Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[O:12]1[C:16]2[CH:17]=[CH:18]C=CC=2N=C1>>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:18][CH:17]3[CH2:16][O:12]3)[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc2ocnc2c1
Reactant: Cc1nc2ccc(O)cc2s1
Product: Cc1nc2ccc(OCC3CO3)cc2s1

Procedure:
Compound 51 was prepared in the manner of compound 6 substituting compound 50 for compound 8 in part C-5 of Example 1.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[CH3:5][NH:6][NH:7][CH3:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[S:18])=[CH:12][CH:11]=1>O.C(O)C>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([N:6]([CH3:5])[NH:7][CH3:8])=[S:18])=[CH:12][CH:11]=1
Reactant: CNNC
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNN(C)C(=S)Nc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 38.9 %

Procedure:
To a stirred solution of sodium hydroxide (6.1 g, 0.15 mole) in 40 ml of water and 250 ml of ethanol was added N,N'-dimethylhydrazine dihydrochloride (10 g, 0.076 mole). The reaction mixture was warmed to 50° C., and 4-chlorophenylisothiocyanate (12.8 g, 0.076 mole) was added in small portions. Upon complete addition, the reaction mixture was heated under reflux for two hours and then allowed to cool. The cooled reaction mixture was filtered and the filtrate concentrated under reduced pressure to remove most of the solvent. The concentrate was taken up in 200 ml of toluene. The toluene was removed under reduced pressure. This procedure was repeated with two additional 200 ml portions of toluene to remove the remaining ethanol and water traces by azeotropic distillation. The brown residual oil was recrystallized twice from ethanol to give N-(4-chlorophenyl)-1,2-dimethylhydrazinecarbothioamide (6.8 g, mp 103°-104° C.). The nmr spectrum of the product was consistent with the assigned structure.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:21][C:22]1[CH:36]=[CH:35][C:25]2[C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[N:27][O:28][C:24]=2[CH:23]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:19])[CH2:15][CH2:16][CH2:17][N:32]3[CH2:31][CH2:30][CH:29]([C:26]4[C:25]5[CH:35]=[CH:36][C:22]([F:21])=[CH:23][C:24]=5[O:28][N:27]=4)[CH2:34][CH2:33]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2C(=O)CCCCl)C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2C(=O)CCCN2CCC(c3noc4cc(F)ccc34)CC2)C1
Yield: 62 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.4 g of 6-acetyl-3-(4-chlorobutyryl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 1.3 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 1.4 g of 6-acetyl-3-(4-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)butyryl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][CH:7]=[CH2:8])C.[OH-].[Na+].CCOC(C)=O>CCO.C1COCC1>[CH3:12][C:11]([CH3:14])([CH3:13])[C:10]([NH:9][CH:5]([CH2:6][CH:7]=[CH2:8])[C:4]([OH:16])=[O:3])=[O:15]
Reactant: C=CCC(NC(=O)C(C)(C)C)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: C=CCC(NC(=O)C(C)(C)C)C(=O)O
Reaction time: 1 h
Yield: 91.8 %

Procedure:
10.50 g of the above prepared 2-(2,2-dimethyl-propionylamino)-pent-4-enoic acid ethyl ester (46.19 mmol) were dissolved in 146 ml of a 1:1 mixture of EtOH and THF and treated under cooling with an ice bath with 46.19 ml of 2N NaOH (2 eq.). After 1 h, the reaction mixture was poured onto crashed ice/AcOEt/HCl, the aqueous phase reextracted once more with AcOEt, the combined organic layers washed with water, dried over sodium sulfate, and evaporated to dryness. Thereby, 8.45 g of the title product was obtained as white solid of mp. 87–88°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]#[C:34][NH2:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([O:28][CH2:29][C:30]([NH:35][C:34]#[N:33])=[O:32])=[C:21]([C@@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19][CH2:20][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH:26]=1
Reactant: N#CN
Reactant: O=C(O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CNC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2-carboxymethoxy-5-chloro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (138 mg, 0.30 mmol, 1.0 eq.), cyanamide (16 mg, 0.36 mmol, 1.2 eq.), and NEt3 (84 μL, 0.60 mmol, 2 eq.) in DMF (3.3 mL), HATU (137 mg, 0.36 mmol, 1.2 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The mixture was purified by prep. HPLC (column: Waters XBridge, 30×75 mm, 10 um, UV/MS, basic conditions) and evaporated to give a pale yellow oil, contaminated with NEt3. The contaminated product was redissolved in AcOEt and washed with 1M aq. HCl soln. and sat. aq. NaCl soln. The org. phase was dried over MgSO4, filtered and concentrated in vacuo to give the desired product as a pale yellow oil.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:29])[N:11]([CH:26]([CH3:28])[CH3:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)[CH:14]=1)C1C=CC=CC=1.C(S)C.B(F)(F)F.O(CC)CC>C(Cl)Cl.CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:14]=[C:9]([OH:8])[C:10](=[O:29])[N:11]([CH:26]([CH3:28])[CH3:27])[CH:12]=2)=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: CC(C)n1cc(-c2ccc(Cl)c(C(F)(F)F)c2)cc(OCc2ccccc2)c1=O
Agent: FB(F)F
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)n1cc(-c2ccc(Cl)c(C(F)(F)F)c2)cc(O)c1=O
Yield: 35.5 %

