Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCOC(=O)c1ccc(Br)nc1
Product: CCOC(=O)c1ccc(-c2ccc(Br)cc2)nc1
Yield: 98 %

Procedure:
In accordance with Example 11-(1), but using ethyl 6-bromonicotinate instead of 4-bromobenzylbromide, and 4-bromophenylboronic acid instead of [3-(hydroxymethyl)phenyl]boronic acid, the title compound (yield 98%) was afforded as a white solid.
Reaction SMILES: OO.O.[OH-].[Li+].C(OC(N([C@@H](C1C=CC=CC=1)C)[C:12](=[O:23])[CH:13]([CH2:20][CH:21]=[CH2:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=O)C.S([O-])([O-])=[O:33].[Na+].[Na+]>C1COCC1.O>[CH2:20]([CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:23])=[O:33])[CH:21]=[CH2:22]
Reactant: C=CCC(CCCCCC)C(=O)N(C(=O)OCC)[C@H](C)c1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(CCCCCC)C(=O)O
Reaction time: 1 h

Procedure:
An aqueous solution of hydrogen peroxide (31% by weight; 0.6 ml, 5.6 mmol) and 0.047 g (1.1 mmol) of lithium hydroxide monohydrate were added dropwise to a solution of 0.20 g (0.56 mmol) of N-ethyloxycarbonyl-N-(2-allyloctanoyl)-(R)-1-phenylethylamine (diastereomer ratio (1R,2S):(1R,2R)=81:19) in a mixture of 4 ml of THF and 1 ml of water on an ice bath. The mixture was stirred on an ice bath for 1 hour and then at room temperature for 18 hours. A 2 N aqueous solution of sodium sulfite (10 ml) was added dropwise to the reaction mixture on an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. Water (15 ml) was added to the reaction mixture, and the whole mixture was washed with 5 ml of ethyl acetate. To the aqueous layer was added 6 ml of a 1 N aqueous solution of hydrochloric acid (pH=2), and the resulting mixture was extracted with two 40-ml portions of ethyl acetate. The organic layer was concentrated under reduced pressure to give 0.043 g (42%, 62% ee) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1Cl)[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[F:18]C(F)(F)C(NCC1OCCNC1)=O.FC1C=CC(CCl)=CC=1>>[F:18][C:16]1[CH:15]=[CH:14][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]2)=[CH:3][CH:2]=1
Reactant: O=C(NCC1CNCCO1)C(F)(F)F
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Fc1ccc(CCl)cc1
Product: NCC1CN(Cc2ccc(F)cc2)CCO1

Procedure:
Intermediate 21 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 4-fluorobenzyl chloride, followed by deprotection to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH2:20])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([NH:20][C:30](=[O:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1nn(N)c(=O)c2ccccc12
Product: CC(C)(C)OC(=O)NCc1nn(NC(=O)Cc2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 41B and 2-(4-fluorophenyl)acetyl chloride were treated using a method similar to that described in Example 4C to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.32 (dd, J=7.8, 1.4, 1H), 8.11 (d, J=8.0, 1H), 8.04-7.94 (m, 1H), 7.95-7.86 (m, 1H), 7.45-7.36 (m, 3H), 7.23-7.13 (m, 2H), 4.47-4.41 (m, 2H), 3.66 (s, 2H), 1.37 (s, 9H); MS (ESI−) M/Z 425 (M−H)−.
Reaction SMILES: C(OC(=O)[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=1)[C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[CH3:17])(C)(C)C.[ClH:31]>O1CCOCC1.CCOCC>[ClH:31].[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][NH:7][C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH3:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)C(=O)OC(C)(C)C)sc2ccccc12
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(NCc2ccc(F)c(C(F)(F)F)c2)sc2ccccc12
Reaction time: 3 h

