Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][CH2:18][CH2:19]Br.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:19][CH2:18][O:17][CH3:16])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Oc1ccc(F)c(F)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a suspension of 3,4-difluorophenol (2 g) and cesium carbonate (7.51 g) in N,N-dimethylformamide (15 mL) was added 2-methoxyethyl bromide (2.14 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 3,4-difluoro-1-(2-methoxyethoxy)-benzene (2.49 g). To the solution of the obtained 3,4-difluoro-1-(2-methoxyethoxy)benzene (1.47 g) in tetrahydrofuran (39 mL) was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dry ice (10 g), and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.48 g).
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[N:4][N:3]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH3:34][O:35][NH2:36]>CO>[CH3:34][O:35][NH:36][C:8](=[O:10])[CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: CON
Reactant: O=C(O)Cn1nnnc1S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CONC(=O)Cn1nnnc1S
Temperature: 0 °C
Reaction time: 7 h
Yield: 495.6 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-acetic acid (320 mg) in methanol (3 ml) are added triethylamine (0.33 ml) and N,N'-dicyclohexylcarbodiimide (495 mg), and th mixture is stirred for 7 hours. To this solution is added a solution of methoxyamine hydrochloride (33.4 mg) and triethylamine (56 μl) in methanol (0.3 ml). After the addition of a further amount of N,N'-dicyclohexylcarbodiimide (124 mg), the mixture is left stand at room temperature overnight. The reaction mixture is concentrated under reduced pressure to about 1 ml and then diluted with ethyl acetate (8 ml) and 5% sodium hydrogen carbonate (7 ml). After the separated solid (461 mg) is removed by filtration, the filtrate is saturated with sodium chloride and diluted with ethyl acetate-methyl ethyl ketone mixture (1:1). The mixture is acidified to pH 1 with hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated under reduced pressure to give 5-mercapto-1H-tetrazole-1-acetohydroxamic acid methyl ester (375 mg), identical with the product prepared with N,N'-carbonyldiimidazole.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH2:11]O)=[C:6]([F:13])[CH:5]=1.[BrH:15]>C(OCC)C>[Br:15][CH2:11][C:7]1[C:8]([F:10])=[CH:9][C:4]([O:3][CH:2]([F:14])[F:1])=[CH:5][C:6]=1[F:13]
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Reactant: Br
Solvent: CCOCC
Product: Fc1cc(OC(F)F)cc(F)c1CBr
Temperature: 25 °C
Yield: 66.3 %

Procedure:
162 mg [4-(difluoromethoxy)-2,6-difluorophenyl]methanol (0.769 mmol, 1.0 eq.) were dissolved in 0.348 mL hydrogen bromide (2.12 mmol, 2.8 eq.). and stirred at rt over night. The reaction mixture was diluted with diethylether and stirred for 5 minutes. The aqueous layer was washed twice with diethylether. The combined organic layers were washed with brine, dried over a silicon filter and concentrated in vacuo to provide the 149 mg (0.51 mmol, 67%) of the crude product, which was used without further purification.
Reaction SMILES: O[CH2:2][NH:3][CH:4]=[O:5].[CH2:6]([O:8][P:9]([O:13]CC)[O:10][CH2:11][CH3:12])[CH3:7]>C(O)C>[CH2:6]([O:8][P:9]([CH2:2][NH:3][CH:4]=[O:5])(=[O:13])[O:10][CH2:11][CH3:12])[CH3:7]
Reactant: O=CNCO
Reactant: CCOP(OCC)OCC
Solvent: CCO
Product: CCOP(=O)(CNC=O)OCC

Procedure:
The mole ratio of N-(hydroxymethyl)formamide to triethylphosphite in step (2) of the process of the invention is 1:1. The reaction is conducted in the presence of heat and at a temperature sufficient to cause the reaction to go to completion. The reactants are heated until ethyl alcohol starts to evolve and this occurs at reflux temperature. When triethylphosphite is used, this temperature is approximately 120°-125° C. At this point, the alcohol is distilled off, leaving the product diethyl-N-(formyl)aminomethylphosphonate as the residue.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.3 %

