Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([C:15]#[C:16][Si](C)(C)C)=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.[F-].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([C:15]#[CH:16])=[C:13]([O:21][C:22](=[O:24])[CH3:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(OC(C)=O)c1C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1c(CC(=O)OC)cc2ccc(F)cc2c1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of (4-acetoxy-6-fluoro-3-trimethylsilanylethynyl-naphthalen-2-yl)-acetic acid methyl ester (200 mg, 0.538 mmol) in N,N-dimethylformamide and water (6 mL, v/v=150:1), was added potassium fluoride (156 mg, 2.7 mmol). The resulting mixture was stirred at room temperature for 4 hours, then poured into water (10 mL), and extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (elution with 10% ethyl acetate in petroleum ether) to afford (4-acetoxy-3-ethynyl-6-fluoro-naphthalen-2-yl)-acetic acid methyl ester (153 mg, 95%) as a light yellow solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:17]1([CH:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:35]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([OH:33])([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][C:7]=3[OH:11])[N:4]=[CH:3][CH:2]=[N:1]4)[C:25]2=[O:34])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Oc1ccc2nccnc2c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2nccnc2cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 34 %

Procedure:
To a stirred solution of quinoxalin-6-ol (King et al.; J. of the Chem. Society 1949:3012.) (11.2 g, 76.66 mmol) in tetrahydrofuran (800 mL) was added isopropylmagnesium chloride (38.3 mL, 2.0 M THF solution, 76.60 mmol) at −40° C. to −30° C. The mixture was allowed to stir at 0° C. for 2 h, followed by the addition of 1-(diphenylmethyl)-1H-indole-2,3-dione (20.00 g, 63.84 mmol) in tetrahydrofuran (400 mL). The mixture was stirred at ambient temperature for 20 h, and quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×1000 mL). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (dichloromethane/methanol, 100/1) to give 1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxyquinoxalin-6-yl)-1,3-dihydro-2H-indol-2-one (10.0 g, 34%): 1H NMR (300 MHz, CDCl3) δ 10.21 (s, 1H), 8.47 (s, 1H), 7.97-7.92 (m, 2H), 7.60-7.58 (m, 2H), 7.54-7.49 (m, 4H), 7.46-7.35 (m, 6H), 7.14 (s, 1H), 7.05-7.00 (m, 1H), 6.89-6.87 (m, 1H), 6.56-6.52 (m, 1H).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18]Br)[CH3:13].CCOCC>CN(C)C=O>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH3:13]
Reactant: O=Cc1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1C=O
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A solution of 12.2 g of salicylaldehyde in 20 ml of dimethylformamide is instilled into a suspension of 4.36 g of sodium hydride (55% dispersion in mineral oil) in 80 ml of dimethylformamide by stirring and ice cooling within 15 minutes. After 3 hours, a solution of 21.5 g of 4-bromobutyric acid ethyl ester in 16 ml of dimethylformamide is instilled by ice cooling within 15 minutes, and the mixture is stirred for 72 hours at room temperature. The batch is poured on ice/water, shaken with ether, the organic phase is washed briefly with 1 n sodium hydroxide solution, dried with sodium sulfate and concentrated by evaporation. The crude product is distilled at 130°-140° C./0.1 mbar in a bulb tube and 11.2 g of 4-(2-formylphenoxy)-butyric acid ethyl ester is thus obtained as a colorless oil.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]1([C:11]2[C:12](=[O:17])[O:13][CH2:14][CH2:15][CH:16]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[Si](C)(C)C>O1CCCC1.[Cu]I>[C:5]1([CH:11]2[CH:16]([CH:1]=[CH2:2])[CH2:15][CH2:14][O:13][C:12]2=[O:17])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=C[Mg]Br
Reactant: O=C1OCCC=C1c1ccccc1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C=CC1CCOC(=O)C1c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Vinylmagnesium bromide (77 ml, 1M THF) was added to a slurry of copper (I) iodide (7.37 g) in tetrahydrofuran (80 ml) at −78° C. under a nitrogen atmosphere. This mixture was stirred at −40° C. for 30 minutes, then recooled to −78° C. A solution of 3-phenyl-5,6-dihydro-2-pyrone (J. Org. Chem. 1967, 32, 2354) (4.6 g) and chlorotrimethylsilane (3.28 ml) in THF (80 ml) was added to the stirred mixture. Thin layer chromatography showed all starting material had reacted. The mixture was quenched with ammonium chloride (saturated aqueous solution) at −78° C. and the resulting mixture was allowed to come to room temperature and was stirred for 2 hours until the aqueous layer became dark blue. The mixture was filtered through Celite™ to remove any insoluble inorganics and the solution was extracted with ethyl acetate (3×100 ml). The pooled organic extracts were washed with brine, dried (MgSO4) and concentrated to give a yellow oil. This was purified on silica using 30-40% ether in hexane as eluant to afford the title compound (4.9 g, crystallised on standing) as a mixture of cis and trans isomers (2:1). Recrystallisation of this mixture from ether-hexane afforded the pure cis isomer as white prisms.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:5][CH:6]=1.[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@H:22]([OH:33])[C:23]1[CH:28]=[CH:27][C:26]([Sn](C)(C)C)=[CH:25][CH:24]=1)=[O:19]>>[Cl:16][CH:17]([Cl:36])[C:18]([NH:20][C@H:21]([CH2:34][F:35])[C@@H:22]([C:23]1[CH:24]=[CH:25][C:26]([C:2]2[CH:3]=[C:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[S:5][CH:6]=2)=[CH:27][CH:28]=1)[OH:33])=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1cc(Br)cs1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Product: CC(C)(C)OC(=O)NCc1cc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cs1
Yield: 20.3 %