Procedure:
To compound 6-C was added a solution of 4N HCl in dioxane (20 mL) and the reaction mixture was stirred for 3 hours. The reaction mixture was diluted with ether, the solid filtered, washed with ether, and dried under vacuo to afford 1.86 g of compound 6-D as a white solid. 1H NMR (CD3OD, 300 MHz): δ 7.61-7.83 (m, 3H), 7.52 (d, 1H), 7.26-7.39 (m, 2H), 7.10-7.26 (m, 1H), 4.57 (s, 2H), 2.22 (s, 3H); MS (method 2): m/z 340.0 (MH+); HPLC (method 1): Rt 6.78 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH:14]=[CH2:15])=[CH:5][CH:4]=1.C=O.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[S:9][CH2:10][CH2:11][N:12]([C:13](=[O:16])[CH:14]=[CH2:15])[CH2:19][C:5]=2[CH:4]=1
Reactant: C=CC(=O)NCCSc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=O
Solvent: c1ccccc1
Product: C=CC(=O)N1CCSc2ccc(OC)cc2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of compound 32 (280 mg), paraformaldehyde (600 mg), p-toluenesulfonic acid (140 mg) in benzene (7.0 mL) was stirred at 80° C. for 16 h. The reaction mixture was filtered and washed with sat. NaHCO3 solution (2×3 mL). The solvents were removed by evaporation under reduced pressure to give product 33 as an oil. Yield: 253 mg, 86%.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O>[CH:1]1([CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C(=O)OC)ccc1OCC1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(=O)O)ccc1OCC1CCCCC1
Reaction time: 40 h

Procedure:
To a solution of 23-5 (290 mg, 1.0 mmol) in 7.6 mL of THF and 10 mL of water was added 210 mg (5.0 mmol) of LiOH. The resulting solution was stirred for 40 h, then acidified by the addition of 10 mL of 1N HCl. The aqueous phase was extracted with 2×20 mL of EtOAc. The organic extracts were washed with brine (5 mL) and dried over MgSO4. Evaporation of the solvent afforded acid 23-6 which was used without purification.
Reaction SMILES: Cl[C:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:7])[C:3]([F:6])([F:5])[F:4].[CH3:16][Al](C)C>Cl>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:2]([CH3:16])([CH3:7])[C:3]([F:6])([F:5])[F:4])=[CH:9][CH:10]=1
Reactant: COc1ccc(C(C)(Cl)C(F)(F)F)cc1
Reactant: C[Al](C)C
Agent: Cl
Product: COc1ccc(C(C)(C)C(F)(F)F)cc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
A solution of 1-(2-chloro-1,1,1-trifluoropropan-2-yl)-4-methoxybenzene (18.0 g, 75 mmol) in 400 ml of hexanes was treated with trimethylaluminum (151 ml, 302 mmol) (2.0 M in heptane) at rt and the resulting mixture was heated at 95° C. overnight. The reaction mixture was cooled in an ice-water bath, conc. HCl was added to the reaction mixture dropwise. Fumes were generated. After about 10 ml of conc. HCl was added, more rapid addition of acid was possible due to the near complete quenching of the unreacted AlMe3. After addition of 100 ml of conc. HCl, 250 ml of H2O was added and the mixture was stirred vigorously for 1 h. The layers were separated. The org layer was dried (Na2SO4) and concentrated to give the title compound as an oil, which solidified upon drying on the vac line.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:8][C@H:7]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=3[O:31][CH3:32])[C:6]=2[CH:33]=1.[CH2:34](I)[CH3:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]([CH3:15])([CH3:14])[CH3:16])[C:10](=[O:17])[C@@H:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:8][C@H:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:34][CH3:35])=[CH:26][C:25]=3[O:31][CH3:32])[C:6]=2[CH:33]=1
Reactant: CCOC(=O)C[C@H]1O[C@H](c2ccc(O)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1O[C@H](c2ccc(OCC)cc2OC)c2cc(Cl)ccc2N(CC(C)(C)C)C1=O
Reaction time: 3 h

Procedure:
A mixture of ethyl trans-7-chloro-5-(4-hydroxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (0.25 g), ethyl iodide (0.06 ml), potassium carbonate (0.15 g) and N,N-dimethylformamide (200 ml) was stirred for 3 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (100 ml). The extract was washed with 1N hydrochloric acid and aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in vacuo to give ethyl trans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (0.24 g) as colorless crystals (mp=164°-166° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9](O)=O)[CH:7]=1.[C@@H]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][C:31]3[S:32][C:33](CC)=[CH:34][CH:35]=3)C=2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][CH2:9][C:33]2[S:32][C:31]([C:30]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=3)=[CH:35][CH:34]=2)[CH:7]=1
Reactant: CCc1ccc(Cc2cccc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)s1
Reactant: O=C(O)Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1CCc1ccc(-c2ccccc2)s1

