@@H:4]2[CH2:8]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Oc1cc(-c2cn[nH]c2)ccc1-c1ccc(N2C[C@H]3CNC[C@H]3C2)nn1
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCN1C[C@@H]2CN(c3ccc(-c4ccc(-c5cn[nH]c5)cc4O)nn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
To a solution of 2-(6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (31.4 mg, 0.09 mmol), 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (47.1 mg, 0.270 mmol), and sodium triacetoxyhydroborate (57.2 mg, 0.270 mmol) in CH2Cl2 (2 mL), was added acetic acid (0.013 mL, 0.225 mmol). The reaction mixture was stirred at RT overnight, then quenched with water and diluted with DCM. The organic layer was acidified with 1N HCl solution to pH˜3 and filtered to remove insoluble materials. The filtrate was loaded onto an SCX column, washed with MeOH, then eluted with 7N NH3 in MeOH. Concentration provided a brownish solid, 2-(6-((3a R,6aS)-5-(2-((tert-butyldimethylsilyl)oxy)ethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridazin-3-yl)-5-(1H-pyrazol-4-yl)phenol (23 mg, 0.020 mmol, 51% yield), MS (M+1)=507.1.
Reaction SMILES: [CH2:1]([N:8](C)[C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])C1C=CC=CC=1.[H][H]>[Pd].CO>[C:19]([O:18][C:16]([NH:15][C@@H:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]1[NH:8][CH3:1])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CN[C@H]1CCCC[C@H]1NC(=O)OC(C)(C)C
Yield: 92.3 %

Procedure:
(±)-cis-N1-Benzyl-N2-tert-butoxycarbonyl-N1-methyl-1,2-cyclohexanediamine (1.92 g) was added to methanol (50 ml), 10% palladium on carbon (containing 50% of water, 900 mg) was added, and the mixture was stirred for 20 hours in a hydrogen atmosphere. After separating the catalyst by filtration, the filtrate was concentrated to obtain the title compound (1.27 g) as a colorless oil.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22](=O)[NH2:23])[CH3:21])([CH3:16])([CH3:15])[CH3:14].[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[C:30](N)=[CH:31][CH:32]=1>C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][C@H:20]([C:22]1[N:34]([C:35]2[N:36]([CH3:40])[N:37]=[CH:38][CH:39]=2)[C:29]2[CH:28]=[C:27]([F:26])[CH:32]=[CH:31][C:30]=2[N:23]=1)[CH3:21])([CH3:16])([CH3:15])[CH3:14]
Reactant: Cn1nccc1Nc1cc(F)ccc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccnn1C
Yield: 130.3 %

Procedure:
Triethyloxonium tetrafluoroborate (1.06 g, 5.60 mmol) was added to a solution of ((S)-1-carbamoylethyl)carbamic acid tert-butyl ester (1.26 g, 6.67 mmol) in DCM (20 mL) at 20° C. under nitrogen and the resultant mixture stirred for 3 h then concentrated in vacuo. The resultant residue was dissolved in ethanol (20 mL) and 4-fluoro-N2-(2-methyl-2H-pyrazol-3-yl)-benzene-1,2-diamine (0.55 g, 2.67 mmol) added, and the reaction mixture stirred at reflux for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-5% (2M ammonia in methanol) in DCM) to give the title compound as a yellow oil (1.25 g, 100%). LCMS (Method C): RT 3.08 min [M+H]+ 360.2. 310091751
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=O)[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br.[C:27]([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[CH2:27])[N:13]=[C:12]1[NH:17][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Clc1ccccc1CBr
Agent: [K+]
Solvent: CC#N
Product: C=C1CN(C(=O)OCc2ccccc2)C(NCc2ccccc2Cl)=N1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester* (46.62 mg, 0.20 mmol), 2-chlorobenzylbromide (41.0 mg, 0.20 mmol) and K2CO3 (41.4 mg, 0.30 mmol) in acetonitrile (1.5 mL) was heated to reflux under argon for 3 hrs. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give 2-(2-chloro-benzylamino)-4-methylene-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (63.0 mg, 88.2%). * 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester was prepared according to the method described by C-H Kwon et al. J. Med. Chem. 1991, 34,1845-1849.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:18][CH3:19])([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)[C:10]#[N:11].CS(C)=[O:22].O.[OH-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1)([CH2:18][CH3:19])[C:10]([NH2:11])=[O:22]
Reactant: CS(C)=O
Reactant: CCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1Cl
Temperature: 91 °C
Yield: 79 %

