Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]([CH3:29])[CH3:28])[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:17]=[C:12]2[C:11]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:10]1)(=O)C(C)(C)C.[OH-].[K+].Cl>O1CCOCC1.O>[C:33]([NH:32][C:31]([C:11]1[C:12]2[C:13](=[N:14][CH:15]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]([CH3:28])[CH3:29])[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:17]=2)[NH:9][CH:10]=1)=[O:37])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)c1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)NC(C)(C)C)cn3COC(=O)C(C)(C)C)nn2C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(c1)c(-c1cnc3[nH]cc(C(=O)NC(C)(C)C)c3n1)nn2C
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a stirred solution of (7-(tert-butylcarbamoyl)-2-(5-isopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl pivalate (0.2 g, crude) in dioxane/water (5 mL/10 mL) was added KOH (0.23 g, 4.1 mmol). The mixture was stirred at room temperature for 3 hours. Then the reaction mixture treated with 1N HCl to pH=3-4. The solvent was removed under reduced pressure and the residue triturated with water (15 mL) and dried to give a crude product which was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 62% acetonitrile/38% water (0.1% trifluoroacetic acid, v/v) initially, and then proceed to 64% acetonitrile/36% water (0.1% trifluoroacetic acid, v/v) in a linear fashion after just 9 min.) to give N-tert-butyl-2-(5-isopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.05 g) as a yellow solid. LCMS: (M+H)+=391; 1H NMR (300 MHz, CD3OD): δ 9.05 (s, 1H), 8.29 (s, 1H), 8.16 (s, 1H), 7.61 (d, 1H, J=8.7 Hz), 7.48 (dd, 1H, J1=8.7 Hz, J2=1.5 Hz), 4.18 (s, 3H), 3.19-3.02 (m, 1H), 1.58 (s, 9H), 1.35 (d, 6H, J=6.6 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][CH:21]=2)=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C=O)C>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][C:23]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[N:22][CH:21]=2)=[CH:16][CH:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccc(Cl)nc2)cc1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-n3cccn3)nc2)cc1
Temperature: 100 °C

Procedure:
Pyrazole (0.34 g, 5 mmol) in 10 mL of DMF was treated with sodium hydride (0.2 g in 60% mineral oil) at room temperature. The mixture was then treated with the product from Example 21A in DMF (20 mL) and heated at 100° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and quenched with water. The mixture was filtered and the filter cake was collected as the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.39 (bs, 1H), 9.01 (dd, 1H), 8.71 (dd, 1H), 8.52 (dd, 1H), 8.07 (d, 1H), 7.7 (m, 1H), 7.65 (m, 2H), 7.4 (m, 2H), 6.6 (m, 1H) 1.25 (s, 9H); MS (ESI+) m/z 321 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[NH:12]1[CH:16]=[C:15]([C:17](Cl)=[O:18])[CH:14]=[N:13]1>C(Cl)Cl>[CH:1]1([NH:4][C:17]([C:15]2[CH:16]=[N:12][NH:13][CH:14]=2)=[O:18])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cn[nH]c1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)c1cn[nH]c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of cyclopropylamine (0.52 mL, 0.43 g, 7.5 mmol) and triethylamine (1.4 mL, 1.01 g, 10.0 mmol) in CH2Cl2 (5 mL) was added to a suspension of 1H-pyrazole-4-carbonyl chloride (0.69 g, 5.3 mmol) in CH2Cl2 (20 mL) at 0° C. The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent, the crude product was purified by MPLC using EtOAc on silica gel to give 0.79 g (99%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.52-0.62 (m, 2 H), 0.72-0.82 (m, 2 H), 2.69-2.86 (m, 1 H), 7.91 (s, 1 H), 8.09 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][NH:23][C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].CS(C)=O.Br[CH:34]([CH3:36])[CH3:35]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]([CH:34]([CH3:36])[CH3:35])[C:22]4=[O:26])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cn[nH]c4=O)cc3)CC2)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2CCN(c3ccc(-n4cnn(C(C)C)c4=O)cc3)CC2)cc1
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of 10 parts of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one, prepared as described in Example XVII of U.S. Pat. No. 4,267,179, 1.5 parts of a sodium hydride dispersion 50% and 300 parts of dimethyl sulfoxide was stirred at 60° C. under nitrogen atmosphere till foaming had ceased. Then there were added 5.24 parts of 2-bromopropane and stirring was continued for 1 hour at 60° C. Another 1.5 parts of a sodium hydride dispersion 50% was added and stirring was continued till foaming had ceased. Then another 5.24 parts of 2-bromopropane was aded and the whole was stirred for 1 hour at 60° C. The reaction mixture was cooled and poured into water. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1-butanol, yielding 5.2 parts (47%) of 2,4-dihydro-4-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]- 2-(1-methylethyl)-3H-1,2,4-triazol-3-one; mp. 209.5° C. (intermediate 9).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([Cl:16])=[C:10]([OH:17])[CH:9]=2.[I-].[CH3:25][N:26]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:27](N1C=C[N+](C)=C1)=[O:28]>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([Cl:16])=[C:10]([O:17][C:27](=[O:28])[N:26]([CH3:25])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:9]=2
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)c(Cl)cc12
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N(C)c3ccccc3)c(Cl)cc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-6-chloro-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(methyl-phenyl-carbamoyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=502 (M+1), Rt: 5.68 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([NH2:14])=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:23][C:24](=O)[CH3:25]>C(OCC)(=O)C>[NH2:13][C:12]1[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:23]=[C:24]([CH3:25])[N:14]=1
Reactant: N=C(N)NC(=O)OCc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cn(C(=O)OCc2ccccc2)c(N)n1
Temperature: 50 °C
Reaction time: 10 h
Yield: 21.6 %

