Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([CH3:11])[CH2:5][CH:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3]1.[Li+].[CH3:13]C([N-]C(C)C)C.CI>C1COCC1>[F:1][C:2]1([CH3:11])[CH2:3][C:4]([CH3:13])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5]1
Reactant: CCOC(=O)C1CC(C)(F)C1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CC(C)(F)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.1 %

Procedure:
To a solution of Intermediate 288A (0.13 g, 0.812 mmol) in THF (2 mL) was added LDA (1.623 mL, 1.623 mmol, 1 M in THF) dropwise at −78° C. and the reaction mixture was stirred at the same temperature for 45 min. MeI (0.203 mL, 3.25 mmol) was then added at −78° C. and the mixture was allowed to slowly warm to RT and stir for 12 h. The reaction mixture was quenched with a saturated aq. solution of NH4Cl and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 307A as a yellow liquid (85 mg, 60%). The crude product was reacted under saponification conditions without further purification 1H NMR (400 MHz, DMSO-d6) δ ppm 4.08 (q, J=7.0 Hz, 2H), 2.60-2.53 (m, 1H), 2.37-2.22 (m, 3H), 1.44 (d, J=18 Hz, 3H), 1.36 (s, 3H) 1.22-1.11 (m, 3H).
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>O1CCCC1>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][N:27]([CH2:15][CH:2]([OH:1])[CH2:3][O:4][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:14]=2[S:13][CH2:12][CH2:11][CH2:10]3)[CH2:26][CH2:25]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: c1cc2c(c(OCC3CO3)c1)SCCC2
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3c2SCCC3)CC1

Procedure:
140 mg (0.63 mmol) of the compound obtained in Step A are dissolved in 1.5 cm3 of anhydrous tetrahydrofuran. 600 mg (3.15 mmol) of 1-(2-methoxyphenyl)piperazine, diluted in 1.5 cm3 of anhydrous tetrahydrofuran, are added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[C:20]([OH:22])=[O:21])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12]>C(OC(=O)C)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[CH:12])/[CH:13]=[CH:14]/[C:15]1[O:21][C:20](=[O:22])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N:17]=1
Reactant: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C#CCOc1ccc(/C=C/c2nc3ccccc3c(=O)o2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A solution of (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.5 g, 1.4 mmol) in acetic anhydride (3 mL) was −5 heated to reflux and stirred for 3 h. The reaction was cooled to rt and the resulting suspension was diluted with water. The suspension was stirred at rt for 1 h and the precipitate was collected by filtration, providing (E)-2-(3-methoxy-4-propargyloxystyryl)-4H-benzo[d][1,3]oxazin-4-one (0.44 g, 93%) as a yellow crystalline solid; mp 177-178° C.; δH (500 MHz, DMSO-d) 3.59 (m, 1H, C≡CH), 3.85 (s, 3H, OCH3), 4.85 (s, 2H, OCH2), 6.96 (d, J=16.0 Hz, 1H, CH═CHCO), 7.07 (d, J5,6=8.0 Hz, 1H, H5′), 7.34 (d, J5′,6=8.0, 1H, H6′), 7.49 (s, 1H, H2′), 7.57 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.60 (d, J3,4=8.0 Hz, 1H, H3), 7.72 (d, J=16.0 Hz, 1H, CH═CHCO), 7.91 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.11 (d, J5,6=8.0 Hz, 1H, H6); νC (125 MHz, DMSO-d6) 55.7, 55.9, 78.5, 79.0, 110.8, 113.6, 117.0, 117.2, 122.3, 126.5, 128.0, 128.1, 128.3, 136.8, 141.2, 146.8, 148.5, 149.4, 157.2, 158.8; HRMS (ESI) calculated for C20H15NO4 [M+H]+ 334.1074, found 334.1074; νmax 970, 1136, 1270, 1471, 1743, 2135, 3268 cm−1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.[C-:17]#[N:18].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1)#[N:18]
Reactant: Cc1cc(CCl)ccc1Sc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thus obtained 1-chloromethyl-3-methyl-4-phenylthiobenzene was dissolved in 56 ml of N,N-dimethylformamide, and 18.16 g of finely ground sodium cyanide was added, and the mixture was stirred overnight at room temperature. After adding 300 ml of saturated brine and 300 ml of ice water to the reaction mixture, it was extracted with ethyl acetate (300 ml×3). The extract was washed with saturated brine (200 ml×3), and dried with anhydrous sodium sulfate, concentrated in vacuo, and 1-cyanomethyl-3-methyl-4-phenylthiobenzene was obtained (45.95 g).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].C([Li])CCC.[CH3:11][O:12][C:13]1[C:18]2[O:19][C:20]([C:22](OC)=O)=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O>O1CCCC1.O>[CH3:11][O:12][C:13]1[C:18]2[O:19][C:20]([C:22]3[O:5][N:4]=[C:2]([CH3:3])[CH:1]=3)=[CH:21][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc2cccc(OC)c2o1
Reactant: CC(C)=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2cc(-c3cc(C)no3)oc12
Temperature: 0 °C
Yield: 16.9 %