Procedure:
The compound is prepared from tert-butyl ((4-bromothiophen-2-yl)methyl)-carbamate (132 mg, 0.45 mmol) and 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (200 mg, 0.45 mmol) in a manner analogous to Example 2 to give the tile compound (45 mg): 1H-NMR (400 MHz, CDCl3) 1.47 (s, 9H), 2.73 (bs, 1H), 4.26-4.38 (m, 1H), 4.39-4.52 (m, 2.5H), 4.53-4.61 (m, 1H), 4.65-4.72 (m, 0.5H), 4.87-5.03 (m, 1H), 5.12 (d, J=4.0 Hz, 1H), 5.87 (s, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.20 (s, 1H), 7.32 (d, J=1.5 Hz, 1H), 7.39 (d, J=8.1 Hz, 2H), 7.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[C:11]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:12][C:13](Cl)=[N:14][CH:15]=1>>[Br:9][C:10]1[C:11]([NH:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:19])=[N:12][C:13]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:14][CH:15]=1
Reactant: CC(Nc1nc(Cl)ncc1Br)c1ccc(F)cc1
Reactant: Nc1cccc(O)c1
Product: CC(Nc1nc(Nc2cccc(O)c2)ncc1Br)c1ccc(F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and (±)-5-bromo-2-chloro-N4-[1-(4-fluorophenyl)ethyl]-4-pyrimidineamine were reacted to produce (±)-5-bromo-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.97 (s, 1H), 7.36-7.31 (m, 2H), 7.17 (s, 1H), 7.09-7.01 (m, 4H), 6.82 (dd, 1H, J=2.2 and 8.2 Hz), 6.46 (d, 1H, J=2.2 and 8.2 Hz), 5.50 (br d, 1H, J=7.0), 5.27 (overlapped dq, 1H, J=7.1 and 7.9 Hz), 1.58 (d, 3H, J=7.0 Hz); LCMS: ret. time: 22.64 min.; purity: 94%; MS (m/e): 404 (MH+)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([O:11][CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:10]2[C:9]([O:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[C:4]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:3]1
Reactant: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(OC3CCNCC3)c21
Reaction time: 1 h

Procedure:
To tert-butyl 4-(5-methyl-7-(4-methanesulfonyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)piperidine-1-carboxylate obtained in Example 25, dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were added, and stirred for 1 hour. After completion of the reaction, the reaction was terminated with saturated sodium bicarbonate, and dichloromethane layer was extracted and washed with a saline solution. Subsequently, the washed layer was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: S([O-])([O-])(=O)=O.[Ca+2].[CH2:7]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH3:10].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:7]([N:11]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:18][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCN(CCCC)CCCCc1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Product: CCCCCCCN(CCCC)CCCCc1ccc(NS(C)(=O)=O)cc1
Temperature: 15 °C
Reaction time: 8 h
Yield: 114.4 %