Procedure:
A mixture of N-benzyloxycarbonylguanidine 1.93 g (10 mmol), triethylamine 1.39 ml (10 mmol), chloroacetone 2.40 ml (30 mmol) and ethyl acetate 40 ml was stirred at 50° C. for 10 hours. The reaction solution was washed with water and an aqueous sodium chloride solution and dried on magnesium sulfate. After evaporation of the solvent, the residue was purified by a column chromatography on silica gel and further recrystallized from n-hexane to give 500 mg of the title compound (yield: 22%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][CH:14]=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Na+]>C(O)C>[C:1]([O:5][C:6]([C@@H:8]1[S:12][C@@H:11]([CH2:13][CH2:14][OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H]1CC[C@H](CC=O)S1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H]1CC[C@H](CCO)S1
Reaction time: 1 h

Procedure:
To a stirred solution of trans-5-tert-butoxycarbonyl-2-formylmethyltetrahydrothiophene (1.2 g) in ethanol, sodium borohydride (0.3 g) is added under ice-cooling and the mixture is stirred for 1 hour. Saturated sodium chloride solution is added to the mixture under ice-cooling and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue is purified by a silica gel column chromatography to give the titled compound (compound No. 3-1).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([C:6]1([CH2:15][CH:16]=[CH2:17])[C:13](=[O:14])[N-:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])[CH3:5].[Na+].[CH2:19]([O:26][CH2:27]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([O:26][CH2:27][N:9]1[C:7](=[O:8])[C:6]([CH2:15][CH:16]=[CH2:17])([CH:4]([CH2:3][CH2:2][CH3:1])[CH3:5])[C:13](=[O:14])[N:12]([CH2:27][O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]1=[O:11])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C=CCC1(C(C)CCC)C(=O)[N-]C(=O)NC1=O
Reactant: ClCOCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C(C)CCC)C(=O)N(COCc2ccccc2)C(=O)N(COCc2ccccc2)C1=O
Temperature: 25 °C

Procedure:
Sodium secobarbital (25.5 g.) was dissolved in 250 ml of hot dimethylformamide. The solution was vigorously stirred and allowed to cool to room temperature to provide a fine suspension. To the suspension was added chloromethyl benzyl ether (16.5 g.) over a period of 10 minutes. The reaction mixture was stirred overnight and poured into 500 ml of ice water; the mixture was stirred for 1 hour and was extracted into methylene chloride. The methylene chloride solution was dried and the methylene chloride evaporated under reduced pressure to yield an oil. This crude oil was adsorbed on 60-200 mesh silica gel; elution with a solvent mixture containing 1 part of ethyl acetate and 20 parts of benzene (by volume) provided pure 1,3-dibenzyloxymethyl-5-allyl-5-(2-pentyl) barbituric acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:46]C)=[C:6]([C:8]([CH3:45])([CH3:44])[CH2:9][C@:10]([OH:43])([C:39]([F:42])([F:41])[F:40])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]3[CH2:38][CH2:37][CH2:36][C@@H:32]3[C:33]([NH2:35])=[O:34])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1.C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:46])=[C:6]([C:8]([CH3:44])([CH3:45])[CH2:9][C@:10]([OH:43])([C:39]([F:40])([F:42])[F:41])[CH2:11][NH:12][C:13]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]3[C:14]=2[CH:15]=[N:16][N:17]3[C:23]2[CH:24]=[C:25]([C:29]([N:31]3[CH2:38][CH2:37][CH2:36][C@@H:32]3[C:33]([NH2:35])=[O:34])=[O:30])[CH:26]=[CH:27][CH:28]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@@](O)(CNc1cc(C)cc2c1cnn2-c1cccc(C(=O)N2CCC[C@@H]2C(N)=O)c1)C(F)(F)F
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(NC[C@](O)(CC(C)(C)c2cc(F)ccc2O)C(F)(F)F)c2cnn(-c3cccc(C(=O)N4CCC[C@@H]4C(N)=O)c3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.5 %