Procedure:
Thionyl chloride (10 ml) was added dropwise to methanol (100 ml) with stirring under ice-cooling. 7-Methoxybenzo(b)furan-2-carboxylic acid (10 g) was successively added, and the mixture was refluxed under heating for 1 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g). This was used in the next reaction without purification. Acetone oxime (4.8 g) was dissolved in tetrahydrofuran (100 ml), and butyllithium (1.6M hexane solution) (80 ml) was added dropwise to this solution at −5° C. with stirring. Thereafter, the mixture was stirred under ice-cooling for 1 hr, and a solution (50 ml) of methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g) in tetrahydrofuran was added. The mixture was stirred at room temperature for 20 hr. A solution of sulfuric acid (28 g) dissolved in tetrahydrofuran (120 ml)-water (30 ml) was prepared, into which the reaction mixture was poured. The mixture was refluxed under heating for 2 hr. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.1 g).
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.O.C(O)C.[OH-].[Na+]>[H][H].[Pd]>[NH:4]1[C:5]([NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:10]=2)=[O:8])=[N:1][N:2]=[N:3]1
Reactant: [H][H]
Reactant: O=C(Nc1nnn[nH]1)c1cccc(C=Cc2ccccc2)n1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(Nc1nnn[nH]1)c1cccc(CCc2ccccc2)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
A mixture of 2 g of N-(5-tetrazolyl)-6-styryl-2-pyridinecarboxamide, 30 ml of water, 15 ml of ethanol, 5 ml of an aqueous 10% sodium hydroxide solution and 0.18 g of 10% palladium-on-carbon is shaken at 40° C. for 2 hours and then at room temperature for 15 hours in hydrogen gas stream under atmospheric pressure. After the reaction, ethanol is added to the mixture to dissolve the precipitates therein. Insoluble materials are filtered off, and the filtrate is adjusted to pH 3 with 10% hydrochloric acid. The crystalline precipitates are collected by filtration, washed with water, dried and then recrystallized from a mixture of dimethylformamide and ethanol. 1.34 g of N-(5-tetrazolyl)-6-phenethyl-2-pyridinecarboxamide are thereby obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)#[N:4].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[S:15]>O>[CH3:12][N:13]([CH3:17])[C:14]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]#[N:4])=[CH:6][CH:7]=1)=[S:15]
Reactant: N#Cc1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=S)Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.6 %

Procedure:
Add sodium hydride (1.21 g, 95%) to a solution of 4-cyanophenol (5.71 g, 47.98 mmol) in anhydrous TI-IF (70 mL) and stir the mixture for 5 min. Add dimethylthiocarbamoyl chloride (5.93 g, 47.98 mmol) and heat the mixture at reflux for 3 h. Cool the mixture to room temperature and add water. Extract the aqueous phase with EtOAc, dry the organic phase over MgSO4, filter and concentrate in vacuo to obtain a solid. Wash the solid with diethyl ether, filter and dry in vacuo to obtain the desired intermediate as a solid (4.41 g, 75%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[N+:12]([O-])([O-:14])=[O:13].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[C:4]=1[OH:9])([O-:14])=[O:13]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Reaction time: 24 h
Yield: 48 %

Procedure:
2-trifluoromethyphenol (3.00 g, 18.5 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (1.73 g, 20.4 mmol). The addition of sulfuric acid (23 mL/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.84 g, 47%). 1H NMR (CD3COCD3): d 8.35 (d, 1H), 7.95 (d, 1H), 7.13 (t, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:17]O>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:17])=[O:14]
Reactant: CO
Reactant: NCCCCCCCCCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCCCCCCCCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a suspension of 12-aminododecanoic acid (5.00 g, 23.3 mmol) in anhydrous MeOH (90 mL) was introduced hydrogen chloride gas for 25 minutes, during which time the suspension became clear. The solution was then stirred at room temperature for 3 hours and the solvent was removed in vacuo. The white solid residue was dissolved in H2O. Solid NaHCO3 was added to neutralize the solution to pH 8-9. The white precipitates thus formed were collected by vacuum filtration (5.20 g) (Yield: 98%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]23[CH2:22][CH:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=42)[C:14]2[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:2]1.[CH:23]1([CH2:26]Br)[CH2:25][CH2:24]1.[NH2-].[Na+]>C1C=CC=CC=1.O>[CH:23]1([CH2:26][N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][C:8]34[CH2:22][CH:15]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=53)[C:14]3[C:9]4=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:2]2)[CH2:25][CH2:24]1
Reactant: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21
Reactant: BrCC1CC1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: c1ccc2c(c1)C1CC2(CC2CN(CC3CC3)CCO2)c2ccccc21

