Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][NH:19][C:20](=[O:21])[C:10]3=[CH:9]2)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3=[N:18][N:19]([CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:20](=[O:21])[C:10]3=[CH:9]2)=[CH:5][CH:6]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc2c3ccccc3n(Cc3ccc(-c4ccccc4)cc3)cc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2cn(Cc3ccc(-c4ccccc4)cc3)c3ccccc3c-2nn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Biphenyl-4-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one [(Example 8, Step 3), 110 mg, 0.313 mmol] was dissolved in N,N-dimethylformamide (5 mL), cooled to 0° C. and treated with sodium hydride (37.6 mg, 0.939 mmol, 3 equiv). After stirring for 15 minutes, the mixture was warmed to ambient temperature and stirred for an additional 15 minutes. The mixture was cooled to 0° C., treated with benzyl bromide (0.112 mL, 0.939 mmol, 3 equiv) and after 5 minutes, was warmed to ambient temperature over 2 hours and stirred for an additional 14 hours at ambient temperature. The mixture was poured into water (40 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 95:5; dichloromethane:methanol), providing the titled compound: high resolution mass spectrometry (ES+) m/z 442.1922 [(M+H)+; calculated for C30H24N3O: 442.1914].
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([OH:22])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])OC(C)(C)C)[CH3:27].[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.Cl.C(OCC)(=O)C>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:13][C:14]4[C:20]([F:21])=[C:19]([O:22][CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[CH3:36])[CH3:27])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: Oc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4)c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3-fluorophenyl)-7-fluoro-1,3-benzoxazol-6-ol (3.96 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (3.28 g) and triphenylphosphine (4.91 g) in THF (50 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 9.85 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give a solid. To this solid was added 4 M hydrogen chloride/ethyl acetate (50 mL), and the mixture was stirred at room temperature for 10 min, and concentrated. To the residue were added pyridine (50 mL) and acetic anhydride (50 mL), and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated under reduced pressure, and the obtained solid was dissolved in ethyl acetate/methanol, and the solution was subjected to silica gel column chromatography (NH, ethyl acetate), and concentrated. The obtained solid was recrystallized (hexane/ethyl acetate) to give the title compound as white crystals (2.80 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C([Li])CCC.CON(C)[C:21]([CH:23]1[CH2:26][CH:25]([NH:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:24]1)=[O:22]>O1CCCC1>[CH3:1][O:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:21]([CH:23]1[CH2:24][CH:25]([NH:27][C:28]2[C:33]([N+:34]([O-:36])=[O:35])=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:26]1)=[O:22]
Reactant: CON(C)C(=O)C1CC(Nc2ncccc2[N+](=O)[O-])C1
Reactant: COCn1cnc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1c(C(=O)C2CC(Nc3ncccc3[N+](=O)[O-])C2)nc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a solution of 1-(methoxymethyl)-1H-benzo[d]imidazole (1.5 g, 9.04 mmol) in dry tetrahydrofuran (20 mL) at −78° C. was added butyllithium (2.5 M in hexane, 3.7 mL, 9.16 mmol). The solution was stirred at −78° C. for 30 min and a solution of N-methoxy-N-methyl-3-((3-nitropyridin-2-yl)amino)cyclobutanecarboxamide (1.92 g, 6.87 mmol) in dry tetrahydrofuran (20 mL) was added dropwise via cannula. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to room temperature and quenched with water. The reaction mixture was extracted with ethyl acetate (3×30 mL) and the organic phases were combined and washed with water (20 mL), then brine (20 mL). The organic was dried over magnesium sulfate and concentrated to get a residue, which was purified by flash column chromatography on silica gel (10% to 40% ethyl acetate in hexanes) to give (1-(methoxymethyl)-1H-benzo[d]imidazol-2-yl)(3-((3-nitropyridin-2-yl)amino)-cyclobutyl)methanone (1.17 g, 3.07 mmol, 80% yield) as solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:12])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:62][C:63]1[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=1>CN(C=O)C.CCOC(C)=O>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:62][C:63]2[CH:68]=[CH:67][N:66]=[CH:65][CH:64]=2)=[CH:3][C:2]=1[Br:1])[CH3:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1Br
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (7496 to 61011 μmol) in DMF (10 to 30 ml) were added DIEA (2 eq.), TBTU (1.3 eq.) and HOBt (0.3 eq.). The reaction mixture was stirred at RT for 5 minutes. 4-Aminopyridine (1.5 eq) was added and the reaction mixture was stirred at RT for 2.5 hours up to overnight. When there was still starting material observed, more DIEA (0.39 eq), TBTU (0.25 eq), HOBt (0.06 eq) and 4-aminopyridine (0.28 eq) were added and the reaction mixture was stirred at RT for another 2 hours. The reaction mixture was diluted with EtOAc, washed with 0.1 M HCl and saturated Na2CO3 or with saturated NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][CH:4]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[C:21]([O:20][C:19]([F:18])([F:29])[F:30])[CH:22]=2)=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Reactant: OCc1cccc(OC(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(OCc2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and 3-trifluoromethoxybenzyl alcohol (123 mg, 0.640 mmol) were dissolved in tetrahydrofuran (2 mL), and triphenylphosphine (165 mg, 0.629 mmol) and a diethyl azodicarboxylate toluene solution (2.2 M, 290 μL, 0.638 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 4 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (124 mg, 72%).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[C:7]([Br:14])=[N:8][CH:9]=[C:10]([S:12][CH3:13])[N:11]=1>O.C(O)(=O)C>[Br:14][C:7]1[C:6]([OH:2])=[N:11][C:10]([S:12][CH3:13])=[CH:9][N:8]=1
Reactant: O=N[O-]
Reactant: CSc1cnc(Br)c(N)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1cnc(Br)c(O)n1
Temperature: 25 °C

Procedure:
A SOLUTION OF SODIUM NITRITE (842 MG, 12.2 MMOL) IN WATER (100 ML) WAS ADDED TO A STIRRED SOLUTION OF 3-AMINO-2-BROMO-5-METHYLTHIOPYRAZINE (2.44 G, 11.1 MMOL) IN ACETIC ACID (100 ML) AT 0°C. THE REACTION WAS WARMED TO RT AND AFTER 16 H THE REACTION MIXTURE WAS PARTITIONED BETWEEN WATER AND METHYLENE CHLORIDE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE CRUDE PRODUCT WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (40% ETHYL ACETATE/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([O:28][C:29](=[O:34])[CH2:30]C(O)=O)[CH3:27]>O1CCCC1>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](=[O:6])[CH2:30][C:29]([O:28][CH2:26][CH3:27])=[O:34]
Reactant: CCOC(=O)CC(=O)O
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1C
Yield: 76.4 %

Procedure:
A solution of 2-methyl-3-nitrobenzoic acid (10.0 g, 55.2 mmol) and carbonyldiimidazole (13.4 g, 82.8 mmol) in tetrahydrofuran (200 mL) is stirred at room temperature for 2 hours under an argon atmosphere. The magnesium salt of malonic acid monoethyl ester (47.4 g, 165 mmol) is added and the reaction mixture is heated at reflux for 18 hours. The reaction mixture is quenched with water (200 mL) and acidified to pH=1 with concentrated HCl. The product is extracted into ethyl acetate and washed with 1.0 N HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer is dried over magnesium sulfate and evaporated. Recrystallization of the residue gives ethyl 2-methyl-3-nitro-β-oxobenzenepropanoate (10.6 g, 76%), mp=50-51° C.
