Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=1.O>CN(C=O)C>[CH3:39][O:38][C:36](=[O:37])[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC(=O)OC)cc1
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (278 mg, 0.83 mmol) in anhydrous DMF (5 mL) add cesium carbonate (297 mg, 1.66 mmol) and methyl 4-hydroxyphenylacetate (200 mg, 1.20 mmol). Stir the resulting mixture overnight then pour into water and extract twice with ethyl acetate. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum to give the title compound (290 mg) as a yellowish solid.
Reaction SMILES: [CH2:1]([PH2:8]=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:10]([O-])([OH:12])=[O:11].S(=O)(=O)(O)O.N>>[N+:10]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][PH2:8]=[O:9])=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: O=[PH2]Cc1ccccc1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: O=[PH2]Cc1ccc([N+](=O)[O-])cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 1-benzylphosphorane-1-oxide (4.17 g) were added nitric acid (1.7 ml) and sulfuric acid (11 ml) at 0° C., and the mixture was stirred at 50-60° C. for 2 hours. The reaction mixture was added to crushed ice and neutralized with ammonia solution. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:4→1:1) to give 1-(4-nitro-benzyl)phosphorane-1-oxide (2.22 g) as yellow crystals.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:21])[C:7](=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[C:8](=O)[CH3:9])#[N:2].[NH2:22]/[C:23](/[CH3:35])=[CH:24]\[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>CCO>[CH2:28]([O:27][C:25]([C:24]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:21])=[C:8]([CH3:9])[NH:22][C:23]=1[CH3:35])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Reactant: C/C(N)=C/C(=O)OCc1ccccc1
Solvent: CCO
Product: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(C)N1

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid 2-cyanoethyl ester (15.06 g, 52.3 mmol) and benzyl 3-amino-crotonate (10.00 g, 52.3 mmol) in 150 ml of EtOH was refluxed for 36 hrs. After solvent was evaporated, the residue was dissolved in 250 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine was obtained as a yellow oil (23.4 g, 97%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:21].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Cl)=[CH:25][N:24]=1>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:21][C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=3)=[CH:9][C:4]=2[Cl:3])=[CH:25][N:24]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Oc2ccc(OCc3ccc(Cl)nc3)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution 0.07 g of sodium hydride (60% oil dispersion) in 10 ml of N,N-dimethylformamide, there was added dropwise a solution of 0.50 g of 2-chloro-4-(3-trifluoromethylphenoxy)phenol in 3 ml of N,N-dimethylformamide with stirring and ice-cooling. After 30 minutes, a solution of 0.28 g of 2-chloro-5-chloromethylpyridine in 5 ml of N,N-dimethylformamide was added thereto at room temperature, followed by stirring at the same temperature for 10 hours. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 2-chloro-5-[2-chloro-4-(3-trifluoromethylphenoxy)phenoxy]methylpyridine.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH2:10]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCCCOc1cccc(B(O)O)c1
Product: CCCCOc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 52 %