Procedure:
A mixture of 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (50 mg), cyclopropylmethyl bromide (40 mg) and sodium amide (15 mg) in dry benzene was refluxed for 10 hours. The reaction mixture was diluted with benzene and water. The benzene layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-cyclopropylmethyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 88° - 90° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH2:7]([S:11][CH:12]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:8][CH2:9][CH3:10].CC(C)=O>C(N(CC)CC)C>[CH2:7]([S:11][CH:12]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:1]([O:2][CH2:3][CH3:4])=[O:5])[C:13]([Cl:15])([Cl:16])[Cl:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCCCSC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCSC(NC(=O)c1ccccc1OC(=O)OCC)C(Cl)(Cl)Cl
Yield: 78.3 %

Procedure:
13 g of ethyl chlorocarbonate was added to the mixture of 3.4 g of N-(1-n-butylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide and 50 ml of acetone under stirring, and 1.0 g of triethylamine was added dropwise thereto at 0°-5° C. After effecting the reaction at room temperature for one hour, the solvent was distilled off under reduced pressure, 50 ml of water was added thereto and the solution was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to obtain 3.2 g of N-(1-n-butylthio-2,2,2-trichloroethyl)-2-ethoxycarbonyloxybenzamide as a brown oily substance. nD25 1.5350
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][CH2:30][C@@H:31]([C@@H:33]([OH:35])[CH3:34])[N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:35][C@H:33]([C@@H:31]1[CH2:30][O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:36])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32]1)[CH3:34]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=N[C@H]([C@H](C)O)CO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](O)[C@@H]1COC(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(O[C@@H](C)CO)c3)[nH]2)=N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
(1S)-1-{(4S)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-4-yl}ethanol (187 mg, 0.36 mmol) synthesized in Example (93b) was dissolved in methylene chloride (5 mL) and subsequently cooled to −78° C., and boron tribromide (1.0 mol/L methylene chloride solution, 0.73 mL, 0.73 mmol) was added under nitrogen atmosphere. The temperature was raised naturally, followed by stirring at room temperature for 30 minutes, and subsequently a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with methylene chloride (70 mL). The organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride-0%-4%) to afford the desired compound (134 mg, 74%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[C:13]1([NH:19][C:20](=[O:28])[CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]([NH:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:28])[CH2:23][CH2:24]2)[C:5]([Cl:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: O=C(CN1CCNCC1)Nc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3ccccc3)CC2)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.031 g, 0.15 mmol) and isopropanol (3.5 ml) was added N-phenyl-2-piperazin-1-yl-acetamide×2HCl salt (0.048 g, 0.16 mmol) followed by diisopropylethylamine (0.10 ml, 0.54 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 10% to 30% ethyl acetate in dichloromethane. The title compound was obtained as a yellow solid (0.041 g, 71%); 1H-NMR (500 MHz, DMSO-d6) 2.64 (br s, 4H, piperazine N(CH2)2), 3.13 (br s, 4H, piperazine N(CH2)2), 3.19 (s, 2H, NCH2CO), 7.00 (br s, 2H, 2-NH2), 7.06 (t, J=7.34 Hz, 1H, p-ArH), 7.31 (t, J=8.26 Hz, 2H, m-ArH), 7.63 (d, J=7.34 Hz, 2H, o-ArH), 8.07 (s, 1H, 6-H), 9.76 (s, 1H, CONH);
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:23]([CH3:34])[CH:22]=3)[CH2:16][O:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].O.[OH-].[Na+].Cl>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C@H:15]([O:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:23]([CH3:34])[CH:22]=3)[CH2:16][O:17][CH2:18][CH3:19])[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC[C@@H](Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C#N)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC[C@@H](Oc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Ethyl [(4-{[(1S)-1-[6-(4-cyanophenyl)-2-pyridinyl]-2-(ethyloxy)ethyl]oxy}-2-methylphenyl)oxy]acetate (0.886 g) was dissolved in THF (8.8 mL). Water (8.8 mL) and aq 2M NaOH (1.8 mL) were added and the mixture stirred at ambient temperature for 30 mins. The reaction mixture was acidified to pH 1 by the addition of aq 2M HCl and extracted with EtOAc (2×10 mL). The organic extracts were washed with brine (20 mL), dried (Na2SO4) and evaporated to give the title compound as a white foam (729 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[C:6]([C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:32])=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:10][CH:9]=1)#[N:7].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:32])=[C:19]([NH:21][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([CH2:29][NH:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:25][CH:24]=3)[CH:20]=2)=[O:13])=[CH:33][CH:34]=1)#[N:7]
Reactant: Cc1ccc(NC(=O)c2ccc(C#N)cc2)cc1NC(=O)c1ccc(CCl)cc1
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCNCc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(C#N)cc3)ccc2C)cc1
Temperature: 55 °C
Reaction time: 96 h
Yield: 59 %

