Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[C:24](Cl)(Cl)=[O:25].C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[Cl:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]2[NH:1][C:24](=[O:25])[N:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:3]=2[CH:4]=1
Reactant: Cc1cc(N)c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c2cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1,1-Dimethylethyl 4-[(2-amino-5-chloro-4-methylphenyl)amino]-1-piperidinecarboxylate (D7) (0.292 mmol, 100 mg) was dissolved in 10 ml of dichloromethane and a 20% solution in toluene of phosgene (1.05 eq., 150 microliters) followed by triethylamine (2.1 eq., 85 microliters) were added at 0° C.; the reaction mixture was then stirred at 0° C. for 30 minutes and subsequently quenched with citric acid (10% aqueous solution). The reaction mixture was diluted with dichloromethane, the two phases were separated and the aqueous phase was extracted with dichloromethane (1×); the organic phases were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate-hexane) to yield the title compound, 50 mg, 50%, M+−H=364.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: Fc1ccc(NCc2cccnc2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cccnc1)c1ccc(F)cc1F
Temperature: 25 °C

Procedure:
A 8.9 g. portion of 3-(2,4-difluorophenylaminomethyl)pyridine was dissolved in 30 ml. of dichloromethane, and to it was added 6.9 g. of potassium carbonate and 3.9 ml. of methanesulfonyl chloride. The mixture was stirred at ambient temperature for several days, and then was heated and stirred at the reflux temperature overnight. It was then cooled, extracted with aqueous sodium bicarbonate, dried over magnesium sulfate and evaporated to a small volume. The residue was chromatographed over silica gel, eluting first with dichloromethane and then with 9:1 dichloromethane:ethyl acetate. The product-containing fractions were combined and evaporated to obtain impure product, which was triturated with diethyl ether and dried to obtain 5.6 g. of the desired product, m.p. 132°-135°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:9]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:8]([CH:43]([CH3:45])[CH3:44])[N:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O.C(OCC)(=O)C>[OH:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:9]([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:8]([CH:43]([CH3:44])[CH3:45])[N:7]=1
Reactant: CCCCCc1c(COC(C)=O)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCc1c(CO)nc(C(C)C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1-c1ccc(F)cc1
Yield: 107 %

Procedure:
A mixture of the intermediate obtained in Step A (60 mg, 0.096 mmol) and potassium carbonate (5 equiv) in methanol (8 mL) and water (2 mL) was refluxed for 1.5 h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. Concentration of the organic phase provided a colorless solid (60 mg, 100%) that was used in the next step without purification. 1H NMR (300 MHz, CDCl3): δ 7.4-7.2 (m, 10H), 7.11 (m, 4H), 4.90 (s, 2H), 4.39 (s, 2H), 3.34 (sept, 7.0 Hz, 1H), 2.34 (m, 2H), 1.25 (d, 7.0 Hz, 6H), 1.2 (m, 2H), 1.04 (m, 4H), 0.90 (s, 9H), 0.68 (t, 7.0 Hz, 3H).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([O:20]C)=[CH:15][CH:16]=3)[C:11]2=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6]1>C1C=CC=CC=1>[CH:5]1([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][C:14]([OH:20])=[CH:15][CH:16]=3)[C:11]2=[O:22])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COc1ccc2c(c1)C(=O)N(C1CCCC1)CC2
Agent: BrB(Br)Br
Solvent: c1ccccc1
Product: O=C1c2cc(O)ccc2CCN1C1CCCC1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
BBr3 (1.836 g, 7.35 mmol) was added dropwise to a solution of 2-cyclopentyl-7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (0.600 g, 2.45 mmol) in benzene (50 mL) at 0° C. The mixture was gradually warmed to room temperature and then heated at 80° C. for 30 min. The reaction mixture was then cooled to room temperature and carefully quenched with H2O. The resulting mixture was then heated at reflux for 1 hour and then cooled. Extraction with ethyl acetate and removal of the solvent in vacuo, followed by chromatographic separation (silica gel, CHCl3: CH3OH, 9:1) afforded 2-cyclopentyl-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one as a colorless solid (0.373 g, 66%). 1H NMR (DMSO-D6): δ 9.42 (s, 1H), 7.25 (s, 1H), 7.02 (d, 1H, J=8.6 Hz), 6.80 (d, 1H, J=8.5 Hz), 4.97-4.93 (m, 1H), 3.32 (t, 2H, J=6.1 Hz), 2.73 (t, 2H, J=6.7 Hz), 1.73-1.64 (m, 4H), 1.53-1.45 (m, 4H). LC-MS (ESI) Calcd for C14H17NO2 [M+H]+: 232.13. Found: 232.00.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][N+:17]([O-])=[CH:16][C:15]=2[CH3:21])[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(Cl)(=O)=O)=CC=1.C(C[NH2:36])O>N1C=CC=CC=1.C(#N)C>[NH2:36][C:18]1[CH:19]=[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:15]([CH3:21])=[CH:16][N:17]=1
Reactant: NCCO
Reactant: Cc1c[n+]([O-])ccc1-c1cccc(C(=O)OC(C)(C)C)c1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cnc(N)cc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 75 °C
Reaction time: 72 h
Yield: 36.3 %