Procedure:
To a stirred solution of 2-hydroxy-4-nitrobenzonitrile (5.0 g, 30.48 mmol) in DMF (50 mL) was added Cs2CO3 (19.9 g, 60.97 mmol). The mixture was cooled to 0° C., and allyl bromide (4.39 g, 36.58 mmol) was added dropwise. The reaction mixture was stirred for 12 h at 90° C. under nitrogen. The reaction mixture was cooled to rt and concentrated to remove DMF, then EtOAc (50 mL) was added to the residue. The mixture was washed with water (2×30 mL) and brine (30 mL). The organic layer was dried with Na2SO4, and concentrated in vacuo to afford the yellow solid, 2-(allyloxy)-4-nitrobenzonitrile (4 g, 65% yield). LC-MS (M+H)+=205.2 1H NMR (400 MHz, CDCl3) δ ppm 7.87-7.86 (m, 1H), 7.811 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 6.11-6.01 (m, 1H), 5.56-5.55 (dd, 1H, J=1.6, 3.2 Hz), 5.52 (d, 1H, J=1.6 Hz), 4.79 (d, 2H, J=4.8 Hz).
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:31])C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:31])[CH2:15][CH2:16]1
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 40 mg (0.1 mmol) of 3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-1α,3,8-triaza-spiro[4.5]dodecan-2,4-dione hydrochloride in 1.7 mL of anhydrous DCE were added successively 24 mg (0.1 mmol) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide and 17 μL (0.12 mmol) of triethylamine. The reaction mixture was agitated at room temperature for 10 minutes before adding 26 mg (0.125 mmol) of sodium triacetoxyborohydride. After an overnight agitation, 2 mL of saturated solution of sodium bicarbonate was added. The solution was then extracted with DCM (2×2 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by Bond Elut (ethyl acetate to 5% methanol/DCM) to yield the 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[3-(4-methanesulfonylbenzyl)-bicyclo[3.2.1]-2,4-dioxo-1α,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide as a white solid (40 mg, 62.3%).
Reaction SMILES: O=CC[C@H](N[C:12]([CH:14]1[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=[O:24])C.[Na+].C(N(CC)CC)C>ClCCCl>[F:20][C:17]1([F:21])[CH2:18][CH2:19][CH:14]([C:12]([OH:13])=[O:24])[CH2:15][CH2:16]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 148.1 %

Procedure:
To 21.1 mg (0.072 mmol) of 1-methyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-1β,3,8-triaza-spiro[4.5]dodecan-2-one in 1.5 mL of DCE was added 21.2 mg (0.072 mmol, 1 eq.) of 4,4-difluoro-cyclohexanecarboxylic acid ((S)-3-oxo-1-phenyl-propyl)-amide, 19 mg (0.09 mmol, 1.25 eq.) of sodium triacetoxyborohydride and 12 μL (0.086 mmol, 1.2 eq.) of triethylamine. The reaction mixture was stirred overnight at room temperature and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (DCM/MeOH: 0 to 100) and redissolved in 1 mL of methanol and 100 μL of HCl (1N). The solution was then concentrated in vacuo and diluted with 2 mL of water to give after lyophilization 17.5 mg (40%) of 4,4-difluoro-cyclohexanecarboxylic acid {(S)-3-[1-methyl-3-(tetrahydropyran-4-ylmethyl)-bicyclo[3.2.1]-2-oxo-1β,3,8-triaza-spiro[4.5]dodec-8-yl]-1-phenyl-propyl}-amide hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][OH:17]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:17][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: OCc1cccc(F)c1
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Cl)c1

Procedure:
This compound was prepared from 3-chloro-4-fluoronitrobenzene and 3-fluorobenzyl alcohol using the method described above in Example 13.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH3:15])([O-:13])=[O:12].C([O-])(=O)C>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([N+:11]([O-:13])=[O:12])[CH3:15]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=Cc1ccc(Cl)cc1Cl)[N+](=O)[O-]
Temperature: 0 °C
Yield: 55.2 %

Procedure:
The 1-aryl-2-nitropropenes were prepared according to the procedure of Koremura, Oku, Shono and Nakanishi (6). The starting aldehydes, commercially available, were used without further purification. To prepare 1-(2,4-dichlorophenyl)-2-nitropropene, a mixture of 43.5 g (0.25 mol) of 2,4-dichlorobenzaldehyde, 18.75 g (0.25 mol) of 1-nitroethane, and 20 g of ammmonium acetate, dissolved in 100 ml of glacial acetic acid, was refluxed for two hours, and then poured onto 200 g of ice. The yellow precipitate was collected and recrystallized from absolute ethanol to give 32 g (60%) of 1-(2,4-dichlorophenyl)-2-nitropropene mp 75°; ir (KBr) 1661 (C=C), 1520 and 1319 cm-1 (NO2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH3:13]>>[NH2:13][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: N
Product: Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 5 °C
Yield: 45 %