Procedure:
1-{[3-(4-{[(2R)-4-[5-Fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1H-indazol-1-yl)phenyl]carbonyl}-D-prolinamide (340 mg, 0.5185 mmol) was dissolved in anhydrous dichloromethane (12 mL) and cooled to −78° C. (cardice/acetone bath) under nitrogen. Boron tribromide (1.0M in dichloromethane, 2.57 mL, 2.57 mmol) was then added portionwise and after 5 minutes the stirred mixture was allowed to warm slowly to room temperature under nitrogen. After 4 hours, LCMS suggested little reaction had occurred and the mixture was re-cooled to −78° C. and additional boron tribromide (1.0M in dichloromethane, 2 mL, 2 mmol) was added and the mixture was then stirred at room temperature overnight. LCMS still indicated the reaction was incomplete and the mixture was re-cooled to −78° C. once more and more boron tribromide (1.0M in dichloromethane, 2 mL, 2 mmol) was added and the mixture stirred at room temperature for 3 hours before being re-cooled to −78° C. and quenched by the gradual addition of methanol (5 mL). The reaction was warmed to room temperature when more dichloromethane (30 mL) and aqueous saturated sodium hydrogen carbonate solution (75 mL) were added and the mixture stirred vigorously for 5 minutes. The organic phase was separated by passing through a hydrophobic frit and evaporated in vacuo. This crude product was purified by mass-directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was washed successively water and brine, dried through a hydrophobic frit and evaporated in vacuo to give the title compound (98 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7]CC)=O.[F:13][C:14]([F:34])([F:33])[C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:31]=[C:30]([NH2:32])[NH:29][N:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:10][C:3]1([C:2]([F:1])([F:11])[F:12])[CH2:4][C:5](=[O:7])[NH:32][C:30]2[NH:29][N:28]=[C:27]([CH:24]3[CH2:25][CH2:26][N:21]([C:18]4[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:34])[F:33])=[CH:20][N:19]=4)[CH2:22][CH2:23]3)[C:31]1=2
Reactant: Nc1cc(C2CCN(c3ccc(C(F)(F)F)cn3)CC2)n[nH]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CC(O)(C(F)(F)F)c2c(C3CCN(c4ccc(C(F)(F)F)cn4)CC3)n[nH]c2N1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Ethyl trifluoroacetoacetate (1.50 g, 8.15 mmol) was added to a solution of 3-{1-[5-(trifluoromethyl)pyridin-2-yl]piperidin-4-yl}-1H-pyrazol-5-amine (880 mg, 2.83 mmol) produced in Reference Example 10 in acetic acid (10 mL), and the mixture was stirred at 60° C. for 2 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [NH-silica gel column, elute: ethyl acetate/methanol=100/0-96/4 (gradient)] and further purified by silica gel column chromatography [elute: hexane/ethyl acetate=60/40-0/100 (gradient)] to obtain the title compound (610 mg, yield: 48%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:22]([CH2:23][CH3:24])=[CH:21][N:20]([CH2:25]C)[N:19]=1>CN(C=O)C>[CH2:23]([C:22]1[C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:19][N:20]([CH3:25])[CH:21]=1)[CH3:24]
Reactant: CCc1cn(CC)nc1CBr
Reactant: Cc1cc(O)nc(S)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cn(C)nc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (604 mg, 4.2 mmol) was dissolved in anhydrous DMF (30 mL), and then potassium carbonate (1.76 g, 12.8 mmol) and 3-(bromomethyl)-1,4-diethyl-1H-pyrazole (5.1 mmol) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-12% DCM/MeOH to afford 2-{[(4-ethyl-1-methyl-1H-pyrazol-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (454 mg, 41% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.07 (t, J=7.4 Hz, 3H), 2.17 (s, 3H), 2.37 (q, J=7.4 Hz, 2H), 3.70 (s, 3H), 4.29 (s, 2H), 6.00 (s, 1H), 7.41 (s, 1H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:18][O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:32]
Reactant: NCc1ccccc1
Reactant: COCCCCCCCCCCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCCCCCCCCCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 70 %

