Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1.O[N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[CH3:11][N:8]1[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][O:1][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH2:10][CH2:9]1
Reactant: CN1CCN(CCCO)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(CCCON2C(=O)c3ccccc3C2=O)CC1
Temperature: 20 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
N-[3-(4-Methyl-1-piperazinyl)propoxy]phthalimide may be obtained in the following manner: a solution of 1-(3-hydroxypropyl)-4-methylpiperazine (8.4 g), N-hydroxyphthalimide (8.2 g) and triphenylphosphine (13.1 g) in tetrahydrofuran (120 cc) is cooled to a temperature in the region of 0° C. and ethyl azodicarboxylate (10.1 g) is added in the course of 30 minutes. The solution obtained is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 60° C. The crude oil obtained is chromatographed on a column 5 cm in diameter containing silica (0.063-0.2 mm) (400 g). The column is eluted with mixtures of ethyl acetate and methanol, collecting 500-cc fractions. The first 5 fractions originating from elution with pure ethyl acetate and the next 5 fractions originating from elution with a mixture of ethyl acetate and methanol (70:30 by volume) are discarded. The next fraction originating from elution with a mixture of ethyl acetate and methanol (70:30 by volume), the next 5 fractions originating from elution with a mixture of ethyl acetate and methanol (50:50 by volume) and the next 2 fractions originating from elution with pure methanol are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the region of 60° C. N-[3-(4-Methyl-1-piperazinyl)propoxy]phthalimide (11.4 g) is thereby obtained in the form of a red oil (Rf=0.2; thin-layer chromatography on silica, eluent: ethyl acetate/methanol, 50:50 by volume).
Reaction SMILES: [C:1]1([C:11]([N:13]2[C:17](=[O:18])[C:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:15][C:14]2=[O:31])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[CH3:34][N:15]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:18])[N:13]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:12])[C:14]1=[O:31]
Reactant: CI
Reactant: O=C1NC(c2ccccc2)(c2ccccc2)C(=O)N1C(=O)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) was dissolved in DMF (4 mL), and sodium hydride (60%, in oil) (10 mg) was added at 0° C. under ice-cooling. After stirred for 30 minutes, methyl iodide (37 mg) was added at 0° C., and the mixture was stirred at room temperature overnight. Water (100 mL) was added to the reaction solution, and separated out white precipitates were filtered. Further recrystallization using hexane:ethyl acetate=1:1 afforded 64 mg of white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Na+].[I-:13].[OH-].[Na+].N#N.[O-]Cl.[Na+].Cl>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([I:13])=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Oc1cccc2cccnc12
Reactant: [I-]
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: CO
Product: Oc1ccc(I)c2cccnc12
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 8-hydroxyquinoline (25.0 g, 172.3 mmol), NaI (26.0 g, 172.5 mmol) and NaOH (6.9 g, 172.5 mmol) in MeOH (750 ml) is degassed by passing-through of N2 for 60 min. at room temperature. After cooling to −30° C., a 5% aqueous NaOCl solution (250 ml) is added dropwise. The mixture is stirred vigorously at −30° C. for 30 min. and then neutralised using a 10% aqueous HCl solution. The precipitated product is filtered off. After two recrystallisations from MeOH/heptane (1:1, v/v), a pale-yellow solid is obtained (14 g, 27%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45](O)=[O:46])=[CH:40][CH:39]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].C(OC(=O)C(OCC)CC1C=CC(OC(=O)CC2N=C(C3C=CC=CC=3)OC=2C)=C(CC2C=CC=CC=2)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:45](=[O:46])[CH2:44][C:41]2[CH:40]=[CH:39][C:38]([NH:37][C:35]([O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:36])=[CH:43][CH:42]=2)=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Agent: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Product: CCOC(Cc1ccc(OC(=O)Cc2ccc(NC(=O)OC(C)(C)C)cc2)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1