Procedure:
With stirring, 1.0 g of 2,4-dichloro-5-(trifluoromethyl)pyrimidine, Aldrich order no. 684864, is added to a methanolic ammonia solution (ca. 8 mol of ammonia in methanol) cooled to ca. 5° C., the mixture is heated to 25° C. and stirred for 2 hours at this temperature. The mixture is concentrated by evaporation and added to water. After filtering off with suction, 0.56 g of a mixture of 4-amino-2-chloro-5-trifluoromethylpyrimidine (ca. 45%) and 2-amino-4-chloro-5-trifluoromethylpyrimidine (ca. 45%) is obtained.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:10][C:11]1[CH:30]=[CH:29][C:14]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:3][CH2:4][N:5]4[CH2:9][CH2:8][CH2:7][CH2:6]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[C:13]([F:31])[CH:12]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCCC1
Temperature: 100 °C
Yield: 10 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg, 1.26 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). The mixture was heated to 100° C. and further portions of 1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were added periodically over 4 hours while the reaction mixture was maintained at 100° C. The reaction was then allowed to cool and volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water, separated and the organic phase passed through phase separating paper. Column chromatography eluting with methylene chloride/methanol (95/5) gave 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(pyrrolidin-1-yl) ethoxy)quinazoline (50 mg, 10%).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]1([O-:13])[C:7]([CH3:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>O>[N+:14]([C:9]1[CH:8]=[C:7]([CH3:12])[N+:6]([O-:13])=[CH:11][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc[n+]1[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 25 °C

Procedure:
98% sulfuric acid (17.5 ml) was added dropwise to 2-picoline-1-oxide (5.22 g) under stirring at cooling in an ice-bath. To the mixture was added dropwise nitric acid (fuming, 15 ml) under the same condition. After completion of the additieon, the mixture was heated at 80°-90° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, poured into water (100 ml) and alkalined with aN aqueous sodium hydroxide. The resultant mixture was extracted with chloroform four times. The combined extracts were dried over sodium sulfate. Removal of the solvent gave 4-nitro-2-picoline-1-oxide (6.52 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 48.8 %

Procedure:
Following Example 188a, 1-fluoro-4-nitrobenzene (2.8 g, 20 mmol) and N-Boc-piperazine (11 g, 60 mmol) were reacted to give 327a as a yellow solid (3 g, 51%). MS: [M+H]+ 308.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][N:12]([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: Oc1cccc(Br)c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CN(C)CCOc1cccc(Br)c1
Temperature: 80 °C

Procedure:
3-Bromophenol (1 eq, 1.156 mmol, 0.2 g), 2-chloro-N,N-dimethylethanamine (1.1 eq, 1.272 mmol, 0.137 g) and potassium carbonate (3 eq, 3.47 mmol, 0.479 g) are mixed together in NMP (5 ml). The reaction mixture is heated at 80° C. for 6 hrs. The reaction mixture is dissolved in EtOAC and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo to afford [2-(3-Bromo-phenoxy)-ethyl]-dimethyl-amine; [M+H]+ 245/247
Reaction SMILES: Br[C:2]1[C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]=1[O:8]CC.CN(C)C=O.Cl.[CH3:18][CH:19]([CH3:23])[C:20](=[NH:22])[NH2:21].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:18][CH:19]([C:20]1[NH:22][C:3]2[CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:2]=2[N:21]=1)[CH3:23]
Reactant: CCOC1=C(Br)C(=O)CCC1
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)c1nc2c([nH]1)CCCC2=O
Temperature: 50 °C

Procedure:
To 2-bromo-3-(ethyloxy)-2-cyclohexen-1-one (160 g) was added N,N-Dimethylformamide (1000 mL) followed by 2-methylpropanimidamide hydrochloride (107 g) and potassium carbonate (151 g). The suspension was then stirred at 50° C. under nitrogen. After 2.75 hr the mixture was filtered and as much DMF as possible was evaporated off under high vacuum. The residue was partitioned between ethyl acetate (400 ml) and a minimum of aq lithium chloride (120 ml). The aqueous layer was extracted well with ethyl acetate (3×200 ml). The combined organics were washed with brine, filtered to give a small amount of a white solid and the filtrate dried (MgSO4), filtered and evaporated, including high vacuum. This was stirred with TBME (350 ml) then filtered to give a white solid, 16.27 gm. The filtrate from this was evaporated and weighed; this partly solidified overnight. Ether and cyclohexane were added to try and precipitate out more product but the solid was oily. The solution was decanted off and gave a golden oil on evaporation, 77 gm. The oily solid was evaporated: 38 gm, dissolved in DCM and purified by column chromatography (silica cartridge), eluting with 0-100% ethyl acetate in dichloromethane over 10 column volumes. Fractions were evaporated and the resulting solid slurried in ether and collected by filtration: This gave a white solid, 4.0 gm. No solid came out from the aqueous phase overnight. So it was extracted with more ethyl acetate and DCM. The organics were dried and evaporated and gave 69 gm of a beige slurry that was stirred with diethyl ether and filtered to give a white solid, 11.3 gm. The filtrate was combined with aqueous extraction solvents from a previous experiment and purified by column chromatography (silica), eluting with 0-100% ethyl acetate in dichloromethane. All product came through in fractions 1 & 2 so they were combined and washed with aq LiCl, dried and re-evaporated to a beige slurry, 46.4 gm, that was stirred in ether and filtered to give a white solid, 5.85 gm. Because all the batches were of the same purity, they were combined: This gave the title compound, a white solid, 37.42 gm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O.C[O-].[Na+]>CO>[Cl:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)\[C:7]#[N:8])[CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: N#CCc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
Method B To a solution of 4-chlorobenzyl cyanide (Aldrich) (4.5 g, 30 mmol) and 3-chloro-benzaldehyde (Aldrich) (4 g, 29 mmol) in methanol (150 mL) was slowly added a methanolic solution (Aldrich, 25 wt. %) of sodium methoxide (10 mL, 44 mmol). The reaction mixture was heated and stirred at 50° C. for 3 h. The mixture became cloudy, and was cooled to room temperature and filtered. The white precipitate was washed with water, cold methanol, and then dried in vacuo to give the first batch of desired product (5.5 g). The filtrate was concentrated, diluted with water, neutralized by aqueous HCl solution to “pH” 7, then extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:20, then 1:10) to give the second batch of the desired product (1.6 g). The two batches were combined to give (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile as a white powder (7.1 g, 88%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=C(O)c1ccc(CBr)cc1