Procedure:
To a solution of crude 3-(benzyloxy)-5-[4-chloro-3-(trifluoromethyl)phenyl]-1-(propan-2-yl)pyridin-2(1H)-one (86 mg) in CH2Cl2 (1 mL) was added ethanethiol (0.075 mL, 1.019 mmol) then BF3—OEt2 (0.13 mL, 1.026 mmol) at RT. After 5 h the mixture was diluted with MeOH and concentrated. The residue was taken up in DMSO:H2O and purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-70% CH3CN/water over 20 min at 20 mL/min) to give the title compound (24 mg, 36%) as a light tan solid. 1H NMR (500 MHz, d6-DMSO): δ 9.28 (s, 1 H); 7.97 (s, 1 H); 7.92 (dd, J=8.4, 2.2 Hz, 1 H); 7.74 (d, J=8.4 Hz, 1 H); 7.68 (d, J=2.4 Hz, 1 H); 7.14 (d, J=2.4 Hz, 1 H); 5.18-5.11 (m, 1 H); 1.39 (d, J=6.8 Hz, 6 H). HRMS (ES) calc (M+H)+=332.0660, found 332.0661.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[CH2:7][C:8]([C:18]1([F:21])[CH2:20][CH2:19]1)([OH:17])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>CN(C)C=O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:18]2([F:21])[CH2:19][CH2:20]2)([OH:17])[CH2:7][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:15][CH:14]=1
Reactant: c1nc[nH]n1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1)C1(F)CC1
Solvent: CN(C)C=O
Product: OC(Cc1ccc(Cl)cc1)(Cn1cncn1)C1(F)CC1
Temperature: 80 °C
Yield: 30.1 %