Procedure:
The title compound (170 mg) was prepared from 4-bromo-2-fluoroaniline (240 mg, 1.26 mmol) and 3-butoxyphenylboronic acid (310 mg, 1.59 mmol) as a yellow liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:26]([F:29])([F:28])[F:27])=[N:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][NH:20][C:21]([NH2:23])=[O:22])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:26]([F:28])([F:29])[F:27])=[N:9]2)=[CH:6][CH:7]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)NCCOc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(OCCNC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of N-(2-{4-[1-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea obtained by Example 81 (148.5 mg) in dichloromethane (1.5 ml) was added pyridine (163 μL) and acetic anhydride (45 μL), and the mixture was stirred at room temperature for 1 hr and stirred under reflux for 3 hrs.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[C:16]2=[O:32])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[BH4-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[CH:16]2[OH:32])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
Ethyl 2-(4-benzyloxyphenyl)-4,5,6,7-tetramethoxy-1-oxo-2-indancarboxylate (3.78 g, 7.46 mmols) was dissolved in ethanol (40 mmols), and sodium borohydride (564 mg, 14.9 mmols) was added thereto with cooling with ice. The reaction mixture was warmed to room temperature, and then stirred for further 6 hours. Water was added to the reaction mixture, which was neutralized with 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain ethyl 2-(4-benzyloxyphenyl)-1-hydroxy-4,5,6,7-tetramethoxy-2-indancarboxylate (3.02 g).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[F:18][C:19]1[C:20]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[N:54]=[CH:53][CH:52]=[N:51]3)=[CH:46][CH:45]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][O:31]C2CCCCO2)=[O:29])[CH:24]=1>C(O)C>[F:18][C:19]1[C:20]([C:44]2[CH:45]=[CH:46][C:47]([N:50]3[N:54]=[CH:53][CH:52]=[N:51]3)=[CH:48][CH:49]=2)=[CH:21][C:22](=[O:43])[N:23]([CH2:25][CH2:26][C@@:27]([CH3:42])([S:38]([CH3:41])(=[O:40])=[O:39])[C:28]([NH:30][OH:31])=[O:29])[CH:24]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@](CCn1cc(F)c(-c2ccc(-n3nccn3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
Pyridinium p-toluenesulfonate (360 mg, 0.50 mmol) was added to a solution of (2R)-4-{5-fluoro-2-oxo-4-[4-(2H-1,2,3-triazol-2-yl)phenyl]pyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.53 g, 2.87 mmol) in ethanol (60 mL). The solution was heated to 70° C. and was stirred at this temperature for 3 h. The reaction was allowed to cool and was stirred at rt for three days. The solid was collected via filtration, washed with ethanol (20 mL) and hexanes (20 mL). The solid was dried under vacuum to afford the title compound as a white solid (1.05 g, 81.5%). MS (LCMS) m/z 450.0 (M+1), 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.08-2.27 (m, 0H) 2.38-2.59 (m, 1H) 3.12 (s, 3H) 3.72-3.90 (m, 1H) 4.00-4.17 (m, 1H) 6.62 (d, J=7.61 Hz, 1H) 7.70-7.88 (m, 2H) 8.08 (d, J=6.63 Hz, 1H) 8.12-8.18 (m, 2H) 8.19 (s, 2H) 9.25 (d, J=1.95 Hz, 1H) 11.09 (d, J=1.76 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]2[N:9]=[CH:10][NH:11][C:5]=2[CH:4]=1.Cl[C:13]1([C:19]([O:21][CH3:22])=[O:20])[C:17](=[O:18])[CH:16]=[CH:15][S:14]1>C(Cl)(Cl)Cl>[OH:18][C:17]1[CH:16]=[C:15]([N:9]2[C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[N:11]=[CH:10]2)[S:14][C:13]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COc1cc2[nH]cnc2cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cc(OC)ncc32)cc1O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 2.00 g of 6-methoxy-1H-imidazo[4,5-c]pyridine in 50 ml of chloroform were added 1.25 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in portions and the reaction mixture was stirred for 120 h at room temperature. The reaction mixture was washed with water (3×50 ml) and the organic layer was dried and concentrated under vacuum. The residue was recrystallized from methanol to yield the title compounds as an isomeric mixture.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:20]=[CH:21][CH:22]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH3:15][N:16]([C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:17]1[CH:18]=[C:19]([C:23]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[CH:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=[CH:21][CH:22]=1
Reactant: CNc1cccc(C(=CCCCC(=O)OC)c2cccnc2)c1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)CCc1c[nH]c2ccccc12)c1cccc(C(=CCCCC(=O)O)c2cccnc2)c1