Procedure:
The title compound was prepared from 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid benzyl ester (48 mg, 0.123 mol) and (4-tert-butoxycarbonylamino-phenyl)-acetic acid (31 mg, 0.123 mmol) in the same manner as described for 3-{3-benzyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-2-ethoxy-propionic acid benzyl ester. The crude product was purified by column chromatography using n-heptane/EtOAc (7:3) as the solvent to afford the product as a as an oil (65.1 mg, 72.2%). 1H NMR (400 MHz, CDCl3): δ 6.90-7.32 (m, 17H), 6.42 (br s, 1H), 5.08 (d, 2H), 3.97-3.98 (m, 1H), 3.73 s, 2H), 3.67 (s, 2H), 3.51-3.60 (m, 1H), 3.22-3.32 (m, 1H), 2.92-2.94 (m, 2H), 1.51 (s, 9H), 1.06-1.10 (t, 3H). Mass Spectrum: M−H+ 622.87.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1>CO.[O-2].[O-2].[Mn+4]>[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:1])=[O:15])=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(=O)Cl
Reactant: O=C(O)Cc1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Product: COC(=O)Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 28 %

Procedure:
Acetyl chloride (5 mL) was added to an ice-cooled solution of 4-(hydroxymethyl)phenylacetic acid (5.78 g, 34.8 mmol) in methanol (200 mL). The reaction mixture allowed to warm to RT at stirred at this temperature for 42 hours. The solvent was evaporated at reduced pressure and the residue dissolved in DCM (100 mL). Manganese dioxide (29.47 g, 339 mmol) was added and the resultant suspension stirred at RT for 18 hours. The suspension was filtered through celite and the filter cake washed with further DCM. The solvent was evaporated at reduced pressure and the residue was purified by flash column chromatography eluting with 0-25% ethyl acetate in iso-hexane to afford the title compound (1.72 g, 28%).
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:13]=[C:14]4[C:20]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:19][N:18](COCC[Si](C)(C)C)[C:15]4=[N:16][CH:17]=3)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>ClCCl.FC(F)(F)C(O)=O>[N:1]1([C:5]([C:7]2[CH:11]=[CH:10][N:9]([C:12]3[N:13]=[C:14]4[C:20]([C:21](=[O:26])[C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ccc(C(=O)N4CCC4)c3)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-n3ccc(C(=O)N4CCC4)c3)nc12
Reaction time: 17 h
Yield: 31.2 %

Procedure:
A solution of 1-[2-[3-(azetidine-1-carbonyl)-pyrrol-1-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (0.066 g, 0.137 mmol) in 2 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred for 5 h then concentrated. The resulting residue was dissolved in 1 mL of ethanol and treated with sodium acetate trihydrate (0.186 g, 1.37 mmol). The mixture was stirred for 17 h, then concentrated. Column chromatography (1->8% MeOH/CH2Cl2) afforded 0.015 g (31%) of 1-{2-[3-(azetidine-1-carbonyl)-pyrrol-1-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a yellow solid.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH2:18][CH3:19]>CN(C=O)C>[CH2:18]([N:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15](=[O:16])[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:19]
Reactant: O=c1c2c([nH]n1-c1ccccc1)CCCC2
Reactant: CCI
Solvent: CN(C)C=O
Product: CCn1c2c(c(=O)n1-c1ccccc1)CCCC2
Temperature: 100 °C