Procedure:
Under an atmosphere of nitrogen, 27.6 g (0.4 mol) of 1,2,4-triazole and 33.6 g (0.3 mol) of potassium tert.-butylate in 100 ml of absolute dimethylformamide are introduced as an initial charge and heated to 80° C. At this temperature, a solution of 26.3 g (0.1 mol) of 1-chloro-2-(1-fluoro-cyclopropyl)-3-(4-chlorophenyl)-propan-2-ol in 50 ml of absolute dimethylformamide is added dropwise thereto while stirring. The mixture is stirred for another 6 hours at 100° C. and then concentrated by stripping off the diluent under reduced pressure. The residue is taken up in ethyl acetate, the solution is washed with water, and, after drying over sodium sulphate, the solvent is evaporated under reduced pressure. The product left behind is chromatographed on a silica gel column, using chloroform as the mobile solvent. In this way, 8.9 g (35% of theory) of 1-(4-chlorophenyl)-2-(1-fluoro-cyclopropyl)-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in the form of a solid.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[OH:7][C@@H:8]1[CH2:13][C@@H:12]([CH3:14])[C:11](=O)[C:10]([CH3:17])([CH3:16])[CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[CH3:16][C:10]1([CH3:17])[C:11](=[CH2:1])[CH:12]([CH3:14])[CH2:13][C@@H:8]([OH:7])[CH2:9]1
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H]1C[C@@H](O)CC(C)(C)C1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=C1C(C)C[C@@H](O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.79 g (6.86 mmol) of potassium tert-butoxide (KOtBu) was added to a solution of 2.5 g (6.86 mmol) of methyltriphenylphosphonium bromide in 10 ml of dimethyl sulfoxide (DMSO) under N2, and the mixture was then stirred at RT for 30 min. 0.36 g (2.29 mmol) of (4R,6R)-4-hydroxy-2,2,6-trimethyl-1-cyclohexanone was added to this mixture, which was then stirred at RT for 5 min. during which a white precipitate appeared. The mixture was then stirred at 60° C. for 15 min, cooled to RT, poured into 150 ml of ice-water and extracted twice with 50 ml of methylene chloride. The organic phase was separated off, washed with 50 ml of a 5% strength aqueous Na2CO3 solution and 50 ml of water and dried over MgSO4, and the solvent was removed under reduced pressure.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH:9]2[C:14]3[N:15]=[CH:16][NH:17][C:13]=3[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:27]=1[CH2:28][N:29]=[C:30]=[O:31]>C(O)C>[CH:1]1([CH2:7][CH2:8][CH:9]2[C:14]3[N:15]=[CH:16][NH:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:30]([NH:29][CH2:28][C:27]2[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:26]=2[Cl:25])=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: c1nc2c([nH]1)CCNC2CCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCc2[nH]cnc2C1CCC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-cyclohexylethyl)-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine (0.47 g, 2.0 mmol, prepared as described in Example 13) in ethanol (10 mL), triethylamine (0.28 ml, 2.0 mmol) and 2,4-dichlorobenzyl isocyanate (0.41 g, 2.0 mmol) were added dropwise. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was re-evaporated with acetone and then dissolved in acetone (15 mL) and left for crystallization. The solid was isolated by filtration, washed with acetone and dried. This afforded 0.60 g (69%) of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([N:28]([CH3:44])[C:29]2[CH:30]=[N:31][CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=2)[CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:28]([CH3:44])[C:29]2[CH:34]=[C:33]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)[CH:32]=[N:31][CH:30]=2)[CH2:25][CH2:26][CH2:27]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CN(c1cncc(B2OC(C)(C)C(C)(C)O2)c1)C1CCC1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(N(C)C5CCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and Cyclobutyl-methyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-amine (Stage 174.1.1) to give the title compound as a white solid. (HPLC: tR 2.39 min (Method A); M+H=454 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.15-8.04 (m, 4H), 7.96-7.92 (m, 1H), 7.60-7.57 (m, 11-1), 7.06-7.03 (m, 1H), 4.17 (qt, 1H), 3.88 (s, 3H), 3.58 (s, 3H), 2.89 (s, 3H), 2.28-2.02 (m, 4H), 1.97 (s, 3H), 1.81-1.63 (m, 2H))
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[C:4](F)[CH:3]=1.C(NC([O:23][CH2:24][CH3:25])=O)C.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[C:4]([O:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCNC(=O)OCC
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2F)C[C@H](C)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1cc(Br)ccc1CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 100 °C
Yield: 13.9 %

Procedure:
To a solution of cis 4-(4-bromo-2-fluorobenzyl)-2,6-dimethylmorpholine (0.76 g, 2.5 mmol) in 1,4-dioxane (7.5 mL) under nitrogen was added ethyl urethane (1.2 mL, 10.0 mmol) followed by portionwise addition of sodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol). The reaction mixture was heated at 100° C. for 24 h then partitioned between DCM and water and the phases were separated. The aqueous phase was further extracted with DCM and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane) to afford the title compound (0.114 g, 14%). 1H NMR (CD3OD and CDCl3, 300 MHz): 7.22 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1 H), 6.97 (d, J=1.9 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.75-3.62 (m, 2H), 3.47 (s, 2 H), 2.75-2.66 (m, 2H), 1.86-1.76 (m, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): RT=3.24 min, M+H+=328.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([NH:11]C(=O)C(F)(F)F)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[S:6][C:5]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1sc(Br)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1sc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
A mixture of methyl 5-bromo-3-[(trifluoroacetyl)amino]thiophene-2-carboxylate (8.15 g, 24.5 mmol), potassium carbonate (4.15 g, 30 mmol), MeOH (200 mL) and water (100 mL) was stirred at room temperature for 2 h. The mixture was concentrated to about a half volume and poured into saturated aqueous NaHCO3 (300 mL). Extraction with EtOAc (300 mL), washing with brine, drying over MgSO4, filtration and concentration under reduced pressure gave the title compound as a yellow solid (5.67 g, 98%):
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCCn1ccc2ccccc21
Reactant: C1=C(c2ccccc2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1=C(c2ccccc2)CCN(CCCCn2ccc3ccccc32)C1
Temperature: 90 °C

