Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2=[CH:8][C:9](=[O:14])[CH:10]=[CH:11][CH2:12][CH2:13]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>C(#N)C>[N:22]([CH:11]1[CH2:10][C:9](=[O:14])[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:13][CH2:12]1)=[N+:23]=[N-:24]
Reactant: Cn1ncc([N+](=O)[O-])c1C1=CC(=O)C=CCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC#N
Product: Cn1ncc([N+](=O)[O-])c1C1=CC(=O)CC(N=[N+]=[N-])CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of (2E,6Z)-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohepta-2,6-dienone (690 mg, 2.95 mmol) in acetonitrile (10 mL) was added trimethylsilyl azide (1 mL, 7.57 mmol) and Amberlite™ IRA900F resin (590 mg, 1.47 mmol). The reaction mixture was stirred at 40° C. for 5 hr, cooled to room temperature, filtered and concentrated under reduced pressure to give (E)-6-azido-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-2-enone as a yellow oil. To a solution of this oil (810 mg, 2.93 mmol) in THF (20 mL) and water (6 mL) was added sodium borohydride (166 mg, 4.40 mmol). The mixture was stirred at room temperature for 18 hr before being diluted with water (50 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (E)-6-azido-3-(1-methyl-4-nitro-1H-pyrazol-5-yl)cyclohept-2-enol as a yellow oil. This oil (810 mg, 2.91 mmol) was dissolved in THF (15 mL) and added to a suspension of polymer-supported triphenylphosphine (3.1 g, 5.76 mmol) in THF (45 mL) and water (1.5 mL). The mixture was gently stirred at 60° C. for 18 hr, cooled to room temperature and concentrated under reduced pressure. The residue was diluted in DCM (30 mL) and di-tert-butyl dicarbonate (754 mg, 3.46 mmol) and DIPEA (1.51 mL, 8.64 mmol) were added. The mixture was stirred at room temperature for 5 hr, diluted with DCM (50 mL) and quenched with a saturated solution of sodium hydrogencarbonate (50 mL). The organic layer was washed with water (50 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (E)-tert-butyl 5-(1-methyl-4-nitro-1H-pyrazol-5-yl)-3-oxocyclohept-4-enylcarbamate as a white foam (620 mg, 59% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 6.03-5.99 (m, 1H), 4.82-4.60 (m, 2H), 3.86-3.82 (m, 4H), 2.82-2.34 (m, 1H), 2.29-2.35 (m, 1H), 2.34-2.20 (m, 2H), 2.15-2.04 (m, 1H), 1.85-1.51 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Cu](C#N)[C:12]#[N:13].N>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[C:12]#[N:13]
Reactant: N#C[Cu]C#N
Reactant: Fc1cc(Br)cc(F)c1F
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(F)c(F)c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
To 50 ml of N-methylpyrrolidone were added 10 g of 3,4,5-trifluorobromobenzene and 8.5 g of copper cyanide, and the resulting mixture was stirred at 150° C. for 4 hours. Thereafter, aqueous ammonia was added to the reaction mixture which had been allowed to cool to near room temperature, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and 5.0 g of 3,4,5-trifluorobenzonitrile was obtained.