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml), and pyridine (2 drops), and the mixture was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification. (3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at 160° C. overnight. The mixture was further diluted with water, and cooled to 0° C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H). (4) The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118-(4) and (5) to give the desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@H:18]([NH2:26])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29](=[O:40])[C:30](=[CH:35][CH:36]=[CH:37]OC)[C:31](OC)=[O:32].C[O-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C@@H:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:26]2[CH:37]=[CH:36][CH:35]=[C:30]([C:29]([O:28][CH3:27])=[O:40])[C:31]2=[O:32])=[CH:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: COC=CC=C(C(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccn([C@@H](Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)C(=O)OC(C)(C)C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of (S)-3-(2-Amino-2-tert-butoxycarbonyl-ethyl)-indole-1-carboxylic acid tert-butyl ester (2.5 g, 7 mmol) in methanol (15 ml) was added 2-(3-methoxy-allylidene)-malonic acid dimethyl ester (1.5 g, 7 mmol) and stirred overnight at room temperature. Sodium methoxide (78 mg, 1.4 mmol) was added and stirred for three hours at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with ethylacetate (60 ml). The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to afford the crude product, which was perified by flash chromatography (30-70% ethylacetate/petroleum ether) to afford the title compound as a white solid (2.3 g, 57%); 1H NMR (400 MHz, CDCl3) δ 1.43 (9H, s), 1.72 (9H, s), 3.50 (2H, m), 3.91 (3H, m), 5.68 (1H, br s), 6.08 (1H, t), 7.2-7.5 (5H, m), 8.15 (2H, m); M+H 497.5, M−H 495.5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28](O)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[C:25]([C:28]([NH:1][C:2]3[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:4][CH:3]=3)=[O:29])[NH:26][CH:27]=2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c[nH]1
Reactant: Nc1ccc(OCCN2CCCC2)nc1
Product: O=C(Nc1ccc(OCCN2CCCC2)nc1)c1cc(-c2ccc(Cl)cc2)c[nH]1

Procedure:
5-Amino-2-((pyrrolidin-1-yl)ethoxy)pyridine was converted to the title compound (18 mg) by acylation with 4-(4-chlorophenyl)-1H-pyrrole-2-carboxylic acid (21 mg) following the procedure described in step C of Example 1. MS (ESI) 411 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[N:10][CH:9]=[CH:8][CH:7]=2.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[N:10][CH:9]=[CH:8][CH:7]=2
Reactant: ClCc1cc2ncccc2[nH]1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1cc2ncccc2[nH]1
Reaction time: 8 h

Procedure:
Crude 2-chloromethyl-4-azaindole monohydrochloride (3.0 g, approximately 14.8 mmol) is added to a 25% solution of sodium methoxide in methanol (16.8 ml) and the reaction is refluxed with stirring for 8 hours under an argon atmosphere. The reaction is concentrated and the residue is chromatographed on silica gel using mixtures of CH2Cl2, MeOH, and NH4OH as eluents to give pure 2-methoxymethyl-4-azaindole.
Reaction SMILES: C([O:5][C:6](=[O:26])[CH2:7][CH2:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:12][N:11]=1)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O.O>[F:24][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:16]([C:13]2[CH:14]=[N:15][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:26])=[O:5])=[N:11][CH:12]=2)=[O:25])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)CCNc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(O)CCNc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 98 %