Reaction SMILES: [OH-:1].[Na+].S(O)(O)(=O)=O.[NH2:8]O.[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:36]([F:39])([F:38])[F:37])=[CH:19][C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]([O:34][CH3:35])=[O:33])=[CH:24][CH:23]=2)=O)[CH:14]=[C:15]([Cl:17])[CH:16]=1>O.O1CCCC1.CO>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:36]([F:39])([F:38])[F:37])[O:1][N:8]=[C:20]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]([C:32]([O:34][CH3:35])=[O:33])=[CH:24][CH:23]=3)[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: [OH-]
Reactant: NO
Reactant: COC(=O)c1ccc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)c2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Sodium hydroxide (50%, 3.50 g, 43.7 mmol) was added to a solution of hydroxylamine sulfate (1.8 g, 11.0 mmol) in water (22 mL). When the mixture had cooled to room temperature a portion of the mixture (˜50%) was added dropwise over 4 minutes to methyl 4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-1-oxo-2-buten-1-yl]-1-naphthalene-carboxylate (i.e. the product of Step A) (5.00 g, 11.0 mmol) in tetrahydrofuran (55 mL) at room temperature. After 30 minutes a further portion (˜10%) of the aqueous mixture was added. The mixture was stirred for a further 15 minutes. The mixture was partitioned between hydrochloric acid (1 N, 50 mL) and tert-butyl methyl ether (50 mL). The organic phase was evaporated, and the solid obtained was stirred in hot methanol. The mixture was cooled and filtered to give the product as a white solid (4.50 g, 87%) melting at 137.3-138° C. (after recrystallization from methanol). The following spectra were of the product recrystallized from methanol.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21]O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:1]1([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: OC[C@@H]1CSC(c2cc3cccc(NC4CCCC4)c3[nH]2)=N1
Product: c1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CN4CCCC4)CS3)cc2c1

Procedure:
[(R)-2-(7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-methanol prepared in Example 2 and pyrrolidine were reacted according to the same procedure as Example 156 to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][C@@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:13]([C@H:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:14]
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1
Reactant: CN
Solvent: CC(=O)OC(C)=O
Product: CNC(=O)[C@@H]1CC[C@H](C(=O)O)N1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
Cis-N-benzylpyrrolidine-2,5-dicarboxylic acid (41.3 g, 0.166 mole) and acetic anhydride (206.5 ml) were heated carefully together to 100° C; the solid gradually dissolved, and the mixture assumed a dark brown color. In typical experiments, solution was complete in 10-30 minutes, depending on the state of subdivision of the starting material. Heating time was minimized. Just before the last solid dissolved, the excess acetic anhydride was removed in vacuo, and the brown oily residue of crude cis-N-benzylpyrrolidine-2,5-dicarboxylic acid anhydride was taken up in 400 ml benzene. Anhydrous methylamine (0.33 mole as 9.9% solution in benzene) was added in two portions, and the mixture was heated on the steam bath for 45 minutes. After cooling, the crude cis-5-(N-methylcarbamyl)-1-benzylpyrrolidine-2-carboxylic acid (35.8 g) was collected by filtration, washed with benzene and recrystallized from ethanol. Yield: 31.4 g (72%), melting point 190°-192° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=1)=[O:4].[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1>C(#N)C>[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([CH2:2][C:3]([C:5]3[CH:18]=[CH:17][C:8]([O:9][CH2:10][C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])=[CH:7][CH:6]=3)=[O:4])[CH2:29][CH2:30]2)=[CH:21][CH:20]=1
Reactant: CC(C)OC(=O)COc1ccc(C(=O)CBr)cc1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: CC(C)OC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 1 h

Procedure:
iso-Propyl 4-bromoacetylphenoxyacetate (6.3 g) was added to a stirred, cooled (4° C.) solution of 1-(4-pyridyl)piperazine (6.5 g) in acetonitrile (225 ml). Stirring was continued for 1 hour at 4° C., then overnight at ambient temperature when the precipitated solid was removed. The filtrate was evaporated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica, eluting firstly with 0 to 10% v/v methanol/dichloromethane and then toluene/ethyl acetate/0.880 ammonium hydroxide/ethanol (60:20:10:35 v/v/v/v), gave a cream solid. Recrystallisation from iso-propanol gave the title compound, 2.1 g: m.p. 121°-122° C.; NMR (d6DMSO) δ8.14 (2H, d), 7.98 (2H, d), 7.02 (2H, d), 6.80 (2H, d), 4.99 (1H, m), 4.85 (2H, s), 3.84 (2H, s), 3.33 (4H, t), 2.62 (4H, t), 1.22 (6H, d); m/e 398 (M+H)+; calculated for C22H27N3O4 : C, 66.5; H, 6.9; N, 10.6. found: C, 65.8; H, 6.8; N, 10.4%.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=2)=[O:26])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g), 4-(chloromethyl)benzoyl chloride (756 mg), triethylamine (1.53 mL), and tetrahydrofuran (30 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (1.35 g, quant.) as crystals.