Procedure:
To a solution of 2-phenyl-1,2,4,5,6,7-hexahydro-indazol-3-one (0.1 g) in DMF (1 mL) was added iodoethane (0.073 mL) and the mixture was placed into a pressure bomb and sealed. The reaction vessel was then heated in an oil bath to 100° C. over three days. The reaction vessel was then cooled and the DMF was evaporated in vacuo. The residue was dissolved in EtOAc and saturated and washed with saturated sodium bicarbonate solution. The phases were separated and the aqueous solution was extracted with EtOAc another two times at neutral pH. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to afford a crude residue. Flash column chromatography over silica gel using ISCO combiflash chromatography and eluting with EtOAc/heptane and 3% AcOH afforded the desired 1-ethyl-2-phenyl-1,2,4,5,6,7-hexahydro-indazol-3-one (0.084 g) as a light brown solid. MS (ESI+): MS (ESI+): 243.4 [M+H]+).
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].Cl[CH2:28][CH2:29]CC(OC(=O)C)CCCCCCC.ClCCCC(OC(=O)C)CCCCC>>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Reactant: CCCCCCCC(CCCCl)OC(C)=O
Agent: CCCCCC(CCCCl)OC(C)=O
Product: CCCCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
This compound is prepared by the method described in Example 1 for 4-(4-acetyl-8-hydroxytridecyl)benzoic acid except that in Step D an equivalent quantity of 1-chloro-4-acetoxyundecane is substituted by 1-chloro-4-acetoxynonane. The intermediates and final product thus obtained are, Step D: ethyl 4-(4-acetyl-4-tert-butoxycarbonyl-8-acetoxypentadecyl)benzoate; Step E: ethyl 4-(4-acetyl-8-acetoxypentadecyl)benzoate; and Step F: 4-(4-acetyl-8-hydroxypentadecyl)benzoic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:19][CH2:20][CH3:21])[CH3:18])[CH3:14].[Li+].CC([N-]C(C)C)C.[CH2:31]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])([CH3:18])[CH:43]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:46][CH:45]=1)[OH:44])[CH3:14]
Reactant: CCOC(=O)C(C)OCC
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(OCC)C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Di-isopropylamine (1.1 ml; 7.78 mmole) and dry tetrahydrofuran (35 ml) were mixed and cooled to −78° C. under nitrogen athmosphere. n-Butyllithium (1.6 M in hexane, 4.7 ml; 7.52 mmole) was added slowly and the reaction mixture was stirred for 15 minutes. 2-Ethoxypropionic acid ethyl ester was dissolved in a small amount of dry tetrahydrofuran and added slowly to the LDA mixture. The solution was stirred for 30 minutes at low temperature and then 4-benzyloxybenzaldehyde was added followed after 2 minutes by addition of saturated ammonium chloride solution (20 ml). The mixture was warmed to room temperature and the layers were separated. The aqueous phase was extracted twice with ether and the organic phases were combined and washed with hydrochloric acid (0.3 M, 100 ml) and brine dried with magnesium sulfate and evaporated. Purification of the residue by chromatography on silica gel using ethyl acetate: toluene (1:9) with triethylamine (0.1%) as eluant gave 1.63 g (68%) of 3-(4-benzyloxyphenyl)2-ethoxy-3-hydroxy-2-methyl propanoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]([O:11][CH2:12][CH3:13])[C:9]#[N:10])=[O:6].C(N(CC)CC)C.[SH2:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][CH:8]([O:11][CH2:12][CH3:13])[C:9]([NH2:10])=[S:24])=[O:6]
Reactant: S
Reactant: CCOC(C#N)NC(=O)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(NC(=O)c1cccc(Cl)c1)C(N)=S

Procedure:
Into a solution of 3-chlorobenzoylamino(ethoxy) acetonitrile (1 g) in toluene (50 ml) containing triethylamine (1 g) was passed hydrogen sulphide gas. The precipitated product (0.72 g) was collected and crystallised from chloroform-light petroleum. m.p. 136°-137°.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:8]([O:10]C)=[O:9])[CH3:3].C1COCC1.[OH-].[Na+]>CO>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=1)[C:8]([OH:10])=[O:9])[CH3:1]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Yield: 95 %

Procedure:
To a solution of methyl 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoate (37 g) in a 1:1 mixture of THF:methanol (300 mL) was added 4M sodium hydroxide solution (150 mL). The mixture was refluxed for 45 minutes, following which the organics were removed in vacuo. The aqueous was acidified to pH4 with hydrochloric acid (2M), and extracted with ethyl acetate. The organics were combined, washed with water and brine, dried (MgSO4) and concentrated in vacuo to give the desired compound (33.5 g), which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.Cl.C(N=C=N)C.ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[C:17]([O:16][C:14](=[O:15])[CH2:13][O:12][C@H:3]1[C@H:2]([NH:1][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1N
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CO[C@@H]1Cc2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1 h
Yield: 72.5 %