Reaction SMILES: [CH2:1]([C:3]([CH2:19][OH:20])([CH2:17][CH3:18])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])[CH3:2].[C:21](Cl)(=[O:23])[CH3:22]>>[C:21]([O:20][CH2:19][C:3]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:7]=1[C:8]#[N:9])([CH2:1][CH3:2])[CH2:17][CH3:18])(=[O:23])[CH3:22]
Reactant: CCC(CC)(CO)COc1cccc([N+](=O)[O-])c1C#N
Reactant: CC(=O)Cl
Product: CCC(CC)(COC(C)=O)COc1cccc([N+](=O)[O-])c1C#N
Yield: 82 %

Procedure:
Prepared as in Example 231c from 2-(2-ethyl-2-(hydroxymethyl)butoxy)-6-nitrobenzonitrile (Example 232d) and acetyl chloride in 82% yield. MS 321 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[N:22][C:23]([Cl:29])=[CH:24][CH:25]=2)[N:20]=1>O1CCCC1>[Cl:29][C:23]1[N:22]=[C:21]2[C:26]([CH:27]=[CH:28][C:19]([N:10]3[CH:9]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:18])=[N:20]2)=[CH:25][CH:24]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 37.9 %

Procedure:
3-Dimethylaminopropylamine (4.1 g) is added at a temperature in the region of 20° C. to a suspension of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) in anhydrous tetrahydrofuran (100 cc), and the reaction mixture is heated to reflux for 6 hours. After the reaction mixture has been stirred for a further 20 hours at a temperature in the region of 20° C., it is filtered. The isolated solid is washed with ethyl acetate (3×25 cc). The filtrate is washed with distilled water (3×25 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. 1N aqueous hydrochloric acid solution (20 cc) is added to the residue obtained. An insoluble product is separated by filtration, washed with 1N aqueous hydrochloric acid solution (2×5 cc) and then discarded. The aqueous filtrates are combined and alkalinized with a saturated aqueous potassium bicarbonate solution to a pH in the region of 8, and then extracted with ethyl acetate (3×40 cc). The organic phases are combined, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in ethyl acetate, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(3-dimethylaminopropylamino)-1-isoindolinone (3 g), m.p. 143° C., is obtained.
Reaction SMILES: [Cl:1]C(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH3:35][Si:36]([CH3:49])([CH3:48])[NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)(=O)=[O:39]>>[CH3:35][Si:36]([CH3:49])([CH3:48])[N:37]=[S:38]([Cl:1])([C:41]1[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=1)=[O:39]
Reactant: C[Si](C)(C)NS(=O)(=O)c1ccc(F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N=S(=O)(Cl)c1ccc(F)cc1

Procedure:
The reactants used in the general procedure were hexachloroethane (0.0953 mol, 23.02 g), triphenylphosphine (0.0963 mol, 25.51 g), triethylamine (0.0991 mol, 12.5 ml), and a mixture of N-mono- and N,N-bis(trimethylsilyl sulfonamides (3c) and (5c) containing about 89.5% monosilylsulfonamide (3c) (0.0881 mol, 21.76 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:21][CH2:20][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:18][CH2:17]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:35]I.O>C1COCC1>[CH3:35][N:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:17][CH2:18][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:20][CH2:21]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ccc2c(CN3C(=O)CCCC34CCN(c3cnc5ccccc5n3)CC4)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
The title compound was synthesized from 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (prepared according to method G) via methylation as follows: NaH (7 mg, 0.18 mmol, 60% in mineral oil) was added to an ice-cold solution of 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (synthesized according to method G) (25 mg, 0.06 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 10 min. The mixture was cooled to 0° C., methyl iodide (26 mg, 0.18 mmol) was added at 0° C. and stirring was continued at 0° C. for 1 h. Then the mixture was allowed to warm to rt over a period of 1 h. The mixture was poured into water and the solution was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by preparative reversed phase HPLC (column Zorbax eclipseXDB C18 21.2×150 mm 5 ♀m, flow 20 mL/min, eluent: gradient water/acetonitrile) to yield the title compound (13 mg, 50%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.49 (s, 1H), 7.88 (d, 1H), 7.68-7.50 (m, 2H), 7.45-7.35 (m, 1H), 7.21-7.08 (m, 2H), 6.95 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 4.98 (s, 2H), 4.40 (d, 2H), 3.78 (s, 3H), 3.15 (t, 2H), 2.68 (t, 2H), 2.25-2.05 (m, 4H), 2.00-1.85 (m, 2H), 1.80-1.70 (m, 2H); LCMS RtF=1.50 min, [M+H]+=440.0].