Procedure:
4-(3-(tert-Butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide (0.467 g, 1.64 mmol) was dissolved in a mixture of pyridine (0.53 mL) and acetonitrile (15 mL) under an atmosphere of argon. 4-Methylbenzene-1-sulfonyl chloride (0.406 g, 2.13 mmol) was added and the reaction mixture was stirred at 75° C. for 72 hours. Ethanolamine (7 mL) was then added and the reaction mixture was allowed to stir for 5 minutes at room temperature. The crude product was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The layers were separated and the organic layer was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate and then purified on 40 g of silca gel utilizing a gradient of 0-100% ethyl acetate in hexanes to yield the pure product (0.169 g, 0.594 mmol, 36.3%). ESI-MS m/z calc. 284.2, found 285.1 (M+1)+. Retention time of 1.28 minutes. 1H NMR (400.0 MHz, DMSO-d6) δ 7.94-7.91 (m, 1H), 7.84 (s, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.62-7.56 (m, 2H), 6.33 (s, 1H), 5.78 (s, 2H), 1.99 (s, 3H), 1.55 (s, 9H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:8]([NH:10][C@H:11]([C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:50]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:51]([C:56]([O:58]N1C(=O)CCC1=O)=O)[CH2:52][CH:53]([CH3:55])[CH3:54].CN1CCOCC1.NCCN1CCNCC1>CN1CCCC1=O.[Pd].CO>[NH:50]([C:66]([O:68][C:69]([CH3:70])([CH3:71])[CH3:72])=[O:67])[C@H:51]([C:56]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:29]([NH:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:35])[CH3:36])=[O:30])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:28])[NH:17][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:58])[CH2:52][CH:53]([CH3:54])[CH3:55]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Agent: [Pd]
Agent: NCCN1CCNCC1
Solvent: CN1CCOCC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Reaction time: 5 h
Yield: 83 %