Procedure:
A mixture of 1.9 g of 3-(3-indolyl)-propionic acid, 2.3 g of methyl 6-(3-methylaminophenyl)-6-(3-pyridyl)-hex-5-enoate and 1.8 g of carbonyldiimidazole is refluxed for 48 hours in 50 ml of tetrahydrofuran. The reaction mixture is evaporated down, the residue is taken up in water and extracted with ethyl acetate. The organic phase is evaporated down and the residue is saponified in a mixture of 20 ml of ethanol and 6 ml of 4N sodium hydroxide solution at 50° C. for 30 minutes. The reaction mixture is neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue is recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].[CH3:26][O:27][CH2:28]Cl.Cl>O1CCCC1.O>[C:14]([O:13][C:11](=[O:12])[CH:10]([CH2:26][O:27][CH3:28])[CH2:9][C:4]1([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of t-butyl 3-(1-carboxycyclopentyl)propanoate (1.0 g, 4.13 mmole) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (9.29 mmole) in dry tetrahydrofuran (50 ml) at -78° C. under nitrogen. After 0.5 hours, chloromethyl methyl ether (0.53 g, 6.58 mmole) was added and the mixture was allowed to warm to room temperature over 16 hours. The solution was poured into water, acidified to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate (3×50 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to give a colourless oil that was chromatographed on silica gel eluting with a mixture of diethyl ether and dichloromethane (1:9-1:4 by volume). Evaporation of the appropriate fractions gave the title compound as a colourless oil (0.78 g, 66%). Found: C,62.75; H,8.94. C15H26O5 requires: C,62.91; H,9.15%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH2:10])=[S:9])=[CH:4][CH:3]=1.CO[CH:13](OC)[CH2:14]Br.Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:13]=[CH:14][N:10]=2)=[CH:4][CH:3]=1
Reactant: COC(CBr)OC
Reactant: NC(=S)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-c2nccs2)cc1
Yield: 34.9 %

Procedure:
A stirred mixture of 12.1 grams (0.0703 mole) of 4chlorophenylthiocarboxamide, 12.1 grams (0.0714 mole) of bromoacetaldehyde dimethyl acetal, and 2 ml of concentrated hydrochloric acid in 280 ml of ethanol was heated at reflux for approximately 18 hours. An additional 1 ml of concentrated hydrochloric acid was added, and the mixture was heated at reflux for two days. The reaction mixture was cooled, and the solvent was removed by evaporation under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride:n-hexane (3:1), to yield 4.8 grams of 2-(4-chlorophenyl)thiazole as a solid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH2:13]([NH:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([N:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCNCCCC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1ccccc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.0 g isatoic anhydride is dissolved in 50 ml methylene chloride/5 ml dimethylformamide and 1.87 g 4-dimethylaminopyridine and 1.98 g dibutylamine are added. The mixture is stirred at room temperature for 5 hours, then diluted with 250 ml of ethyl acetate. The organic solution is washed with 10% HCl and brine and dried over sodium sulfate followed by filtration and evaporation to obtain a residue. The residue is dissolved in 25 ml ethyl acetate, the solution filtered, concentrated and this residue purified by flash chromatography on silica gel in ethyl acetate/hexane, 2:3, to give 2-amino-N,N-dibutyl benzamide.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[CH3:14][S:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:29][CH:28]=3)[S:24][C:23]=2[CH:38]=1)(=[O:17])=[O:16].ClCCl.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl>[CH3:14][S:15]([O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([C:9](=[O:11])[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][Br:1])=[CH:13][CH:12]=3)=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][S:34]([CH3:37])(=[O:35])=[O:36])=[CH:31][CH:32]=3)[S:24][C:23]=2[CH:38]=1)(=[O:16])=[O:17]
Reactant: CS(=O)(=O)Oc1ccc(-c2cc3ccc(OS(C)(=O)=O)cc3s2)cc1
Reactant: O=C(O)c1ccc(OCCBr)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCBr)cc2)cc1
Temperature: 0 °C