Procedure:
A solution of 3-[5-(4-fluorophenylcarbamoyl)pyrimidin-2-ylamino]propionic acid tert-butyl ester in 90% trifluoroacetic acid/water was stirred for 15 min. Toluene (4 mL) was added and the solution was concentrated in vacuo. A series of dilutions and concentrations were performed using acetic acid/toluene (1/1) followed by methanol/toluene (1/1). The resulting solids were triturated with ethyl acetate/hexane (2/1) to afford 61.1 mg (98% yield) of the titled product as a white solid. API-MS m/z 305 (MH)+, 303 (M−H)−.
Reaction SMILES: [CH:1]1([N:6]([CH3:40])[C:7]2[CH:8]=[C:9]([N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:10]=[C:11]([C:14](=[O:26])[NH:15][CH2:16][C:17]3[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=3[CH3:23])[C:12]=2[CH3:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]>C(Cl)Cl>[CH:1]1([N:6]([CH3:40])[C:7]2[C:12]([CH3:13])=[C:11]([CH:10]=[C:9]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:8]=2)[C:14]([NH:15][CH2:16][C:17]2[C:18](=[O:25])[NH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([OH:47])([C:43]([F:46])([F:45])[F:44])=[O:42]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCNCC3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of tert-butyl 4-(3-(cyclopentyl(methyl)amino)-5-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-4-methylphenyl)piperazine-1-carboxylate (0.30, 0.54 mmol) in DCM (10 mL) was cooled to 0° C. and TFA (3 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. Upon completion, the mixture was concentrated to dryness. Half crude was purified by solvent washing giving the title compound as TFA salt (0.01 g, 8.33%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:7])(C)(C)C.[BH4-].[Na+]>CO>[CH3:1][O:5][C:6]([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[CH:9]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][CH:12]1[OH:13])=[O:7]
Reactant: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC/C=C\CC1(C(=O)OC)C(O)CCC1CC(=O)OC

Procedure:
A 220 mg quantity of 5-methoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (2-b)) and 60 mg of sodium borohydride are dissolved in 50 ml of methanol, and the solution is refluxed for one hour. The same procedure as in Example 1 is thereafter repeated, affording 2-methoxycarbonyl-3-methoxycarbonylmethyl-2-(cis-2-pentenyl)-cyclopentanol (compound (1-b), R1 =R2 =CH3) in a yield of 94.7%, b.p. 74°-78° C./0.01 mm Hg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)[CH2:20][CH2:19]1)[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.O.NN>>[NH2:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:18]([CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)[CH2:19][CH2:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccc(C(F)(F)F)cc2)c2ccccn2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCN(C(c2ccc(C(F)(F)F)cc2)c2ccccn2)CC1

Procedure:
The title compound was prepared in a quantitative yield in a similar manner to that described in Preparation 15' by reacting 4-[α-(2-pyridyl)-4-trifluoromethylbenzyl]-1-(2-phthalimidoethyl)piperazine (prepared as described in Preparation 52') and hydrazine hydrate.
Reaction SMILES: O.[CH3:2][C:3]([CH3:19])([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=[O:17])[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])[CH3:4].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:37])[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH2:30]>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28](=[O:37])[CH:29]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:30][N:13]1[CH:14]=[N:15][C:11]([CH2:10][C@@H:9]([C:16]([OH:18])=[O:17])[NH:8][C:6]([O:5][C:3]([CH3:19])([CH3:2])[CH3:4])=[O:7])=[CH:12]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(CC(C(=O)c2ccc(Cl)cc2Cl)c2ccccc2)cn1)C(=O)O
Reaction time: 18 h
Yield: 100.2 %

Procedure:
Water was added to a stirred suspension of N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (13.26 g) in ethanol (100 ml) and 1-(2,4-dichlorophenyl)-2-phenylpropen-1-one (14.5 g) until a clear solution was obtained. The clear solution was allowed to stand for 18 hours, and was then concentrated under reduced pressure to yield a foam which was triturated with hexane. The resulting mixture was filtered to yield 1-[3-(2,4-dichlorophenyl)-3-oxo-2-phenylpropyl]-N-[(1,1-dimethylethoxy)carbonyl]-L-histidine (27.7 g), as a mixture of diastereoisomers.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:56])[CH3:55])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47]([O:49]C(C)(C)C)=O)=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)C(O)=O)=[O:61].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:42]1[C:40]1[NH:41][C:37]([C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=2)[C:17]2[NH:18][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]([CH3:55])[CH3:56])=[N:15][C:16]=2[CH:26]=[CH:25]4)[CH:36]=[CH:35]3)=[CH:38][N:39]=1)=[O:49])=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
(S)-tert-butyl 2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (88 mg, 0.116 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane, 1 mL) was added. After stirring for 1 h, the reaction mixture was concentrated and the residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (24 mg, 0.116 mmol), COMU (50 mg, 0.116 mmol) and DMF (3 mL). DIPEA (0.101 mL, 0.58 mmol) was added and the mixture was stirred for 13 min before being quenched with H2O and purified by HPLC to afford the title compound (61 mg, 62%). MS: (ESI) m/z 847 [M+H]+.