Reaction SMILES: C[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=[O:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[OH:42][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: Cc1ncccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cccnc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 152 %

Procedure:
To a stirred solution of 2-methyl-pyridine-3-carbaldehyde (75 mg, 0.62 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (246 mg, 0.62 mmol) and AcOH (40 μL, 0.62 mmol) in THF (6.2 mL) was added NaBH(OAc)3 (394 mg, 1.86 mmol) and the mixture was stirred at room temperature overnight. Purification of the crude white foam (280 mg) by column chromatography on silica gel (200:3:1-CH2Cl2:MeOH:NH4OH) afforded the desired product (116 mg, 37%) as a colorless syrup.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:11])=[CH:6][C:7]([OH:10])=[N:8][CH:9]=1.CC1C=CC(S(O[CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])(=O)=O)=CC=1>CN(C=O)C>[Br:3][C:4]1[C:5]([CH3:11])=[CH:6][C:7]([O:10][CH2:23][CH2:24][C:25]([CH3:27])([OH:28])[CH3:26])=[N:8][CH:9]=1.[Br:3][C:4]1[C:5]([CH3:11])=[CH:6][C:7](=[O:10])[N:8]([CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])[CH:9]=1
Reactant: Cc1cc(O)ncc1Br
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(CCC(C)(C)O)cc1Br
Product: Cc1cc(OCCC(C)(C)O)ncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an atmosphere of nitrogen, sodium hydride was added under ice-cooling to a mixture of 5-bromo-4-methylpyridin-2-ol and DMF, followed by stirring at room temperature for 1 hour. Then, 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate was added thereto, followed by stirring at 40° C. for 14 hours to obtain 4-[(5-bromo-4-methylpyridin-2-yl)oxy]2-methylbutan-2-ol and 5-bromo-1-(3-hydroxy-3-methylbutyl)-4-methylpyridin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:14][CH:13]=2)=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])=[CH:16][CH:17]=2)=[CH:6][C:5]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)ccc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a mixture of ethyl 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (0.58 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2.2 mL) and the mixture was stirred at room temperature for 2 hrs. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.46 g, 85%) of 3-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[ClH:32].C(OCC)C>O1CCOCC1>[ClH:32].[ClH:32].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (5.47 g, 12.25 mmol) in 1,4-dioxane (70 mL) was treated with 4.0M HCl in 1,4-dioxane (30 mL, 122 mmol). The reaction mixture was stirred at ambient temperature for 16 h. Diethyl ether was added to the reaction mixture and the resulting solid was collected by filtration. The crude product was then dissolved in methanol and filtered. The filtrate was concentrated to give 4.36 g (85%) of 2-[4-(methylsulfonyl)phenyl]-5-[(4-piperidinylmethyl)oxy]pyridine dihydrochloride as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.62 (d, 1H, J=2.7 Hz), 8.31 (d, 1H, J=2.7 Hz), 8.23-8.12 (m, 5H), 4.22 (d, 2H, J=6.1 Hz), 3.51-3.46 (m, 2H), 3.20 (s, 3H), 3.13-3.05 (m, 2H), 2.34-2.23 (m, 1H), 2.16-2.10 (m, 2H), 1.75-1.64 (m, 2H); LRMS (APCI), m/z 347 (M+H).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[CH:8]=[C:9]([C:21]([NH:23][C:24]2[CH:28]=[CH:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:25]=2)=[O:22])[CH:10]=[C:11]([O:13]CC2C=CC=CC=2)[CH:12]=1)[CH2:3][O:4][CH3:5]>C1COCC1.C(O)C>[OH:13][C:11]1[CH:10]=[C:9]([C:21]([NH:23][C:24]2[CH:28]=[CH:27][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[N:25]=2)=[O:22])[CH:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][O:4][CH3:5])[CH:12]=1
Reactant: COC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: COC[C@H](C)Oc1cc(O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
A solution of 1,1-dimethylethyl 3-[({3-{[(1S)-1-methyl-2-(methyloxy)ethyl]oxy}-5-[(phenylmethyl)oxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate (23 g, 47.8 mmol) in THF (140 mL) and ethanol (140 mL) was evacuated and purged with nitrogen (×3). 10% Palladium on carbon (2.3 g; 10% w/w) was added and reaction mixture was evacuated and finally purged with hydrogen gas. The reaction mixture was left to stir at RT under a hydrogen balloon for 16 hours. The palladium on carbon was filtered through diatomaceous earth and the filtrate concentrated in vacuo to give a white foam (18 g, 97%).