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16].O>C(Cl)Cl>[CH3:14][S:15]([O:6][C@H:3]1[CH2:4][CH2:5][O:1][CH2:2]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
A solution of (S)-tetrahydrofuran-3-ol (1.0 g, 11 mmol) and triethylamine (9.4 mL, 86 mmol) in CH2Cl2 (20 mL) was cooled in an ice-water bath. To this, methanesulfonyl chloride (3.0 mL, 39 mmol) diluted in CH2Cl2 (10 mL) was added dropwise. The reaction was left stirring for 12 hours at room temperature. Water was added, and organic phases extracted in CH2Cl2 (3×50 mL), which were subsequently dried onto silica and purified by silica gel chromatography (50% EtOAc:Hexanes to 100% EtOAc gradient) to afford (S)-tetrahydrofuran-3-yl methanesulfonate (1.52 g, brown oil, 83% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.[C:28]1([N:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:16][CH2:17][N:18]([C:35]([N:34]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:36])[CH2:19][CH2:20]1
Reactant: COc1cc2ncnc(N3CCNCC3)c2cc1OC
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N3CCN(C(=O)N(c4ccccc4)c4ccccc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
In 10 ml of dimethylformamide was dissolved 400 mg (1.46 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained according to the method described in South African Patent No. 67 06512 (1968), and 1.02 ml (7.32 mmol) of triethylamine was added thereto. To the resulting mixture was added 406 mg (1.75 mmol) of diphenylcarbamoyl chloride, followed by overnight stirring at room temperature. After the reaction mixture was poured into water, the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 680 mg of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12]([O:19][CH2:20][CH2:21]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:12]([O:19][CH2:20][CH2:21][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: OCCOCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
3-Methyl-4-nitrophenol (17.48 g, 114 mmoles), 2-benzyloxyethanol (17.38 g, 114 mmoles, 16.22 ml) and triphenylphosphine (44.6 g, 170.2 mmoles) were dissolved in anhydrous tetrahydrofuran (200 ml) under nitrogen at room temperature. The stirred reaction mixture was then cooled to 0° C. and stirred for 10 minutes. Diisoproplyazo-dicarboxylate (23.49 g, 116.2 mmoles, 22.97 ml) was then added in one lot, and the reaction mixture was allowed to warm to room temperature and stirred overnight (16 hours). The solvent was removed under reduced pressure and the crude mixture was purified via column chromatography (silica gel, 5% ethyl acetate-hexane) to give the product. The remaining impurities were removed by means of crystallization from hexane ethyl acetate. The result crystals were filtered off and the mother liquor was evaporated under reduced pressure to give 21.56 g of 4-(2-(benzyloxy)ethoxy)-2-methyl-1-nitrobenzene. 1H-NMR (CDCl3) 8.08 (d, 1H), 7.38.7.31 (m, 3H), 6.82 (m, 2H), 4.65 (s, 2H), 4.23 (t, 2H), 3.87 (t, 2H), 2.63 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7](=[C:10]1[CH2:14][CH2:13][C:12]2([CH:19]([CH3:20])[CH2:18][C:17]([O:21]C(C)C)=[CH:16][C:15]2=O)[CH2:11]1)([CH3:9])[CH3:8].O.Cl>CCOCC>[C:7](=[C:10]1[CH2:14][CH2:13][C:12]2([CH:19]([CH3:20])[CH2:18][C:17](=[O:21])[CH:16]=[CH:15]2)[CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)=C1CCC2(C1)C(=O)C=C(OC(C)C)CC2C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(C)=C1CCC2(C=CC(=O)CC2C)C1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of lithium aluminum hydride (0.15 g, 4 mmol) in anhydrous ether (10 ml) was added 2-isopropylidene-8-isopropoxy-10-methylspiro[4.5]dec-7-en-6-one (2 g, 8 mmol), prepared according to Example 2. The mixture was heated at reflux for 1 hour and water cautiously added. The solution was mixed with 10% hydrochloric acid (30 mL) and agitated at room temperature for 45 minutes. The aqueous mixture was extracted with ether and the ether extracts washed with saturated sodium bicarbonate solution and dried (Na2SO4). The solution was concentrated and the crude ketone kugelrohr distilled to give 1.4 g, bp 130°/0.5 mm, of enone having the structure: ##STR26##