Procedure:
To a stirred solution of trans 3-amino-2-carbo-t-butoxymethoxy-1,2,3,4-tetrahydronaphthalene (550 mg, 1.98 mmol) and 5-chloroindole-2-carboxylic acid (466 mg, 2.39 mmol) in tetrahydrofuran (12 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (760 mg, 2.39 mmol), 1-hydroxy-7-azabenzotriazole (540, 2.39 mmol), and diisopropylethylamine (0.4 mL). After 1 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel chromatography (20% ethyl acetate in hexane was used) to obtain the title compound (653 mg, 72%). 13C NMR (400 MHz, CDCl3) δ 172.31, 162.11, 134.72, 133.82, 132.8, 132.7, 128.8, 128.7, 126.6, 126.3, 125.7, 124.3, 121.0, 113.2, 102.6, 83.3, 77.6, 66.1, 51.7, 35.8, 34.4, 28.2. 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.92 (d, J=4.0 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.22 (dd, J=2.2, 7.8 Hz, 1H), 7.07-7.19 (m, 3H), 4.27 (d, J=17.6 Hz, 1H), 4.20 (m, 1H), 4.12 (d, J=17.6 Hz, 1H), 3.91 (dd, J=4.5, 16.8 Hz, 1H), 3.76 (dt, J=5.3, 8.0 Hz, 1H), 3.24 (dd, J=5.2, 16.8 Hz, 1H), 2.92 (dd, J=9.5, 15.0 Hz, 1H), 2.77 (dd, J=9.5, 15.0 Hz, 1H). MS [M+H]+, 455; [M−H]−, 453.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:11](=O)[CH2:12][CH3:13])[C:7](=O)[CH2:8][CH3:9])[CH3:2].O=C(CC)C(C(=O)CC)CC(OC(C)(C)C)=O.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([NH:42][NH2:43])[CH3:41])=[CH:36][CH:35]=1.O>CO>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[C:11]([CH2:12][CH3:13])=[N:43][N:42]([CH:40]([C:37]2[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][CH:36]=2)[CH3:41])[C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(C(=O)CC)C(=O)CC
Reactant: CC(NN)c1ccc(Br)cc1
Agent: CCC(=O)C(CC(=O)OC(C)(C)C)C(=O)CC
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1c(CC)nn(C(C)c2ccc(Br)cc2)c1CC
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a solution of 4-oxo-3-propionyl-hexanoic acid ethyl ester (500 mg) (preparation analagous to that of 1,1-dimethylethyl 4-oxo-3-propanoylhexanoate in WO2007/141267) in methanol (20 ml) at room temperature was added [1-(4-bromo-phenyl)-ethyl]-hydrazine (0.75 g). After overnight stirring, water was added and the mixture extracted 3 times with ethyl acetate. The organic layer was separated; washed with water and brine solution, then dried and concentrated to afford 792 mg of the title compound. Retention time HPLC: 1.58 min (Method D), ESI mass spectrum: (Br) [M]+=393/395.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].O.[NH2:20][NH2:21]>CO.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[S:6][C:7]=1[NH:20][NH2:21])#[N:2]
Reactant: NN
Reactant: CC(C)(C)OC(=O)c1cc(C#N)c(S(C)(=O)=O)s1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(C#N)c(NN)s1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-cyano-5-(methylsulfonyl)thiophene-2-carboxylate (2.0 g, 7.0 mmol) and hydrazine hydrate (1.7 mL) in methyl alcohol (30 mL) was stirred at 60° C. for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water. Organic layer was separated, dried over anhydrous sodium sulfate and evaporated. Through chromatography purification (n-hexane/ethyl acetate 3:2), 1 g of the title compound was thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8](=[CH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[C:15]([OH:23])(=[S:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC>[C:15]([S:22][CH2:12][CH:8]([CH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]([OH:11])=[O:10])(=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OC(=S)c1ccccc1
Reactant: C=C(Cc1ccc(OC)cc1)C(=O)O
Solvent: CCOCC
Product: COc1ccc(CC(CSC(=O)c2ccccc2)C(=O)O)cc1