Procedure:
In 235 ml of N-methylpyrrolidone are dissolved 16.9 g (24 millimoles) of Z-Gln-Arg(Tos)-Leu-OH obtained according to the process of Example 1 and 8.7 g (26.4 millimoles) of Boc-Leu-OSu, and 2.64 ml of N-methylmorpholine is added to the solution. Then, 3 g of 10% Pd-C is added to the mixture, and the mixture is stirred for 5 hours in a current of H2. Then, N-(2-aminoethyl) piperazine is added to the mixture, the mixture is stirred for 1 hour and 100 ml of methanol is added to the mixture. The 10% Pd-C is recoved by filtration, and the mixture is concentrated under reduced pressure to distill N-methylpyrrolidone. The residue is added to a liquid mixture of 100 ml of ethyl acetate and 200 ml of a dilute aqueous solution of citric acid. The mixture is sufficiently stirred, and the ethyl acetate layer is recovered, washed with water, dried and concentrated under reduced pressure. Ether is added to the concentrate and the precipitate is recovered by filtration to obtain 15.6 g of intended Boc-Leu-Gln-Arg(Tos)-Leu-OH (the yield being 83.2%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([O:15][CH3:16])[CH:6]=1.[CH2:18]([Li])CCC.C(NC(C)C)(C)C.IC>C1COCC1.Cl>[CH3:16][O:15][C:7]1[CH:6]=[C:5]([CH:4]([CH3:18])[C:3]([O:2][CH3:1])=[O:17])[CH:10]=[C:9]([C:11]([F:13])([F:12])[F:14])[CH:8]=1
Reactant: COC(=O)Cc1cc(OC)cc(C(F)(F)F)c1
Reactant: [Li]CCCC
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1cc(OC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from step (i) (1.3 g) was added to a pre-formed solution of butyllithium (2.5M in hexanes, 2.51 ml), diisopropylamine (0.88 ml) in dry THF (30 ml) at −78° C. The mixture was kept at −78° C. for 1 hour before adding iodomethane (0.4 ml). The mixture was slowly allowed to warm to room temperature overnight. The mixture was diluted with 2M HCl, extracted with ether, dried (MgSO4) and evaporated under reduced pressure to give an oil. The oil was purified by flash column chromatography (eluent 2:1 isohexane/diethylether) (0.8 g).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.C(Cl)(Cl)Cl.[O:31]=[C:32]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])[C:33]([OH:35])=[O:34]>CO>[CH3:1][CH2:2][C@:3]12[CH2:19][C@:18]([OH:24])([C:20]([O:22][CH3:23])=[O:21])[N:17]3[C:9]4=[C:10]([CH2:25][CH2:26][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=13.[O:31]=[C:32]([CH2:36][CH2:37][C:38]([O-:40])=[O:39])[C:33]([O-:35])=[O:34]
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: CC[C@]12CCCN3CCc4c(n(c5ccccc45)[C@@](O)(C(=O)OC)C1)[C@@H]32
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C([O-])CCC(=O)C(=O)[O-]

Procedure:
1.617 g. of vincamine (0.005 mole) is dissolved in 15 ml. of chloroform, and 0.8 g. (0.055 mole) of 2-ketoglutaric acid previously dissolved in 5 ml. of methanol is added. After concentration of the resulting solution in a rotary evaporator until a volume of 5 ml. is obtained, 1.75 g. of vincamine 2-ketoglutarate is obtained. By subsequent successive concentrations, an additional amount of 0.5 g. of salt is obtained. A total of 2.25 g. is thus obtained (yield 90%).
Reaction SMILES: [OH:1][C:2]1([CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:5]=2[O:4][CH2:3]1.[N+](=[CH2:21])=[N-]>C(OCC)C>[OH:1][C:2]1([CH2:14][NH:15][CH:16]([CH3:18])[CH3:17])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:21])=[CH:12][C:5]=2[O:4][CH2:3]1
Reactant: CC(C)NCC1(O)COc2ccc(O)cc2OC1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COc1ccc2c(c1)OCC(O)(CNC(C)C)CO2

Procedure:
3,7-Dihydroxy-3-isopropylaminomethyl-3,4-dihydro-2H-1,5-benzodioxepin (2.53 g.; 10 millimoles) from Example 89 dissolved in 50 ml. of diethyl ether is left 10 hours at ambient temperature with 0.46 g. (11 millimoles) of diazomethane in 25 ml. of diethyl ether. Excess diazomethane is destroyed by addition of a few drops of acetic acid. The solution then is washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to give 3-hydroxy-3-isopropylaminomethyl-7-methoxy-3,4-dihydro-2H-1,5-benzodioxepin.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) suspension of 4-nitroaniline (10 g, 0.072 mol) and Et3N (10 mL) in CHCl3 (120 mL), was added dropwise ethyl chloroformate (6.9 mL) and the mixture was stirred under an argon atmosphere at room temperature overnight. CHCl3 was added and the resulting solution was washed with 1N HCl. The layers were separated, the aqueous phase was washed with CHCl3 and the combined organic extracts were dried and concentrated. The residue was chromatographed on silica gel (hexane:EtOAc, 30%) to afford N-(ethoxycarbonyl)-4-nitroaniline (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([O:17]CC)=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1>C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:6]([CH2:8][C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cccc(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Yield: 97.9 %