Procedure:
2-Methoxyethylamine (0.019 ml) was added to a stirred solution of N-[5-(4-cyanobenzamido)-2-methylphenyl]-4-(chloromethyl)benzamide (0.060 g) and potassium carbonate (0.041 g) in acetone (5 ml) and the reaction mixture was heated to 55° C. overnight. Further portions of 2-methoxyethylamine and potassium carbonate (same quantities as before) were added and the reaction mixture was stirred at 55° C. for a further 4 days. The reaction mixture was evaporated and the residue was triturated with water. The resultant solid-was isolated and dried under vacuum at 55° C. to give the title compound as a solid (0.039 g, 59%); NMR Spectrum: (CDCl3) 2.27 (s, 3H), 2.83 (m, 2H), 3.37 (m, 4H), 3.56 (t, 2H), 3.91 (s, 2H), 7.19 (d, 1H), 7.49 (d, 2H), 7.77 (m, 7H), 7.95 (d, 2H), 8.13 (s, 1H), 8.3 (s, 1H); Mass Spectrum: M−H− 441.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]([CH3:28])[C:7]1[N:27]=[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][C:19]=3[C:24](O)=[O:25])=[O:17])=[CH:14][N:9]2[N:8]=1>>[CH3:5][N:6]([CH3:28])[C:7]1[N:27]=[C:10]2[CH:11]=[CH:12][C:13]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[CH:20][C:19]=3[C:24]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:25])=[O:17])=[CH:14][N:9]2[N:8]=1
Reactant: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)O)cnn3C)cn2n1
Reactant: C1CNC1
Product: CN(C)c1nc2ccc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)cn2n1

Procedure:
Using azetidine and 5-(2-dimethylamino-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Brown solid (93 mg, 42%). MS: m/z=369 (M+H+). Ames test negative.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6](O)(=[O:9])[CH2:7]C.C[C:12]1[CH:17]=[C:16]([C:18](C)(C)C)[C:15]([OH:22])=C(C(C)(C)C)[CH:13]=1>>[CH2:6]([O:9][C:15](=[O:22])[CH:16]([CH3:18])[CH:17]=[C:12]=[CH2:13])[CH3:7]
Reactant: CCC(=O)O
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: C=C=CC(C)C(=O)OCC
Temperature: 150 °C

Procedure:
The autoclave is closed and the reaction mass is heated to 150° C. over a period of 50 minutes. The reaction mass is then maintained at a temperature of between 135°-160° C and at a pressure of 20 up to 60 psig for a period of 3 hours. At the end of this 3-hour period, the autoclave is opened and the reaction mass is cooled to room temperature. 12.6 g of sodium bicarbonate is then added to the reaction mass in order to neutralize the propionic acid. 30 g of Primol ® (see note 1) and 0.1 g of Ionol ® (see note 2) are added and the resulting reaction product is fractionally distilled at atmospheric pressure to a pot temperature of 129° C. A mixture of ethanol and ethyl propionate is distilled over. Vacuum is then applied to the distillation column and the resultant product, ethyl-2-methyl-3,4-pentadienoate is distilled at a vapor temperature of 65°-69° C at a pressure of 24-33 mm Hg as fractions 5-10 of the following fractions:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:5]1)[CH2:2][CH3:3].[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[N:4]([CH2:1][CH2:2][CH3:3])[CH:5]=[C:6]2[CH2:14][C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1cc(Cc2ccncc2)c2cc(O)ccc21
Product: CCCn1cc(Cc2ccncc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
The above compound was prepared from 1-propyl-3-(4-pyridylmethyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:8])[CH:7]=1.[Cl:10][C:11]1([Cl:20])[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]1[Cl:19]>C1(C)C=CC=CC=1>[Cl:16][C:15]12[C:11]([Cl:10])([Cl:20])[C:12]([Cl:19])([CH:4]3[CH:5]1[C:6](=[O:8])[CH:7]=[C:2]([CH3:1])[C:3]3=[O:9])[C:13]([Cl:18])=[C:14]2[Cl:17]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: CC1=CC(=O)C=CC1=O
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 135 °C

Procedure:
To a mixture of methyl-p-benzoquinone (60 g.), and hexachlorocyclopentadiene (140 g.), was added 20 ml. of toluene. This reaction mixture was then heated at 130-140° C. for 3 hours. Upon cooling to room temperature the mixture solidified. This solid was washed with Skelly "B" solvent several times on a Buchner funnel and recrystallized from a Skelly "B"-benzene mixed solvent (20/80). Pale yellow crystals were obtained, m.p. 163°-165° C.