Procedure:
One g. of 4-(2-bromoethoxy)benzoic acid was converted to the acid chloride, and was combined with 1.2 g. of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)benzo[b]thiophene, 20 ml. of dichloromethane and 0.5 ml. of trifluoromethanesulfonic acid. The mixture was stirred under reflux overnight, and was then poured into ice-water. The organic layer was separated, washed with sodium carbonate solution, dried and evaporated under vacuum to obtain 2.1 g. of brown oil. The oil was chromatographed over a 4×8 cm. silica gel column with 9/1 toluene/ethyl acetate and the product-containing fractions were combined and evaporated under vacuum to obtain 1.8 g. of purified product as an oil. The product was identified by its MH+ molecular ion, m/e 626, in the field desorption mass spectrum and by an absorption maximum in the infrared spectrum, in chloroform, at 1645 cm.-1 attributable to the CO function. A small sample was recrystallized from methanol to obtain white crystals, m.p. 105°-107°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8](=[N:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:27]([CH2:32][NH2:33])=[N:28][CH:29]=[CH:30][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8](=[N:16][C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[N:9]1[CH2:10][CH2:11][CH:12]([NH:33][CH2:32][C:27]2[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cccnc1CN
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC1CCN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of [tert-butoxycarbonylimino-(4-oxo-piperidin-1-yl)-methyl]-carbamic acid tert-butyl ester, C-(3-methylpyridin-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave (tert-butoxycarbonylimino-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-methyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:22][C:23]1[C:24](=[O:30])[NH:25][C:26](=[O:29])[NH:27][CH:28]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18]([N:27]2[CH:28]=[C:23]([F:22])[C:24](=[O:30])[NH:25][C:26]2=[O:29])=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3cc(F)c(=O)[nH]c3=O)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (75 mg, 0.25 mmol), 5-fluorouracil (75 mg, 0.58 mmol), and 0.5 mL of pyridine in 2.0 mL of THF was stirred at room temperature for 1 h and filtered. The solid was then washed with THF, acetone, methanol, and ether to give 34 mg (36%) of 1-{3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl}-5-fluoro-1H-pyrimidine-2,4-dione as a light yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 12.22 (d, J=4.69 Hz, 1H, CONHCO), 12.19 (s, br, 1H, NH-1′), 8.33 (d, J=6.64 Hz, 1H, H-6″), 7.92-7.94 (m, 1H, H-4), 7.74-7.76 (m, 1H, H-7), 7.71 (s, 1H, H-vinyl), 7.26-7.29 (m, 2H, H-5, 6), 6.16 (s, br, 1H, H-4′), 2.47 (s, 3H, CH3), and 2.35 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:18]([O:20]C(C)(C)C)=[O:19])[C:11]([O:13]C(C)(C)C)=[O:12])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([C:11]([OH:13])=[O:12])[C:18]([OH:20])=[O:19])[CH3:2]
Reactant: CCOC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 95.3 %

Procedure:
To a solution of triester 61 (500 mg, 1.395 mmol) in CH2Cl2 (20 mL) was added TFA (2.0 mL) and the reaction mixture stirred overnight. Volatile components were evaporated under vacuum, and the residue repeatedly dissolved in CH2Cl2 and evaporated to remove all traces of TFA. A solid 62 (327 mg, 1.33 mmol) was obtained and used directly in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 2H), 4.03 (q, 2H), 3.16 (t, 1H), 2.25 (t, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 1.25 (m, 4H), 1.16 (t, 3H).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[S:19](=[O:27])(=[O:26])[NH:18]2)=[C:9]1[CH3:28])(C)(C)C.Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[O:27]=[S:19]1(=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]([OH:29])=[O:5])[C:9]=2[CH3:28])[N:18]1[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2ccccc2n1CC(=O)OC(C)(C)C
Reactant: BrCCCOc1ccccc1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2CCCOc2ccccc2)c2ccccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 3, step c) and (3-bromo-propoxy)-benzene. MS: ESI (negative): 489 (N−H).
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.[NH2:23][OH:24]>>[C:1]([NH:4][CH:5]([NH:23][OH:24])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Agent: BrB(Br)Br
Product: CC(=O)NC(NO)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BBr3 (1M in CH2Cl2, 8.8 mL, 8.8 mmol), and anhydrous NH2OH (5-6 equiv) gave an oily residue. The residue was separated in three components by flash chromatography on SiO2 gel (7.5% MeOH/CHCl3).
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].[F-:23].[K+]>CS(C)=O.O>[F:23][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: [F-]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(Oc2ccccc2)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1c(F)cncc1-c1ccc(Oc2ccccc2)cc1
Temperature: 120 °C
Yield: 68.5 %

Procedure:
A mixture of 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile (11.8 g, 38.5 mmol) and potassium fluoride (11.17 g, 192 mmol) in DMSO (500 mL) was heated to 120° C. for 10 days. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×400 mL). The combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in dichloromethane-hexanes (1:2), gave 3-fluoro-5-(4-phenoxyphenyl)isonicotinonitrile as tan solid (7.66 g, 69% yield). 1H NMR (500 MHz, CDCl3) δ ppm 8.67 (1H, s), 8.64 (1H, s), 7.52-7.62 (2H, m), 7.36-7.46 (2H, m), 7.20 (1H, t, J=7.42 Hz), 7.05-7.17 (4H, m); MS (ES+) m/z: 291 (M+H); LC retention time: 4.118 min (analytical HPLC Method A).