Procedure:
Ethyl 6-({5-chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-2-pyridinecarboxylate (5.26 g, 13.8 mmol) was stirred at 60° C. for 2 hours in ethanol (15 ml) and 2M sodium hydroxide solution (5 mL). The reaction mixture was cooled and evaporated. The residue was diluted with water and extracted with diethyl ether. The aqueous phase was then acidified with glacial acetic acid and extracted with ethyl acetate (2×30 mL), dried (MgSO4) and evaporated to give the title compound as a yellow oil (4.78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Na]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH2:10][C:9](=[O:13])[CH2:8]2
Reactant: COc1ccc2c(OC)cccc2c1
Agent: [Na]
Solvent: CCO
Product: COc1cccc2c1CCC(=O)C2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
5-Methoxy-2-tetralone was prepared according to the method of Ames et al., J. Chem. Soc.. 1965, 2636, as follows: To a boiling solution of 100 g (0.53 mol) of 1,6-dimethoxynapthalene in 1.4 L EtOH was added 90 g (3.91 mol) sodium shavings and the mixture was stirred until all the sodium was dissolved. The reaction was cooled to 0° C., and 457 mL concentrate HCl and 395 mL H2O was added dropwise and refluxed one hour. The mixture was filtered and the filtrate was concentrated, dissolved in H2O and extracted with diethyl ether. The organic layer was concentrated and dissolved in 60 mL saturated sodium bisulfite, stirred for 20 min., then filtered. The resulting solid was freed and distilled to give the product (65% yield) as a clear oil: NMR (CDCl3)δ7.2(1H,m), 6.8(2H,m), 3.9(3H,s), 3.6(2H,s), 3.1(2H,m), 2.55(2H,m).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[NH:3]1.[Cl:23][C:24]1[C:29](I)=[CH:28][CH:27]=[CH:26][C:25]=1[OH:31].CC([O-])=O.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:24]1[C:29]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])([CH3:22])[CH:11]=[C:10]3[CH3:12])=[CH:28][CH:27]=[CH:26][C:25]=1[OH:31]
Reactant: Oc1cccc(I)c1Cl
Reactant: CC1=CC(C)(C)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Product: CC1=CC(C)(C)Nc2ccc(-c3cccc(O)c3Cl)cc21
Yield: 81 %

Procedure:
2,2,4-Trimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydroquinoline (308 mg) and 393 mg of 2-chloro-3-iodophenol were coupled using of 100 mg of PdCl2(dppf) and 300 mg of KOAc to give 250 mg of 2-chloro-3-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-phenol. Using the procedures described in Example 7, this (85 mg) was reacted with NBS to give 56 mg of 3-(4-bromomethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol. The product (50 mg) was coupled with 0.04 mL of 2-phenylethanethiol to give 40 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](CC(C2C=CC=CC=2)=O)=[CH:4][CH:3]=1.[BH4-].[Na+].C([O:21][CH2:22][CH3:23])C>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:22]([OH:21])[CH3:23])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccccc1
Reactant: CCOCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)ethanol was prepared by mixing 10 g (72 mmol) of 4-fluorophenylacetophenone and 2.74 g (72 mmol) of sodium borohydride in 100 mL of ethanol. After one hour the solvent was removied under vacuum and the residue was taken up in diethyl ether. The ether solution was dried over anhydrous magnesium sulfate and evaporated to yield the crude product which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:7][C:8](=[O:39])[C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:10]=1)[CH3:6]>>[CH2:5]([O:7][C:8](=[O:39])[C:9]1[C:14]([NH:15][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]([C:16]2[CH2:20][CH2:19][CH2:18][C:17]=2[C:21]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:22]=2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:10]=1)[CH3:6]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C(F)(F)F)ccc3OCc3ccccc3)CCC2)ccc1NC(C)=O

