Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S-:21])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].I[CH3:30].[OH-].[Na+]>O>[CH2:1]([NH:5][C:6]1[N:11]2[N:12]=[C:13]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:30])[N:16]=3)=[C:10]2[CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc2c(-c3ccnc([S-])n3)c(-c3ccc(F)cc3)nn12
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCNc1cccc2c(-c3ccnc(SC)n3)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
A mixture of 4-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinethiolate (2.87 g, 6.9 mmol) in 50 mL water was treated with iodomethane (0.86 mL, 13.8 mmol) and sodium hydroxide (4.1 mL, 5 N aqueous solution) and allowed to stir at room temperature for 4 hours. The mixture was diluted with additional water and extracted with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate and concentrated. Flash column chromatography eluting with 9:1 hexanes-ethyl acetate afforded N-butyl-2-(4-fluorophenyl)-3-[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-α]pyridin-7-amine (1.64 g, 56%) as a yellow foam. 1H NMR (CDCl3): δ 8.15 (d, 1H), 7.73 (d, 1H), 7.56 (m, 2H), 7.33 (t, 1H), 7.13 (t, 2H), 6.62 (d, 1H), 6.02 (m, 2H), 3.35 (q, 2H), 2.55 (s, 3H), 1.76–1.41 (m, 4H), 0.95 (t, 3H); 19F NMR (CDCl3): δ −112.75; MS m/z 408 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26].CN(C=O)C>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[CH3:26]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1c(C)cccc1C
Yield: 91.1 %

Procedure:
A solution of 2,6-dimethylphenol (0.87 g, 7.1 mmol), potassium carbonate (0.98 g, 7.1 mmol), 2-fluoro-5-nitrotoluene (1.0 g, 6.4 mmol) and DMF (20 mL) was stirred at 100° C. for 2 h. The reaction mixture was diluted with 100 mL water and extracted with 250 mL EtOAc. The organic layer was washed with brine, dried with sodium sulfate and concentrated to provide the crude titled compound (1.5 g, 92%). This material was used without purification: MS (ESI): mass calcd. for C15H15NO3, 257.3; m/z found, 258.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.16 (dd, J=2.8, 0.7 Hz, 1H), 7.92 (dd, J=9.1, 2.7 Hz, 1H), 7.18-7.07 (m, 3H), 6.33 (d, J=9.0 Hz, 1H), 2.50 (s, 3H), 2.09 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([O:16]CC)=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N:25]1[NH:26][N:27]=[N:28][C:29]=1[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33].C1(N=C=NC2CCCCC2)CCCCC1.OC1C2N=NNC=2C=CC=1>C(O)C.[Pd].CN(C=O)C>[N:28]1[NH:27][N:26]=[N:25][C:29]=1[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:14]([OH:16])=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)=[O:33]
Reactant: O=C(O)c1ccccc1-c1nn[nH]n1
Reactant: CCCCCCC(C(=O)OCC)n1cnc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCC(C(=O)O)n1cnc2c(NC(=O)c3ccccc3-c3nn[nH]n3)cccc21
Reaction time: 4 h
Yield: 9.6 %

Procedure:
Ethyl 2-(4-nitro-1H-benzimidazol-1-yl)octanoate (4.44 moles, 1.48 g.) was hydrogenated over 0.6 g of 5% Pd/C in 100 ml ethanol. The catalyst was filtered over celite. The solution was concentrated. The residue was dissolved in 25 ml DMF and added to a stirred mixture of 2-(2H-tetrazol-5-yl)benzoic acid (4.21 mmoles, 0.80 g), dicyclohexylcarbodiimide (4.31 mmoles, 0.89 g.), and hydroxybenzotriazole (4.44 mmoles, 0.60 g) in 50 mi DMF. The reaction was stirred for 4 hours. The solid was removed by filtration. The reaction was concentrated. The residue was dissolved in ethyl acetate, and washed with water. The pH was adjusted to 8.0 using 5N NaOH. The aqueous layer was acidified to pH 2.5 using 2N HCL, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried and concentrated. The product was purified over silica gel eluted with 2% EtOH in ethyl acetate with 1% acetic acid to yield 0.18 g of 2-[4-[2-(2H-tetrazol-5-yl)benzamido]-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[C:16]2[N:17]([N:21]=[C:22](Cl)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:38][C:35]3[CH:34]=[CH:33][C:32]([N:29]4[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]4)=[CH:37][CH:36]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC1CNc1cccn2nc(Cl)nc12
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCC5CCCN5C(=O)OC(C)(C)C)cccn4n3)cc2)CC1