Procedure:
A 250 ml 3-neck round bottom flask fitted with a thermometer, addition funnel, and calcium sulfate drying tube was charged with 8.5 g (0.027 mol) of N-butyl-N-heptyl-4-aminobenzenebutanamine and 90 ml of dry pyridine. The reaction mixture was cooled to a temperature of about 10°-15° C. and 2.6 ml (0.034 mol) of methanesulfonyl chloride was added thereto while maintaining the temperature below approximate 15° C. The external ice bath was removed and the reaction mixture was stirred overnight at room temperature. The volatiles were evaporated under reduced pressure and the pH of the reaction mixture was raised to about 9 by the addition of water and concentrated ammonium hydroxide. The aqueous solution was extracted four times with chloroform and the organic extracts were combined, washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated to provide 12.246 g of N-[4-[4-(butylheptylamino)butyl]phenyl]methanesulfonamide as an oil.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20][CH:21]([CH3:23])[CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]([S:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)Sc1cccc(C#N)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 10.6 %

Procedure:
A mixture of methyl thiosalicylate (1.21 g, 7.2 mmol), 2-cyano-6-isopropylthiopyridine (1.40 g, 7.9 mmol), triethylamine (1.5 ml, 10.8 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure to give the precipitated crystals, which were recrystallized from ethyl acetate-hexane to give the titled compound (0.24 g, 10%).
Reaction SMILES: [Sn](Cl)Cl.[CH2:4]([O:7][C:8]([NH:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=2)(=[O:27])=[O:26])[CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH:5]=[CH2:6].[OH-].[Na+]>C(O)C>[CH2:4]([O:7][C:8]([NH:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([NH2:34])[CH:29]=2)(=[O:27])=[O:26])[CH:19]=1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:9])[CH:5]=[CH2:6]
Reactant: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOC(=O)NC(CC(=O)OCC)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1

Procedure:
Tin(II) chloride (39.7 g) was added to a solution of ethyl 3-allyloxycarbonylamino-3(3-[3-nitrophenylsulphonylamino]-phenyl)-propionate from II.1e (16.8 g) in 155 ml of ethanol and the reaction mixture was heated under reflux for 2 h. After cooling, the solution was adjusted to pH=7 using 2N NaOH, briefly heated, cooled again and filtered. It was then extracted with dichloromethane, and the org. phase was dried (MgSO4) and concentrated. 7.3 g of product were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23][C:24](=[O:29])[O:25][CH2:26][CH:27]=[CH2:28])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:31].CO>>[NH2:31][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23][C:24](=[O:29])[O:25][CH2:26][CH:27]=[CH2:28])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Reactant: N
Solvent: CO
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F

Procedure:
A solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (535 mg, 1.197 mmol) and ammonia in MeOH 7N (6 ml, 42.0 mmol) was heated to 80° C. for 24 h. The crude reaction mixture was evaporated onto silica gel and chromatographed, (0-15% MeOH in DCM). The title compound was obtained as a yellow foam (233 mg, 41% yield). MS (ESI): 428.1 [M+H]+.
Reaction SMILES: [C:1]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C:31]([CH:38]([CH3:40])[CH3:39])([CH2:34][CH2:35][CH2:36]I)[C:32]#[N:33])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]>>[C:1]([C:6]1([CH2:36][CH2:35][CH2:34][C:31]([C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)([CH:38]([CH3:40])[CH3:39])[C:32]#[N:33])[CH2:15][C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=2)[CH2:8][N:7]1[CH3:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Product: CCOC(=O)C1(CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)Cc2cc(OC)c(OC)cc2CN1C

Procedure:
The resulting ester of formula 31 is then treated with an iodoalkane of formula 22 (see Scheme III, step 2) in the presence of a strong base to form an alkylated tetrahydroisoquinoline ester of formula 32. For example, 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31) is added to a solution of LDA in THF at -70° C. and allowed to stand for 5-60 minutes, preferably about 10 minutes. To this reaction mixture is then added 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) in THF, and the resulting mixture allowed to warm to about 0° C. The mixture is then acidified, for example with dilute HCl, and the product extracted and purified to produce 3-carboethoxy-3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (32).
Reaction SMILES: [CH3:1][S-:2].[Na+].[N+:4]([C:7]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:8]=1F)([O-:6])=[O:5]>C(COC)OC>[CH3:1][S:2][C:8]1[C:7]([N+:4]([O-:6])=[O:5])=[CH:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1
Reactant: C[S-]
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(NC(C)=O)cc1[N+](=O)[O-]

