Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:16][NH:17][CH3:18]>C(OCC)(=O)C>[CH3:16][N:17]([CH3:18])[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(c1ccncc1)c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=O)c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 2.38 g of 4-(4-fluorobenzoyl)pyridine and 7 ml of 50% aqueous dimethylamine solution was stirred for 24 hours at room temperature, followed by addition of 100 ml of ethyl acetate. The mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized from ethanol-ethyl acetate to give 1.1 g of 4-(4-dimethylaminobenzoyl)pyridine as pale yellow crystals melting at 122°-124° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH2:13][CH2:14][CH2:15][CH3:16].O.Cl>N1C=CC=CC=1>[CH2:12]([O:17][CH:18]([CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCOC(C)CCCCCO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOC(C)CCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
A solution of 2.26 g of p-toluenesulfonic acid chloride in 5 ml of pyridine was gradually added dropwise to a cooled solution of 2.04 g of 6-pentyloxyheptanol in 8 ml of pyridine for 7 min. below 5° C. After stirring for 5 hours at room temperature, the reaction mixture was injected into 150 ml of cold water and, after being acidified to pH 3 with 6N-hydrochloric acid, was extracted with ethyl acetate. The resultant solution was washed with water and dried with anhydrous magnesium sulfate, followed by distilling-off of the solvent to obtain 2.98 g of (6-pentyloxyheptyl)-p-toluenesulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[NH:12][C:11]3([CH:20]2[CH2:22][CH2:21]2)[CH3:19])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:25]I.[Cl-].[NH4+].Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[N:12]([CH3:25])[C:11]3([CH:20]2[CH2:21][CH2:22]2)[CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C2CC2)NC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reactant: CI
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)Nc2ccc(-c3cccc(Cl)c3)cc2C1(C)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of half of the crude addition product from Example 9 in anhydrous DMF (5 mL) was added under nitrogen at room temperature sodium hydride (25 mg, 0.63 mmol). The mixture was stirred at ambient temperature for 30 minutes and treated with methyl iodide (0.5 mL, excess). After stirring for 3.5 hours, a mixture of saturated aqueous ammonium chloride and 1N HCl aqueous solution (10 mL/5 mL) was added to the reaction mixture. Ethyl acetate (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined organic layers were washed with brine and dried (MgSO4). The solvent was removed and residue was dissolved in a mixture of methylene chloride and TFA (2 mL/2 mL). After stirring for 3 hours, the solution was poured onto ice-water and neutralized by addition of a saturated aqueous sodium bicarbonate solution. The ethyl acetate (30 mL) was added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to afford 6-(3-chlorophenyl)-4-cyclopropyl-3,4-dimethyl-3,4-dihydro-1H-quinazolin-2-one as a white solid (11 mg, 11% for three steps): mp 193-194° C.; 1H-NMR (DMSO-d6) δ 9.51 (s, 1H), 7.68 (s, 1H), 7.59 (d, 1H, J=8.0 Hz), 7.57 (d, 1H, J=1.6 Hz), 7.51 (dd, 1H, J=8.3, 1.7 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.35 (d, 1H, J=8.1 Hz), 6.87 (d, 1H, J=8.3 Hz), 3.02 (s, 3H), 1.51 (s, 3H), 1.25 (m, 1H), 0.32-0.51 (i, 3H), 0.25 (m, 1H); MS (CI) m/z 327 ([M+H]+, 100%). Anal. Calc. For C19H19ClN2O.0.3H2O: C, 68.69, H, 5.95, N, 8.43. Found: C, 68.69, H, 5.70, N, 8.18.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1.Cl.C[Si](C)(C)N[Si](C)(C)C.[CH:24]1[C:29]([O:30][C:31](Cl)=[O:32])=[CH:28][CH:27]=[C:26]([Cl:34])[CH:25]=1.[OH-].[Na+]>O>[Cl:34][C:26]1[CH:27]=[CH:28][C:29]([O:30][C:31]([N:2]([CH3:1])[CH2:3][CH2:4][C@H:5]2[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]2)=[O:32])=[CH:24][CH:25]=1
Reactant: CNCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(CC[C@H]1CC[C@H](C(=O)O)CC1)C(=O)Oc1ccc(Cl)cc1
Temperature: 145 °C
Reaction time: 8 h