Procedure:
To a 1 liter flask was charged 206.5 g (0.7 mole) of alpha-(2,4-dichlorophenyl)-alpha-ethyl-1H-1,2,4-triazole-1-propanenitrile and 500 mL of dimethylsulfoxide and 200 mL of water. To the stirring solution was added 67.2 g (0.84 mole) of 50% sodium hydroxide. The reaction mixture was heated at 91° C. (steam bath) for 3 hours after which GLC indicated the starting material was consumed. The reaction was cooled to 30° C. then poured into water and extracted with ethyl acetate. After drying, the ethyl acetate was treated with charcoal and filtered through Celite®. Removal of the solvent gave a foamy oil which was stirred and diluted with ethyl acetate then triturated with hexane until cloudy. This mixture was cooled at 0° C. for about 1 hour after which a solid formed. The product was filtered and washed with ether and hexane then dried and provided 172 g (79% yield) of a white solid, Example 154 of Table 1.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]([O:13]C([O-])=O)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)Cl>[CH3:12][C:9]([O:8][C:6](=[O:13])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])([CH3:10])[CH3:11]
Reactant: CNCCO
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Product: CN(CCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
A mixture of 2-(methylamino)ethanol (5.2 g, 69.2 mmol) and tert-butyl dicarbonate (15.8 g, 72.7 mmol) in methylene chloride (200 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with methylene chloride, and the organic layer was then washed with water, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give (2-hydroxyethyl)methylcarbamic acid 1,1-dimethylethyl ester (12.1 g, yield 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:17](Cl)(Cl)[S:18]Cl.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>ClCCl.O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]2[C:17](=[N:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:18][N:1]=[C:2]2[CH:7]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: Cc1ccnc(N)c1
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccn2c(=Nc3ccncc3)snc2c1
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
A solution of 3.2 g (30 mmol) of 2-amino-4-methylpyridine and 4.2 ml of triethylamine in 25 ml of dichloromethane is added dropwise at 0° C. to a solution of 3.3 ml (30 mmol) of trichloromethanesulphenyl chloride in 450 ml of dichloromethane, the mixture is stirred for 10 min and a solution of 2.8 g (30 mmol) of 4-aminopyridine and 12 ml of triethylamine in 100 ml of dichloromethane is added dropwise. After stirring at room temperature for 3 h, the mixture is poured into water and extracted with ethyl acetate, the extract is dried and concentrated, and the residue is chromatographed on silica gel (eluant ethyl acetate/isohexane 1:1). 1.2 g of title compound (17% of theory) of m.p. 144-145° C. are isolated.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[Si](C)(C)[N-:13][Si](C)(C)C.[Na+].[C:21]([O:24]CC)(=[O:23])[CH3:22]>C1COCC1.C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:13][C@H:22]([CH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:21]([OH:24])=[O:23]
Reactant: CCOC(C)=O
Reactant: BrCC=Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: N[C@H](CCCc1ccccc1)C(=O)O
Reaction time: 0.5 h

Procedure:
To a stirred solution of N-[(1,1-dimethylethoxy)carbonyl]amino-(2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholinecarboxylate, (1.0 g, 2.8 mmol) and cinnamyl bromide (2.78 g, 14 mmol) in dry THF (70 mL) at -78° C., was added dropwise sodium hexamethyldisilazide (5.6 mL; 1.0M solution in hexane). The reaction mixture was stirred for 30 minutes, then poured into ethyl acetate (150 mL) and washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The crude product was first washed with warm hexane and then with an ether:hexane (1:1) mixture. The solid material was the desired product. A solution of this intermediate (1.0 g, 2.1 mmol) in CH2Cl2 (2 mL) and TFA (2 mL) was stirred at room temperature for 1 h. The solvents were removed under reduced pressure and the residue was dissolved in saturated aqueous sodium bicarbonate solution and extracted with CHCl3. The organic layer was washed with brine, dried over potassium carbonate, filtered and evaporated to give the amine as a foam which was used without purification. Approximately 0.6 g (1.62 mmol) of this material was dissolved in 40 mL of (2:1) EtOH:THF and hydrogenated under 40 psi using PdCl2 /C for 24 h. The catalyst was filtered off through celite pad and the solvent was evaporated to give the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Yield: 76 %

Procedure:
[3-(1H-Indol-6-yl)-3-(2-methoxy-phenyl)-propyl]-methyl-amine XXXIX was prepared from 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide as a white solid in 76% yield using the procedure described above for [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=295.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[C@H:69]12[CH2:75][C@H:72]([CH2:73][CH2:74]1)[C@@H:71]([C:76]1[NH:77][C:78]([C:81]3[CH:82]=[C:83]4[C:88](=[CH:89][CH:90]=3)[CH:87]=[C:86]([C:91]3[CH:92]=[C:93]5[C:120](=[CH:121][CH:122]=3)[C:97]3[NH:98][C:99]([C@@H:101]6[CH2:105][CH2:104][CH2:103][N:102]6[C:106](=[O:119])[C@@H:107]([NH:114][C:115](=[O:118])[O:116][CH3:117])[CH:108]6[CH2:113][CH2:112][O:111][CH2:110][CH2:109]6)=[N:100][C:96]=3[CH:95]=[CH:94]5)[CH:85]=[CH:84]4)=[CH:79][N:80]=1)[NH:70]2>>[CH3:117][O:116][C:115](=[O:118])[NH:114][C@@H:107]([CH:108]1[CH2:109][CH2:110][O:111][CH2:112][CH2:113]1)[C:106]([N:102]1[CH2:103][CH2:104][CH2:105][C@H:101]1[C:99]1[NH:98][C:97]2[C:120]3[C:93]([CH:94]=[CH:95][C:96]=2[N:100]=1)=[CH:92][C:91]([C:86]1[CH:85]=[CH:84][C:83]2[C:88](=[CH:89][CH:90]=[C:81]([C:78]4[NH:77][C:76]([C@@H:71]5[C@@H:72]6[CH2:75][C@@H:69]([CH2:74][CH2:73]6)[N:70]5[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[N:80][CH:79]=4)[CH:82]=2)[CH:87]=1)=[CH:122][CH:121]=3)=[O:119]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@H]7N[C@@H]8CC[C@H]7C8)[nH]6)ccc5c4)ccc3c2[nH]1)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-2-(7-(6-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 915.83 [M+H]+. (44 mg, 60%).