Procedure:
170 b) 2-({2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (400.0 mg, 1.137 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (240.0 mg, 1.255 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (63.0 mg, 0.115 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan resin (0.090 g, 16%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81-7.74 (m, 1H), 7.47 (d, J=7.6 Hz, 2H), 6.95 (dm J=8.8 Hz, 2H), 6.74-6.45 (m, 3H), 5.40-4.90 (m, 1H), 4.23-4.06 (m, 1H), 3.56-3.05 (m, 8H), 2.63-2.57 (m, 4H), 2.36 (s, 3H), 2.05-1.80 (m, 4H), 1.56-1.44 (m, 9H). MS=507 (MH)+.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:10]=2)=[O:8])=[CH:5][CH:4]=1.CSC.B(F)(F)F>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:24])[C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:10]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: COc1ccc(C(=O)c2cccc(C(=O)c3ccc(OC)cc3)c2)cc1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1cccc(C(=O)c2ccc(O)cc2)c1
Reaction time: 27 h
Yield: 37.5 %

Procedure:
To a well-stirred solution of 1,3-bis-(4-methoxybenzoyl)benzene 14 (1.80 g, 5.2 mmol) in dichloromethane (85 mL) was added boron trifluoride dimethyl sulfide complex (BF3.SMe2, 15 mL). The mixture was stirred for 27 h. After the reaction was quenched by water, the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under vacuum. The resulting solid was further purified using flash chromatography (silica gel, hexanes:ethyl acetate, 50:50) to afford the pure 1,3-bis-(4-hydroxybenzoyl)benzene 20 (0.62 g, 1.95 mmol) as a white solid in a 38% yield; 1H NMR (500 MHz, Acetone-d6): δ 9.28 (s, OH), 8.04 (td, J=1.7 Hz, 1.3 Hz, 1H, ArH), 7.98 (dd, J=7.7 Hz, 1.75 Hz, 2H, ArH), 7.80 (ddd, J=9.5 Hz, 4.8 Hz, 2.75 Hz, 4H, ArH), 7.73 (td, J=7.9 Hz, 0.45 Hz, 1H, ArH), 7.00 (ddd, J=9.5 Hz, 4.8 Hz, 2.75 Hz, 4H, ArH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:11][N:10]([CH3:18])[N:9]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:27][C:28]=1[CH3:29])[CH2:6][O:7][C:8]1[C:12]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][N:10]([CH3:18])[N:9]=1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(C)cc2CC(=O)O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of methyl [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-methyl-1H-pyrazol-4-yl]acetate (544 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-methyl-1H-pyrazol-4-yl]acetic acid (482 mg, yield 91%), which was then recrystallized from acetone-hexane. melting point: 153–154° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]2[CH2:15][CH:16](C(OC)=O)[C:17](=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(C)=O.O>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]2[CH2:15][CH2:16][C:17](=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1Cc2cnc(OCc3ccccc3)cc2C1=O
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cnc(OCc3ccccc3)cc21
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
Compound H6.4 (2.50 g, 8.41 mmol) was dissolved in 27 mL DMSO and 3 mL water. The resulting mixture was heated to 150° C. and stirred for 30 minutes. After the reaction was complete, the reaction was diluted with 120 mL water and extracted twice with 50 mL EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated onto silica gel. The resulting product was purified by column chromatography with 10% EtOAc/hexane to afford desired product H6.5 (1.76 g, 87.5%). MS ESI (pos.) m/e: 240.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH3:8].[H-].[Na+].C(O)(=O)C.[CH3:23][O:24][C:25](=O)[O:26]C>>[Cl:1][C:2]1[S:3][C:4]([CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7](=[O:9])[CH2:8][C:25]([O:24][CH3:23])=[O:26]
Reactant: COC(=O)OC
Reactant: CC(=O)c1cc(CN2CCOCC2)sc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)CC(=O)c1cc(CN2CCOCC2)sc1Cl
Temperature: 95 °C
Yield: 41 %