Procedure:
Briefly described, p-toluic acid 2 is refluxed with N-bromo-succinimide and benzoyl peroxide in dry benzene to give α-bromo-p-toluic acid 3 which, upon reaction with nitric acid, is converted to 3-nitro-4-bromomethyl benzoic acid 4. This is believed to be a new compound and represents a parent compound in the synthesis forming the subject matter of this invention. At slightly higher temperatures, above -10° C, the corresponding dinitro derivative 4a predominates.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[O-].[Na+].[C:17]([O:24][CH3:25])(=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>[Cu]Br>[CH3:22][O:21][C:19](=[O:20])[CH:18]([C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:17]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cu]Br
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)C(C(=O)OC)c1cc([N+](=O)[O-])ccc1C(=O)O
Temperature: 70 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
A solution of 2-chloro-4-nitrobenzoic acid (75 g, 372 mmol) in dimethyl malonate (900 mL) was perfused with nitrogen for 15 min. Sodium methoxide (48.3 g, 894 mmol) was added in one portion and the contents exothermed to 48° C. Fifteen minutes later, copper (I) bromide (5.4 g, 37 mmol) was added in one portion and the contents were heated to 70° C. for 24 hrs. The reaction, which was 70% complete as determined by NMR, was subsequently heated to 85° C. for 5 hrs to completely consume the remaining 2-chloro4-nitrobenzoic acid. Water (900 mL) was added to the cooled reaction followed by hexanes (900 mL). The aqueous layer was separated, toluene (900 mL) was added, the mixture was filtered and aqueous layer separated. Fresh toluene (1800 mL) was added to the aqueous layer and the biphasic mixture acidified with 6N aqueous HCl (90 mL). A white precipitate formed and the contents were stirred for 18 hrs. The product was filtered off and dried to give a white solid (78.1 g, 70%) mp 153° C.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[CH:18]=[C:13]3[CH:12]=[C:11]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C>[CH:28]1([CH:27]=[C:26]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([CH:19]4[CH2:23][O:22][C:21]([CH3:24])([CH3:25])[O:20]4)[CH:18]=[C:13]3[CH:12]=2)[C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC1(C)OCC(c2cnc3c(c2)cc(C(=CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n3S(=O)(=O)c2ccccc2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OCC(c2cnc3[nH]c(C(=CC4CCCC4)c4ccc(S(C)(=O)=O)cc4)cc3c2)O1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (510 mg, 0.85 mmol), a 10% aqueous sodium hydroxide solution (1 mL) and ethanol (8 mL) was heated at 100° C. for 1 h. The mixture was cooled to 25° C., extracted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-(2,2-dimethyl-[1,3]dioxolan-4-yl)-1H-pyrrolo[2,3-b]pyridine (320 mg, 81%) as a light yellow oil which was used in the next step without purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1ccc2c(c1)OCO2
Yield: 82.6 %

Procedure:
3-benzo-1,3-dioxol-5-ylacrylic acid (2 g) was hydrogenated in ethanol (50 ml) over 5% Pd—C under a pressure of hydrogen at 10 psi for 40 mins to give 3-benzo-1,3-dioxol-5-ylpropionic acid (1.67 g, 80% yield) as a solid, m.p. 86.1°-88.3° C. (Lit m.p. 87-88° C.)10