Procedure:
1.55 g (7.00 mmol) of trans-4-(2-methylamino-ethyl)-cyclohexanecarboxylic acid·HCl were mixed with 18.4 mL (12.56 mmol, 1.8 eq) of hexamethyldisilazane and heated under reflux to 145° C. for 2.5 h. The solution was evaporated, the residue was suspended in THF and treated with 1.07 g (7.70 mmol, 1.1 eq) of 4-chlorophenylchloroformate at 0° C. and the solution was stirred at RT overnight. 10 mL of water was added at RT followed by 10 mL of 1M NaOH. Stirring was continued for 1 h at RT. The organic solvent was evaporated and the residue partitioned between n-hexane (×3)/H2O. The water phase was acidified with 1M HCl and extracted with EtOAc (3×). The organic phase was dried over Na2SO4 and evaporated to yield 1.92 g (81%) of trans-4-{2-[(4-chloro-phenoxycarbonyl)-methyl-amino]-ethyl}-cyclohexanecarboxylic acid, MS: 338 (M−H−, 1Cl).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[O:8][C:9]1[CH:35]=[CH:34][C:12]([CH2:13][N:14]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[C:16]([CH3:26])=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1.Cl[C:40]([O:42][CH3:43])=[O:41]>C1COCC1>[CH2:27]([N:14]([CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:7]2[CH:6]=[C:5]([CH:38]=[CH:37][CH:36]=2)[O:4][CH2:3][CH2:2][NH:1][C:40](=[O:41])[O:42][CH3:43])=[CH:35][CH:34]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:16]=1[CH3:26])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)Cl
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCN)c2)cc1
Solvent: C1CCOC1
Product: COC(=O)NCCOc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)c1

Procedure:
The product from Example 78C (0.050 g, 0.0942 mmoles) in anhydrous THF (1 mL) was treated with methyl chloroformate (0.009 mL, 0.113 mmoles) and mixed overnight at room temperature. Reaction mixture concentrated under reduced pressure, and the residue was purified by preparative HPLC (CH3CN:0.1% trifluoroacetic acid in H2O) on a YMC ODS Guardpak column to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.10-7.30 (mn, 10 H), 6.95 (m, 1 H), 6.89 (d, 2 H), 6.55 (m, 2 H), 6.43 (s, 1 H), 6.26 (d, 1 H), 5.15 (br.s, 1 H), 4.00-4.20 (m, 4 H), 3.96 (t, 2 H), 3.68 (s, 3 H), 3.55 (m, 2 H), 2.90 (s, 3 H), 2.30 (s, 3 H); MS (ESI+) m/z 590 (M+H)+.
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([OH:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([O:23]C)=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:3][CH:2]=1>CO.C(Cl)Cl>[C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:2]=[CH:3][C:4]([CH2:7][CH:8]([OH:25])[CH2:9][C:10]2[O:14][C:13]([C:15]3[N:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[CH:17][CH:16]=3)=[N:12][N:11]=2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2nnc(CC(O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2nnc(CC(O)Cc3ccc(-c4ccccc4)cc3)o2)n1
Yield: 95.3 %

Procedure:
The title compound was prepared from 36 (7.5 mg, 0.017 mmol) following general procedure A. Flash chromatography (SiO2, 5% MeOH—CH2Cl2) afforded the title compound (6.5 mg, 95%) as a white solid: 1H NMR (DMSO-d6, 600 MHz) δ 8.26 (dd, 1H, J=8.4 Hz), 8.16 (dd, 1H, J=8.4 Hz), 8.06 (t, 1H, J=7.8 Hz), 7.55-7.51 (m, 4H), 7.36-7.33 (m, 3H), 7.24 (t, 1H, J=7.2 Hz), 4.26-4.22 (m, 1H), 3.13-2.99 (m, 2H), 2.86-2.84 (m, 2H); 13C NMR (DMSO-d6, 150 MHz) δ 167.2, 166.2, 164.2, 149.9, 144.1, 141.1, 139.6, 139.2, 138.7, 130.9, 129.5, 127.9, 127.5, 127.3, 126.3, 70.2, 43.4, 33.7; HRMS-ESI-TOF m/z 402.1443 ([M+H]+, C23H19N3O4 requires 402.1448).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[OH:20]O.C1(C)C=CC=CC=1>C(O)(=O)C.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O.C(OCC)(=O)C>[F:19][C:2]([F:1])([F:18])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:20])=[CH:9][CH:10]=1
Reactant: OO
Reactant: FC(F)(F)COc1ccc(Sc2ccccc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=S(c1ccccc1)c1ccc(OCC(F)(F)F)cc1
Reaction time: 18 h
Yield: 99 %

Procedure:
In 120 g of acetic acid was dissolved 17.1 g of phenyl 4-(2,2,2-trifluoroethoxy)phenyl sulfide obtained in Synthesis Example 1-13. While the solution was maintained at an internal temperature of 30° C., 5.8 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 0.5 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 100 g of toluene, 50 g of ethyl acetate, and 50 g of water. The organic layer was separated, washed with water, and concentrated in vacuum. This was followed by crystallization from hexane, filtration, and drying. There was obtained 17.9 g of the target compound, phenyl 4-(2,2,2-trifluoroethoxy)phenyl sulfoxide as white crystals. Yield 99%.
Reaction SMILES: [CH3:1]I.[OH:3][CH:4]1[C:13]2[C:8]3=[C:9]([CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]3[CH2:6][CH2:5]1)[C:10]([CH3:14])=[CH:11][CH:12]=2.[H-].[Na+]>O1CCCC1>[CH3:14][C:10]1[C:9]2[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:7]3[C:8]=2[C:13]([CH:4]([O:3][CH3:1])[CH2:5][CH2:6]3)=[CH:12][CH:11]=1
Reactant: CI
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3OC
Temperature: 25 °C
Yield: 58.8 %