Procedure:
To a solution of 1-(2-chloro-5-(4-morpholinylmethyl)-3-thienyl)ethanone (Preparation 63, 9.53g) in dimethylcarbonate (200 mL) is added NaH (1.53 g; 60% dispersion in mineral oil) portionwise at ambient temperature. The reaction mixture is heated to 95° C. for 3 h. The reaction vessel is cooled to ambient temperature and the mixture is poured into ice cold water (500 mL) containing acetic acid (15 mL). The aqueous layer is extracted with Et2O (3×100 mL). The organic layer is separated, dried over MgSO4, filtered, and concentrated in vacuo. The crude brown liquid is purified by silica gel column chromatography (4/1, hexanes/EtOAc) to afford 4.77g (41%) of the title compound as a tan solid. Physical characteristics: m.p. 67-68° C.; 1H NMR (300 MHz, CDCl3) δ 7.21, 3.99, 3.78, 3.71, 3.60, 2.50; IR (diffuse reflectance) 2822, 1738, 1663, 1461, 1399, 1350, 1336, 1316, 1286, 1265, 1156, 1113, 1009, 1004, 864 cm−1; MS (ESI+) m/z 318; Anal. Found: C, 48.89; H, 5.13; N, 4.45.
Reaction SMILES: F[C:2]1([F:10])[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH2:3]1.Cl[C:12]1[C:13]2[C:26]([CH3:27])=[CH:25][S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:10])=[CH:9][CH:8]=3)[C:13]3[C:26]([CH3:27])=[CH:25][S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: Cc1csc2nc(-c3cccnc3)nc(Cl)c12
Reactant: NCC1=CCC(F)(F)C=C1
Product: Cc1csc2nc(-c3cccnc3)nc(NCc3ccc(F)cc3)c12

Procedure:
With the procedure of Example 1, the reaction of 4-fluoro-4-fluorobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(4-fluorobenzylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[C:5]([Cl:19])=[CH:4][N:3]=1.Cl.[CH3:21][N:22]1[CH:26]=[C:25]([NH2:27])[CH:24]=[N:23]1.C(N(C(C)C)C(C)C)C>CCCCO>[Cl:19][C:5]1[C:6]([N:8]([CH3:18])[CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)=[N:7][C:2]([NH:27][C:25]2[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=2)=[N:3][CH:4]=1
Reactant: CN(c1nc(Cl)ncc1Cl)C1COC2C(O)COC21
Reactant: Cn1cc(N)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nc(Nc2cnn(C)c2)ncc1Cl)C1COC2C(O)COC21
Temperature: 150 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a suspension of 6-((2,5-dichloropyrimidin-4-yl)(methyl)amino)hexahydrofuro[3,2-b]furan-3-ol (342.2 mg, 1.12 mmol) and 1-methyl-1H-pyrazol-4-amine hydrochloride (185.0 mg, 1.38 mmol) in n-BuOH (5 mL) was added N-ethyldiisopropylamine (358.8 mg, 2.78 mmol). The reaction mixture was stirred at 150° C. in a sealed tube overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/40) to give the title compound as a beige solid (156 mg, 38.0%).
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:10][C:11]([SH:14])([CH3:13])[CH3:12].[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([S:14][C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:9])[CH3:8])[CH3:7]
Reactant: CC(C)(C)S
Reactant: CCOC(=O)C(C)(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SC(C)(C)C
Yield: 34.7 %