Procedure:
By the method of Preparation 7, 2-(p-methoxybenzyl)acrylic acid (3.84 gm., 20 mmoles) was reacted with thiobenzoic acid to yield the title product in essentially quantitative yield [6.61 gm.; Rf 0.48 (ether)].
Reaction SMILES: [Li]CCCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:39]1([C:45]2[S:46][CH:47]=[C:48]([CH:50]=O)[N:49]=2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[NH4+].[Cl-]>C1COCC1>[C:39]1([C:45]2[S:46][CH:47]=[C:48](/[CH:50]=[CH:12]\[C:11]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:9]([O:8][CH3:7])[CH:10]=3)[N:49]=2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=Cc1csc(-c2ccccc2)n1
Reactant: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Agent: [Br-]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2csc(-c3ccccc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
Triphenylphosphine (3.41 g, 13 mmol) was added to a solution of 5-(bromomethyl)-1,2,3-trimethoxybenzene (2.61 g, 10 mmol) in dry THF (30 mL). The mixture was refluxed with stirring for 6 h. The resulting white solid was filtered and washed with ether/hexane to afford the product 3,4,5-trimethoxybenzyltriphenylphosphonium bromide in 96.4% yield. 1H NMR (500 MHz, CDCl3) δ 7.77-7.73, 7.65-7.61 (m, 15H), 6.44 (d, 2H, J=1.5 Hz), 5.37 (d, 2H, J=14 Hz), 3.76 (s, 3H), 3.51 (d, 6H); MS (ESI) m/z 443.1 (M-Br]+. At −78° C., n-BuLi (0.42 mL, 2.5 N in hexane) was added to a solution of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (500 mg, 0.96 mmol) in 10 mL THF. After stirring at RT for 2 h, aldehyde 42b (109 mg, 0.58 mmol) in 3 mL THF was charged and stirred for 30 min. The reaction mixture was treated with saturated NH4Cl solution. After a conventional workup, column chromatography (silica gel, petroleum ether/ethyl acetate) gave compounds 3a (57 mg) and 3b (99 mg). 1H NMR (500 MHz, CDCl3) δ 7.90-7.89 (m, 2H), 7.42-7.40 (m, 3H), 7.07 (s, 1H), 6.71 (s, 2H), 6.66 (s, 1H), 3.87 (s, 6H), 3.75 (s, 3H); MS (ESI) m/z 376.1 (M+Na)+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([N+:27]([O-])=O)=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>O1CCCC1.[Ni]>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:26]4[C:21](=[CH:22][C:23]([NH2:27])=[CH:24][CH:25]=4)[CH:20]=[CH:19]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)n1ccc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1ccc2c(ccn2C(=O)OCC2c3ccccc3-c3ccccc32)c1
Reaction time: 20 h

Procedure:
A solution of 5-nitro-indole-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (4.16 g, 0.0108 mol) in 100 ml of tetrahydrofuran was treated with 1.0 g of sponge nickel catalyst (Activated Metals & Chemicals Co. A-7000, water wet) and hydrogenated in a Parr shaker hydrogenation apparatus (52 to 18 psig, room temperature). After 20 h, the resulting slurry was filtered and the filtrate was returned. Solvent was removed in vacuo to afford a brown oil (4.05 g, 106.6% y). NMR (CDCl3) δ 8.03 (br s, 1H), 7.78 (m, 3H), 7.63 (m,3H), 7.51 (d, J=3.2 Hz, 1H), 7.42 (m, 3H), 7.34 (m, 3H), 7.18 (d, J=8.3 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.82 (d, J=2.0), 6.66 (dd, J=8.5, 2.2 Hz, 1H), 6.45 (d, J=3.7 Hz, 1H), 6.38 (m, 1H), 4.78 (br s, 2H), 4.43 (t, J=6.3 Hz, 1H), 4.12 (t, J=6.1 HZ, 1H), 4.03 (d, J=0.49 Hz, 2H), 3.76 (t, J=2.4 Hz, 1H), 1.85 (m, 1H). MS 355 [M+H].