Procedure:
Methyl iodide (0.55 g, 3.86 mmol) was added dropwise to a mixture of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (0.50 g, 1.93 mmol), 60% sodium hydride (0.08 g, 1.93 mmol) and tetrahydrofuran (20 ml) with stirring at room temperature, and the resulting mixture was stirred at room temperature for another 2 hours. The reaction mixture was poured into ice water and extracted three times with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=5/95) to obtain 0.31 g of ethyl 5,6-dihydro-9-methyl-6-methoxy-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([O:35]C)=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2].O.[OH-].[Li+].C(O)=O>O1CCOCC1.O.CO>[CH2:1]([N:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[S:19]([NH:22][C:23]2[C:32]([C:33]([OH:35])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[O:10])[CH2:4]1)[CH3:2]
Reactant: CCN1CC[C@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=CO
Product: CCN1CC[C@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Yield: 63.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 80, 0.148 g) and lithium hydroxide monohydrate (0.168 g) in dioxane (3 mL) and water (1 mL) was irradiated in the microwave at 130° C. for 40 minutes. After cooling, the mixture was diluted with methanol, acidified with formic acid and evaporated in vacuo. The residue was triturated with 10% methanol in DCM and filtered. The filtrate was evaporated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20%. The resultant solid was triturated with ether and filtered off to give (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonyl-amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.091 g) as a white solid.
Reaction SMILES: [F-:1].[K+].[N+:3]([C:6]1[CH:19]=[CH:18][CH:17]=[C:16]([N+]([O-])=O)[C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9])([O-:5])=[O:4].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:16]1[CH:17]=[CH:18][CH:19]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]=1[C:8]([NH:10][C@@H:11]([CH3:15])[C:12]([OH:14])=[O:13])=[O:9]
Reactant: [F-]
Reactant: C[C@H](NC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-])C(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](NC(=O)c1c(F)cccc1[N+](=O)[O-])C(=O)O
Temperature: 175 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
A mixture of spray-dried KF (1.02 g, 17.6 mmol), intermediate 13 (500 mg, 1.76 mmol) and catalytic amount of 18-crown-6 in dry DMSO (10 mL) was stirred at 170-180° C. for 45 min. Work-up of the reaction mixture as described in example 1 gave the product as a pale brown color solid (284 mg, 63%), mp 142-144° C. 1H NMR (400 MHz, DMSO-d6): δ 9.05 (1H, d, J=7.2 Hz), 8.01 (1H, dd, J=6.6, 1.8 Hz), 7.72-7.78 (2H, m), 4.44 (1H, pentet, J=7.2 Hz), 1.34 (3H, d, J=7.2 Hz); LC-MS (positive ion mode): m/z 279 (M+Na)+.
Reaction SMILES: [F:1][C:2]1([F:62])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([O:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:50]([F:61])[C:51]2[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=2)[CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[F:62][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:37]=[CH:38][C:39]([O:42][CH:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)=[CH:40][N:41]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:50]([F:61])[C:51]2[CH:52]=[CH:53][C:54]([C:57]([F:58])([F:60])[F:59])=[CH:55][CH:56]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(OC6CCN(C)CC6)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(Oc2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.3 %