Procedure:
Ethyl 2-bromoisobutyrate (40.0 g, 0.205 mole), 2-methyl-2-propanethiol (20.4 g, 0.0226 mole), potassium hydroxide (14.4 g, 0.226 mole), ethyl alcohol (100 g) were combined and reaction mixture was refluxed for six hours prior to quenching. Crude yield: 61.0%; Distilled yield: 34.7%. Flavor description: astringent, tropical, mango, citrus, grapefruit, onion, catty, marigold, herbal, floral, geranium, green. Fragrance description: grapefruit, passion fruit, papaya, dandelion, marigold, caraway, berries, slight onion.
Reaction SMILES: [C:1]1([CH:7]2[O:12][C:10](=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:13]>>[OH:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]([NH2:13])=[O:11]
Reactant: N
Reactant: O=C1CCC(c2ccccc2)O1
Product: NC(=O)CCC(O)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
A mixture of γ-phenyl-γ-butyrolactone (10.30 g, 63.5 mmol) and an excess of ammonia was stirred under nitrogen and a dry ice trap for 8 hours. The dry ice trap was removed and after evaporation of the ammonia 11.27 g of a tan solid remained. Recrystallization of the solid from ethyl acetate-hexane gave 4-hydroxy4-phenyl-butyramide (8.56 g, 75%) as a white solid, mp 85-87° C.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:47]1([C@H:53]([NH2:56])[CH2:54][CH3:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:56][C@@H:53]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:54][CH3:55])=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC[C@@H](N)c1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N[C@H](CC)c2ccccc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with (R)-(+)-1-phenylpropylamine (Alfa) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:14][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3C#N)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzonitrile (0.22 g, 1 mmol) in isopropanol (8 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2 h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (MeOD) δ: 1.40 (6H, s), 2.30-2.58 (8H, m), 3.00-3.15 (4H, m), 5.20 (1H, br s), 6.18 (1H, t), 6.70 (1H, dd), 7.18-7.84 (7H, m), 8.50 (1H, dd). ESI-MS m/z: 515 (M+1), UV retention time: 1.75 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:27]=[CH:26][NH:25][C:24]=1[CH2:28]O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:13]([CH3:15])[CH3:14])[C:10]([O:12][CH2:28][C:24]2[NH:25][CH:26]=[CH:27][C:23]=2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(Nc1ccc(F)cc1)C(=O)O
Product: CC(C)C(Nc1ccc(F)cc1)C(=O)OCc1[nH]ccc1Cc1ccccc1

Procedure:
The acid 2-(4-fluorophenylamino)-3-methylbutanoic acid is reacted with 3-benzylpyrrolylmethyl alcohol using the procedure of Example 3 to give 3-benzylpyrrolylmethyl 2-(4-fluorophenylamino)-3-methylbutanoate.
Reaction SMILES: [OH:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[C:21](Cl)(=[O:23])[CH3:22]>C(Cl)(Cl)Cl>[C:21]([O:1][C:2]1([CH3:13])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH3:22]
Reactant: CCCCCC1C(=O)C=CC1(C)O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCC1C(=O)C=CC1(C)OC(C)=O
Reaction time: 2 h
Yield: 96 %

Procedure:
Into the same flask as in Example 1, 3-hydroxy-2-n-pentyl-3-methyl-4-cyclopentenone (18.2 g), triethylamine (20.3 g) and chloroform (150 g) were charged, and acetyl chloride (15.8 g) was dropwise added thereto at a temperature of 10° to 15° C. in 2 hours. Then, stirring was continued at room temperature for 20 hours. The reaction mixture was treated as in Example 1. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate (10:1) as an eluent to give dl-3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone (21.5 g). Yield, 96%.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@@H:14]([OH:16])[CH2:15][C@@:9]1([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@H:10]([O:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([CH2:18][O:17][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:15][C@@H:14]3[OH:16])[CH:20]=[C:21]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: O[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: O[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-ol (Example 43; 35 mg 0.065 mmol), 5% palladium on charcoal (150 mg, 0.07 mmol) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallised from iso-hexane:diethyl ether.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34])([O-:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N+:23]([O-:25])=[O:24])=[O:34])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccccc1[N+](=O)[O-]

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 2-nitrophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.