Reaction SMILES: C([N:8]1[CH2:13][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O.CO.[Pd]>[C:14]1([C@H:12]2[C@@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH2:9][NH:8][CH2:13]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)CN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)[C@H]1CCNC[C@H]1c1ccccc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 9.98 g of ethyl 1-benzyl-5-phenyl-1,2,3,6-tetrahydropyridine-4-carboxylate, 10.31 g of ammonium formate, and 90 mL of methanol was added 1.49 g of 10% palladium/carbon while suspending it in 10 mL of water and 10 mL of methanol. The reaction mixture was vigorously stirred at 60° C. for 2 hours. After cooling to room temperature, the insolubles were filtered on a celite layer, and the filtrate was concentrated under reduced pressure. To the obtained residue was added chloroform, followed by washing with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 7.09 g of a pale yellow oily substance of ethyl rel-(3R,4S)-3-phenylpiperidine-4-carboxylate as a crude product. ESI+: 234
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:33])C=1.C(O)C.O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:33])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:11])[F:13]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
2-[[3-Methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylthio]benzimidazole (monohydrate) (20 g) was dissolved in chloroform (200 ml), to which was added slowly dropwise below 5° C. a solution of m-chloroperbenzoic acid (13.5 g) in chloroform (200 ml), and stirred at the same temperature for about 10 minutes. After completion of the reaction, the reaction mixture was washed with a solution of sodium hydrogencarbonate, and dried over magnesium sulfate, and chloroform was evaporated off under reduced pressure. To the residue was added ethanol (100 ml) for crystallization, which was ice-cooled; the resulting crystals were collected by filtration and washed with ice-cooled ethanol. The crystals thus obtained were treated with a mixture of ethanol-water (9:1, 90 ml), heated (65°-70° C.) and stirred so that the crystals were dissolved, then the insoluble matters were removed by hot filtration. The filtrate was ice-cooled for crystallization and the crystals were collected by filtration, washed with ice-cooled ethanol-water mixture (8:2), and dried in vacuo, to give white needles of 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-yl]methylsulfinyl]benzimidazole (14.9 g, yield: 74.9%).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([CH2:16][O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH:14]=[O:15])[CH:10]=[CH:9]2>C(O)C>[Cl:3][C:4]1[C:5]([CH2:16][O:17][CH3:18])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH2:14][OH:15])[CH:10]=[CH:9]2
Reactant: COCc1ccc2ccc(C=O)nc2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCc1ccc2ccc(CO)nc2c1Cl
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
Referring to FIG. 20, NaBH4 (0.0028 g, 0.074 mmol) was added to a solution of 9c (0.0397 g, 0.158 mmol) in ethanol (4 mL). The mixture was stirred for 20 min. The solvent was evaporated, and the resulting solid residue was dissolved in chloroform, then washed with water (×2) followed by brine, dried over MgSO4, and concentrated to afford 10c (0.0396 g, 0.156 mmol, 99%) as a white, crystalline solid (mp 84-87° C.): 1H NMR (CDCl3) δ 8.09 (1H, d, J=8.4 Hz), 7.71 (1H, d, J=8.8 Hz), 7.52 (1H, d, J=9.2 Hz), 7.24 (1H, d, J=8.4 Hz), 5.41 (2H, s), 4.94 (2H, s) 3.58 (3H, s); 13C NMR (CDCl3) δ 160.3, 154.2, 144.1, 137.2, 127.0, 124.4, 120.0, 117.4, 117.2, 95.7, 64.4, 56.8; FTIR (neat) 3342, 2925, 1615, 1155, 1005, 835, 781 cm−1; MS (ESI) m/z calculated for (C12H12ClNO3+H)+ 254 (35Cl) and 256 (37Cl), found 254 (35Cl) and 256 (37Cl); HRMS (ESI) m/z calculated for (C12H12ClNO3+H)+ 254.0584 (35Cl) and 256.0554 (37Cl), found 254.0577 (35Cl) and 256.0546 (37Cl).