Procedure:
A mixture of 4.8 g (30 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine, 6.22 g of 1-(4-chlorobutyl)indole and 8.3 g of potassium carbonate in 100 ml of dimethylformamide is heated at 90° C. for 3 hours. Evaporation to dryness is then carried out at reduced pressure, the residue is redissolved in chloroform and washing is carried out repeatedly with water. The organic phase is dried with anhydrous sodium sulfate and evaporation is carried out at reduced pressure, a crude product being obtained which is purified by chromatography on silica gel. 5.7 g (17.3 mmol). of 1-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]indole are obtained.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19]O)([O-:15])=[O:14].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH2:28][N:27]1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][N:30]1[C:29](=[O:31])[CH2:28][N:27]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:26]1=[O:25])([O-:15])=[O:14]
Reactant: CCOC(=O)CN1CC(=O)NC1=O
Reactant: O=[N+]([O-])c1cc(CO)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CN1CC(=O)N(Cc2ccc(Cl)c([N+](=O)[O-])c2)C1=O
Yield: 78.1 %

Procedure:
A solution of 5.2 mL of diethyl azodicarboxylate in 30 mL of tetrahydrofuran was added to a solution of 5.13 g of 3-nitro-4-chlorobenzyl alcohol, 4.70 g of ethyl 2,4-dioxoimidazolidine-1-acetate and 8.68 g of triphenylphosphine in 30 mL of tetrahydrofuran at 0° C. The reaction mixture was poured over water and the mixture was extracted with ethyl acetate several times. The extracts were combined, washed with a saturated saline solution, dried over sodium sulfate and concentrated. The concentrate was purified by a silica gel column and recrystallized from a mixed solvent of ethanol and water to give 7.01 g of ethyl 3-(3-nitro-4-chlorobenzyl)-2,4-dioxoimidazolidine-1-acetate.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.CI.[Mg].[CH2:14]1[O:16][CH2:15]1>>[OH:16][CH2:15][CH2:14][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2occc2c1
Reactant: C1CO1
Agent: [Mg]
Solvent: CI
Product: OCCc1ccc2occc2c1

Procedure:
The subject compound is prepared by a Grignard reaction with the reagant prepared from 5-bromobenzo[b]furan, methyl iodide and magnesium turnings and ethylene oxide.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1Br.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O.O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=2)=[N:6][C:7]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)n1cc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1cc(-c2nc(-c3ccccc3)c(N)nc2-c2ccccc2)ccc1=O
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of 5-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (100 mg), phenylboronic acid (79 mg), Pd(PPh3)4 (9 mg), a solution of Na2CO3 (110 mg) in water (0.8 ml) and dioxane (2.0 ml) was heated at 90° C. with stirring for 1 hour. After cooling, EtOAc and water were poured into the mixture, and the organic layer was separated, washed with water and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was recrystallized from MeOH-IPE and dried in vacuo to give 5-(5-amino-3,6-diphenyl-2-pyrazinyl)-1-isopropyl-2(1H)-pyridone (84 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28](OCC)=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:34][CH2:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:33])=[C:14]([C:28]([NH:34][CH2:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])=[O:29])[C:15](=[O:27])[N:16]3[CH2:19][C:20](=[O:26])[N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(CN)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O
Product: CC(C)(CO)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-oxo-2-(1-pyrrolidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-2,2-dimethyl-1-propanol employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 14.4 (1H, br), 10.32 (1H, m), 8.56 (1H, s), 7.15 (2H, dd, J=8.6, 5.5 Hz), 7.02 (3H, m), 4.88 (2H, s), 4.12 (2H, s), 3.49 (2H, t, J=7 Hz), 3.46 (2H, t, J=7 Hz), 3.33 (1H, t, J=7 Hz), 3.30 (2H, d, J=7 Hz), 3.24 (2H, d, J=7 Hz), 2.05 (2H, m, J=7 Hz), 1.90 (2H, m, J=7 Hz), 0.94 (6H, s); HRMS calcd for C27H31FN4O5+H+: 511.2357. Found: 511.2341.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:32])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:31])([CH3:30])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:32][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]([CH3:28])[CH3:29])=[CH:25][CH:26]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:30])([CH3:31])[CH2:10]2
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)C)cc3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.9 %

Procedure:
To a stirred mixture solution of 6-chloro-2-(4′-isopropyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (400 mg, 0.9 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 6-chloro-2-(4′-isopropyl-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (351 mg, 90%) as a white solid: LC/MS m/e calcd for C27H28ClNO2 (M+H)+: 434.98, observed: 434.0.