Procedure:
To a solution of 86 mg (99 μmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(1-{5-[(1-methylpiperidin-4-yl)oxy]pyrimidin-2-yl}piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 29, in 1.0 ml of dichloromethane, 0.2 ml of anisole and 0.2 ml of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the solvent in the reaction solution and trifluoroacetic acid were distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [dichloromethane/methanol/28% ammonia water=100/0/0-90/9.5/0.5 (V/V/V)] and thin layer chromatography [dichloromethane/methanol/28% ammonia water=90/9.5/0.5 (V/V/V)] to provide 12 mg of the title compound as a white solid (yield: 17%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:13])[N:4]([CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[NH:20][CH2:19][CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[N:20]([C:2]1[C:3](=[O:13])[N:4]([CH:9]([CH3:12])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:19][CH2:18]2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Reactant: Clc1cc(Br)cc2c1NCC2
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-methylpropyl-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 150° C.; 1H NMR (300 MHz, CDCl3): δ 7.32 (d, J=1.8 Hz, 1 H), 7.26 (d, J=1.9 Hz, 1 H), 6.85 (s, 1 H), 4.97-4.90 (m, 1 H), 4.34 (t, J=8.1 Hz, 2 H), 3.13 (t, J=7.9 Hz, 2 H), 1.77-1.70 (m, 2 H), 1.36 (d, J=7.0 Hz, 3 H), 0.91 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C16H17N3OBrCl2 (M+H)+: 415.9932; Found m/z 415.9943.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8](O[C@H](C2C=CC=CC=2)C)=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[CH:37]1([S:40]([NH:43][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:43][S:40]([CH:37]5[CH2:39][CH2:38]5)(=[O:42])=[O:41])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)(=[O:42])=[O:41])[CH2:39][CH2:38]1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@@H](C)c1ccccc1
Reactant: NS(=O)(=O)C1CC1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(=O)(=O)C5CC5)CC4)cc3)cc2)c1NC(=O)NS(=O)(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 315 using 1-{4′-[3-Methyl-4-((S)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid and cyclopropanesulfonamide.
Reaction SMILES: [C:1]([O:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47](Cl)(=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49]>C1COCC1>[C:1]([O:4][CH:5]1[N:8]([C:47]([C:48]([CH3:51])([CH3:50])[CH3:49])=[O:52])[C:7](=[O:9])[CH:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)OC1NC(=O)C1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OC1C(CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1C(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
To a -78° C. THF (6 mL) solution of compound 13 (trans:cis ratio, 2:1, 600 mg; 1.2 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (1.2 mL, 1.2 mmol), and the resulting solution was stirred for 15 min. Pivaloyl chloride (150 mg, 1.24 mmol) was added, and the solution was stirred for 30 min at -78° C. and for 1.5 h at room temperature. The reaction mixture was partitioned between pH 4.0 aqueous buffer and ether. The organic phase was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (1:1/Et2O:hexane) to afford 300 mg (43%) of the title product as a mixture of trans and cis (3:2) isomers.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19]C)=[O:18])[CH2:13][CH:12]=2)=[C:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN1C2C(=CC=CC=2)C(C2C=CC(C(OC)=O)=CC=2)=C1C1C=CC=CC=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[C:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1CC=C(c2c(-c3ccccc3)n(C)c3ccccc23)CC1
Agent: COC(=O)c1ccc(-c2c(-c3ccccc3)n(C)c3ccccc23)cc1
Product: Cn1c(-c2ccccc2)c(-c2ccc(C(=O)O)cc2)c2ccccc21
Yield: 75.5 %

Procedure:
By a procedure analogous to that of Example 15, 10.2 g of methyl 4-(1-methyl-2-phenyl-1H-indol-3-yl)-3-cyclohexene-1-carboxylate (Example 5) was aromatized to methyl 4-(1-methyl-2-phenyl-1H-indol-3-yl)benzoate [IV; R' and R"=CH3 ], m.p. 165°-166° C., and the latter hydrolyzed to yield 7.3 g (74%) of 4-(1-methyl-2-phenyl-1H-indol-3-yl)-benzoic acid [IV; R'=CH3, R"=H], m.p. 235°-240° C. (from aqueous dioxane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH2:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1.[CH3:21]N>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([NH:11][CH3:21])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:20][C:19]2[C:14](=[N:15][CH:16]=[N:17][CH:18]=2)[N:13]=1
Reactant: CN
Reactant: COc1cc(C(N)=O)ccc1-c1nc2ncncc2[nH]1
Product: CNC(=O)c1ccc(-c2nc3ncncc3[nH]2)c(OC)c1

Procedure:
Forty milliliters of ethanolic methylamine solution were added to 0.42 gm of 8-(2'-methoxy-4'-chlorocarbonyl-phenyl)-purine hydrochloride (see Example 43), with cooling, and the mixture was refluxed for 30 minutes. It was then concentrated by evaporation, and the product was purified by column chromatography on silica gel [eluant:methylene chloride/ethanol (8:2)].
Reaction SMILES: [CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:22]=4[CH:23]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O>[CH:1]1([N:4]([CH3:29])[C:5]2[C:6]([C:19]3[O:20][C:21]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:22]=4[CH:23]=3)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C3CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of methyl 3-[cyclopropyl(methyl)amino]-2-(5-fluoro-1-benzofuran-2-yl)quinoxaline-6-carboxylate (79 mg, 0.20 mmol) in methanol (15 mL) and water (1 mL) was added sodium hydroxide (24 mg, 0.60 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (20 mL), adjusted the pH value to 5 with 3N HCl and filtered to give 3-[cyclopropyl(methyl)amino]-2-(5-fluoro-1-benzofuran-2-yl)quinoxaline-6-carboxylic acid as a light yellow solid (60 mg, 79%).