Procedure:
Prepared by general procedure E but using acetyl chloride instead of propionyl chloride and 3-{2[5-trifluoromethyl-2-(benzyloxy)phenyl]cyclopent-1-enyl}-6-aminobenzoic acid ethyl ester instead of 5-[2-(2-benzyloxy-5-chlorophenyl)cyclopent-1-enyl]-2-aminobenzoic acid methyl ester.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([N:22]([CH2:29][CH:30]1[CH2:32][O:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21]>O1CCCC1.O>[CH2:20]([N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:29][CH:30]([OH:31])[CH2:32][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:21]
Reactant: CCN(CC1CO1)c1ccccc1
Reactant: Cc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCN(CC(O)CCc1cccnc1)c1ccccc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
Under argon gas, a solution of diisopropylamine (1.67 g, 16.5 mmol) in tetrahydrofuran (5 mL) was added dropwise to n-butyllithium (1.53 M in hexane, 9.8 mL, 15 mmol) at 5° C. and the mixture was stirred for 30 minutes. To this was further added a solution of 3-methylpyridine (2.794 g, 30 mmol) in tetrahydrofuran (5 mL) dropwise at 5° C. and the mixture was stirred for 30 minutes. Then, a solution of 2-([ethyl(phenyl)amino]methyl)oxirane (1.77 g, 10 mmol) in tetrahydrofuran (5 mL) was added at 5° C., and the reaction was carried out for 2 hours. This reaction mixture was diluted with 20 mL of water for hydrolysis, and extracted with 20 mL of ethyl acetate. The organic layer was washed with 20 mL of water twice and the solvent was distilled off under reduced pressure to give a yellow oil. This oil was purified by silica gel column chromatography (Merck's Kieselgel 60, hexane/ethyl acetate=1/1) to give 2.322 g (isolation yield: 86%) of 1-[ethyl(phenyl)amino]-4-pyridin-3-ylbutan-2-ol (yellow oil).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([OH:12])=[CH:7]2.[CH3:13][O-:14].[Na+]>CN(C=O)C.CO>[CH3:13][O:14][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([OH:12])=[CH:7]2
Reactant: C[O-]
Reactant: Oc1cc2cccc(F)c2cn1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cccc2cc(O)ncc12
Temperature: 90 °C
Yield: 23.3 %

Procedure:
8-Fluoroisoquinolin-3-ol (561 mg, 3.43 mmol) was dissolved in DMF (3 mL) and sodium methoxide (828 mg, 15.33 mmol) added. The reaction mixture was heated at 90° C. for 14 hours, then diluted with methanol and absorbed onto an SPE (TsOH) cartridge. The column was rinsed with methanol and the compound was then eluted with 7 M ammonia in methanol to afford the title compound (140 mg, 0.798 mmol, 23.2%). LC-MS (2) Rt=1.23 min; m/z (ESI+) 176 (M+H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([S:32]([N:35](CC4C=CC(OC)=CC=4OC)[C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)(=[O:34])=[O:33])[CH:28]=3)[CH2:23]2)([CH3:21])[CH3:20])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9].C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.C(Cl)(Cl)Cl>[C:8]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([S:32]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)(=[O:34])=[O:33])[CH:28]=3)[CH2:23]2)([CH3:21])[CH3:20])=[CH:16][CH:17]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: COc1ccc(CN(c2ccc(F)cc2)S(=O)(=O)c2ccc3c(c2)CCN(C(C)(C)Cc2ccc(C(C)(C)C)cc2)C3)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(CC(C)(C)N2CCc3cc(S(=O)(=O)Nc4ccc(F)cc4)ccc3C2)cc1
Reaction time: 2.5 h

Procedure:
Trifluoroacetic acid (0.2 mL) was added to a solution of 2-[1-(4-tert-butylphenyl)-2-methylpropan-2-yl]-N-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide obtained (22 mg) in a mixture of anisole (1 mL) and chloroform (1 mL) while cooling in ice, and the mixture was stirred for 2.5 hr while cooling in ice. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture while cooling in ice and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and then the desiccant was filtered off, followed by concentration under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (chloroform:methanol=49:1) to afford the title compound as a colorless oil (8 mg).