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[NH:8][C:7](=[O:9])[C:6]([CH3:11])([CH3:10])[C:5]1=[O:12].Br[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([Cl:22])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:16]1[CH:15]=[C:14]([N:8]2[CH:4]([CH2:3][O:2][CH3:1])[C:5](=[O:12])[C:6]([CH3:10])([CH3:11])[C:7]2=[O:9])[CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1ccc(Br)cc1Cl
Reactant: COCC1NC(=O)C(C)(C)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COCC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1

Procedure:
Using 5-(methoxymethyl)-3,3-dimethylpyrrolidine-2,4-dione (700 mg), 4-bromo-2-chlorobenzonitrile (1.06 g), cesium carbonate (2.00 g), tris(dibenzylideneacetone)dipalladium(0) (187 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (355 mg), and in the same manner as in Reference Example 3, the title compound was obtained as colorless crystals (yield: 219 mg, 17%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=O)=O>>[S:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=Cc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)OCc1cccs1
Product: O=Cc1cccc2c1ccn2Cc1cccs1

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2-thienylmethyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 392 mg of 1-(2-thienylmethyl)indole-4-carbaldehyde as pale yellow crystals. The yield thereof was found to be 33%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH2:5]CCC.[OH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1.C(Br)C=C>CCOCC.O.CN(C=O)C>[CH2:5]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=1)[CH:4]=[CH2:3]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: C=CCOc1ccc(C(=O)OC)cc1
Reaction time: 0.67 h

Procedure:
NaH (60% in oil, 10 g., 0.25 mol) was washed 3×100 ml. hexane in place. 350 ml. DMF was then added, the mixture stirred under N2, and methyl 4-hydroxybenzoate (38.0 g., 0.25 mol) added portionwise over 20 minutes as H2 evolved. Allyl bromide (21.6 ml., 0.25 mol) was then added via syringe over 5 minutes. After 40 minutes additional stirring, the reaction mixture was poured into 400 ml. ice and water and 150 ml. ether was added. The layers were separated and the aqueous layer extracted 4×150 ml. fresh ether and 1×100 ml. hexane. The organic layers were combined, washed 2×150 ml. saturated NaHCO3, dried over MgSO4, and stripped to yield title product, 47.6 g., 3.89 (s, 3H), 4.60 (m, 2H), 5.46 (m, 2H), 6.1 (m, 1H), 6.99 (d, 2 H), 8.10 (d, 2H).
Reaction SMILES: Cl.[CH2:2]([N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:3]([CH3:5])[CH3:4].[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][C@H:39]([C:50](O)=[O:51])[CH2:40][C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][C@H:39]([C:50]([NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]([N:6]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:2][CH:3]([CH3:5])[CH3:4])[C:13]([OH:15])=[O:14])=[O:51])[CH2:40][C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)cc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(N)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine hydrochloride (350 mg, 1.0 mmol, example 5, step C) as described in general procedure Bc using Nα-(4-methylbenzenesulfonyl)-L-tryptophan (335 mg, 1.1 mmol) which was prepared in step A of example 2. The final product was purified by preparative HPLC to yield 650 mg (90%) of Nα-(4-nitrobenzenesulfonyl)-Nα-isobutyl-Nε-[N′α-(4-methylbenzenesulfonyl)-L-tryptophanyl]-L-lysine. The latter derivative (300 mg) was hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (235 mg, 75%).