Procedure:
At room temperature, 50.0 g of sodium thiomethoxide are suspended in 500 ml of dimethoxyethane and 99.1 g (0.5 mole) of 2-nitro-4-acetylaminofluorobenzene are added, in portions, over 30 min, while the temperature is maintained between 25° and 27° C. by means of an ice cold water bath.
Reaction SMILES: IC.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([I:11])[CH:5]=1.[C:12](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:12])=[C:6]([I:11])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Br)cc1I
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Iodomethane (103 μL, 1.65 mmol) was added to a solution of 4-bromo-2-iodophenol (450 mg, 1.51 mmol) and potassium carbonate (271 mg, 1.96 mmol) in acetone (10 mL). The resulting mixture was stirred at room temperature for 16 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[CH3:10].[NH:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cc1c(Br)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1c(Br)cccc1Cn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.7 %

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-2-methylbenzene (250 mg, 0.947 mmol), 1H-benzo[d]imidazole (336 mg, 2.84 mmol) and potassium carbonate (131 mg, 0.947 mmol) in acetonitrile (5 mL) was stirred at rt for 5 h, The mixture was diluted with EtOAc and filtered, and the solid was washed with EtOAc. The filtrate was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 60:40 hexane-EtOAc to EtOAc), to provide 1-(3-bromo-2-methylbenzyl)-1H-benzo[d]imidazole as a white solid (233 mg, 82%). 1H NMR (400 MHz, chloroform-d) δ 8.14 (1H, s), 7.68-7.78 (1H, m), 7.56 (1H, d, J=7.9 Hz), 7.36-7.44 (1H, m), 7.25-7.34 (2H, m), 7.03 (1H, t, J=7.8 Hz), 6.82 (1H, d, J=7.7 Hz), 5.58 (2H, s), 2.45 (3H, s). Mass spectrum m/z 301, 303 (M+H)+.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccccc1
Reactant: Ic1ccc(OC2CCCCC2)nc1
Product: C(#Cc1ccc(OC2CCCCC2)nc1)c1ccccc1

Procedure:
The title compound, brown oil, MS: m/e=278.1 (M+H+), can be prepared in accordance with the general method of example 18, step 2 from 2-(cyclohexyloxy)-5-iodopyridine and phenylacetylene.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:12]1([S:18]([NH:7][NH:6][C:4](=[O:5])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=2[Br:1])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNC(=O)c1ccccc1Br
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(NNS(=O)(=O)c1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-bromobenzoic acid hydrazide (132 g) in pyridine (1,2 L) cooled to about 10 C with an ice bath, was added benzensulfonyl chloride (78.3 ml). After complete addition, the reaction was stirred at ambient temperature for four hours, and then poured into ice-hydrochloric acid to precipitate a yellow solid, 135 g. The material was recrystallized from isopropanol to yield 125 g of 2-bromobenzoic acid 2-phenylsulfonylhydrazide, m.p.=154°-156° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[F:22])[CH2:34][CH2:33]2)=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccccc1N1CCNCC1
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2C(C)(C)C)cc1

Procedure:
132 mg (91%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(2-fluorophenyl)piperazine (54 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: Cl.[S:2]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1CC#N)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:20]([OH:23])(=[O:22])[CH3:21]>>[S:2]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:21][C:20]([OH:23])=[O:22])([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: CC(=O)O
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CC#N)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CC(=O)O)cc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
Concentrated hydrochloric acid (20 ml) was added to a solution of (2S)-2-(1-tosylpyrrolidin-2-yl) acetonitrile (4.35 g) prepared in Reference Example 50 in acetic acid (4 ml) and then the reaction solution was heated under reflux for 3 hours. After cooling the reaction solution, it was poured into ice water and then extracted with ether. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/methanol (99/1) to give 6.93 g (yield 48.2%) of the title compound.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br.[NH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=2[OH:19])[C:10]1=[O:21]>C(O)C>[C:1]1(=[N:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=3[OH:19])[C:10]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCc2c(ccc(O)c2O)C1=O
Reactant: O=C1CCCC1
Agent: Br
Solvent: CCO
Product: O=C1c2ccc(O)c(O)c2CCC1N=C1CCCC1

Procedure:
In a mixture of 20 volume parts of cyclopentanone and 100 volume parts of ethanol is dissolved 1 part of 2-amino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide to produce 2-cyclopentylideneamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone. The resulting mixture is subjected to catalytic reduction with 0.1 part of platinum dioxide and 0.39 part of anhydrous sodium acetate at ordinary temperature and pressure.