Procedure:
To a solution of benzylamine (486 mg, 4.5 mmol) in 20 mL of methylene chloride at 0° C. was added dropwise diisopropylethylamine (0.45 ml, 5 mmol) followed by the title product of example 11 (1.0 g, 4 mmol). After stirring at room temperature for 6 days, the reaction mixture was washed successively with 1N HCl, water, saturated NaHCO3, water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in anhydrous methanol and passed through a basic ion exchange resin and eluted with anhydrous methanol. Concentration afforded the title compound (895 mg) as a white solid, m.p. 77.7-79.4 ° C. (DSC). The structure was supported by NMR, infrared spectroscopy, elemental analysis, and mass spectroscopy.
Reaction SMILES: Cl.[CH2:2]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:26])[CH2:24][CH3:25])=[C:19]([O:27]COC)[C:18]=3[F:31])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:3][CH3:4].O>C(O)C>[CH2:2]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23](=[O:26])[CH2:24][CH3:25])=[C:19]([OH:27])[C:18]=3[F:31])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)[CH2:3][CH3:4]
Reactant: CCCC1CCC(c2ccc(-c3ccc(C(=O)CC)c(OCOC)c3F)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCC1CCC(c2ccc(-c3ccc(C(=O)CC)c(O)c3F)cc2)CC1
Temperature: 25 °C

Procedure:
17.7 mL of 1N hydrochloric acid was added to Compound (7) dissolved in 17.7 mL of ethanol, followed by refluxing under heating for 2 hours. After cooling the reaction solution to ambient temperature, water was added to the solution. The aqueous layer was extracted with toluene, which was added to the organic layer, and the organic layer was washed with a saturated salt solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography and recrystallization to obtain 1.48 g of 1-(4-(4-(4-propylcyclohexyl)phenyl)-3-fluoro-2-hydroxyphenyl)-1-propanone (Compound (1-2-2-21)) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:28]([O:30][CH3:31])=[O:29])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:39])C(=O)C1.O>CN(C)C=O>[Br:39][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][CH:25]=1)[N:18]([C:17]1[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]3[C:15]([N:16]=1)=[CH:14][C:13]([C:28]([O:30][CH3:31])=[O:29])=[CH:12][CH:11]=3)[CH2:19][CH2:20][CH2:21]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4ccccc43)nc2c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)nc2c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (300 mg, 0.73 mmol) in N,N-dimethylformamide (20 ml) was added NBS (193 mg, 1.08 mmol) under an inert atmosphere of nitrogen. The resulting solution was stirred for 1.5 h at −10° C. Then water (150 ml) was added and the reaction was extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel chromatography eluting with 1%-2% ethyl acetate in petroleum ether to afford methyl 3-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (200 mg, 56%).
Reaction SMILES: [H-].[Na+].[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([OH:13])[CH2:5][CH2:4]1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[O:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4]1
Reactant: OC1CCOc2ccccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC1CCOc2ccccc21
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 173 mg, 4.33 mmol) in THF was added chroman-4-ol (500 mg, 3.33 mmol) at 0° C. After being stirred at the same temperature for 15 min, ethyl bromoacetate (723 mg, 4.33 mmol) was added. After 1 h, the mixture was poured onto water, and the aqueous phase was extracted with EtOAc (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (7:1-4:1) to give 404 mg (51% yield) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]>C(#N)C>[CH2:23]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH2:22][CH2:21][CH2:20][CH:19]=[CH2:18]
Reactant: C=CCCCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
To an acetonitrile (40 mL) solution of 4-nitrophenol (2.79 g; 20.0 mmol) and potassium carbonate (4.15 g; 30.1 mmol), 6-bromo-1-hexene (4.01 g; 24.6 mmol) was added, and the mixture was refluxed and then reacted for 12 hours. After completion of the reaction, the solution was filtrated by Celite, and then the filtrate was concentrated under a reduced pressure. The residue was purified by flash column chromatography using methylene chloride, and then the effluent was concentrated to obtain 4-(5-hexenyloxy)nitrobenzene (1b) (4.11 g, 93% of yield, a light yellow oil) represented by the following formula.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([OH:23])[CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:16][C:17]1[CH:22]=[C:21]([O:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:20]=[N:19][CH:18]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cncc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cncc(Cl)c3)c2cc1OC
Temperature: 140 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (245 mg), 3-chloro-5-pyridinol (277 mg), and 4-dimethylaminopyridine (377 mg) were suspended in o-dichlorobenzene (13 ml), and the mixture was stirred at 140° C. for 6 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution and water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (283 mg, yield 81%).