Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]=1[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18].[CH3:22][Zn]C.CO.CCOCC>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH3:22])[CH:5]=[CH:4][C:3]=1[CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18]
Reactant: C[Zn]C
Reactant: COC(=O)C(C)c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Solvent: CCOCC
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(C)c1ccc(C)cc1F
Yield: 69.7 %

Procedure:
To a suspension of [1,2-bis(diphenylphospino)ethane]-dichloropalladium(II) [Pd(dppe)Cl2] (14.1 mg and 1.3 mol %) in dry 1,4-dioxane (3 mL), a solution of compound (18) (0.62 g, 1.9 mmol) in dry 1,4-dioxane (3 mL) was added dropwise under argon gas flow. To this suspension, dimethyl zinc (2M-solution in toluene, 9.0 mL, 2.0 mmol) was slowly added dropwise. After completion of the dropwise addition, the suspension was heated to reflux for 4 hours. After cooling, methanol (0.4 mL) was added thereto and the mixture was treated with ether. The organic layer was washed with a 1M aqueous solution (18 mL) of hydrochloric acid and dried (over sodium sulfate), and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (10:1) solution to give 0.26 g (70%) of compound (19) of interest as colorless liquid matter.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br.[NH2:14][CH2:15][CH2:16][Br:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:14][CH2:15][CH2:16][Br:17])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NCCBr
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
In 30 ml of chloroform were added 3 g of 4-nitrobenzoyl chloride, 3.3 g of 2-aminoethyl bromide hydrobromide and 3.9 ml of pyridine under ice cooling, and they were stirred at the same temperature for 1 hour. The reaction mixture was then washed with water, and the resulting organic layer was concentrated to obtain a crude product of 2-(4-nitrobenzoylamino)ethyl bromide. Afterward, the latter was recrystallized from hexane/ethanol, the resulting crystals were collected by filtration, washed and dried to prepare 2.9 g of 2-(4-nitrobenzoylamino)ethyl bromide (compound 46).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:44])[N:20]([CH2:39][C:40]([OH:43])([CH3:42])[CH3:41])[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(CC(C)(C)O)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(CC(C)(C)O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
A mixture of hydroxylammonium chloride (2.23 g), sodium hydrogen carbonate (3.60 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(2-hydroxy-2-methylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.92 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.42 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.25 g, 24%).
Reaction SMILES: [OH-:1].[Na+].O.[CH:4]([CH:6](O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:5].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:1][CH2:5][CH:4]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC(O)c1ccccc1
Reactant: BrCCCCBr
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: BrCCCCOCC=Cc1ccccc1

Procedure:
An amount of 20 g (0.5 mol) of sodium hydroxide and 20 ml of water were placed into a four-necked flask of 300 ml in capacity and then stirred to prepare a homogeneous solution. The temperature of this solution was reverted to room temperature, and then thereto a solution as prepared by dissolving 13.42 g (0.1 mol) of vinylbenzyl alcohol (mixture of m-isomer and p-isomer), 32.39 g (0.15 mol) of 1,4-dibromobutane, and 3.22 g (0.01 mol) of tetrabutylammonium bromide into 100 ml of toluene was added. While being vigorously stirred, the resultant mixed solution was allowed to react at 40° C. for 6 hours. Thereafter, the solution was separated and then sufficiently washed with water. The resultant organic layer was dried by adding thereto magnesium sulfate, and then toluene was distilled off under reduced pressure. The resultant solution was distilled in the presence of DPPH (diphenylpicryl-2-hydrazyl) under vacuum (boiling point: 125˜128° C./16 Pa) to obtain a colorless transparent liquid of 4-bromobutoxymethylstyrene. The yield amount was 15.0 g, and the yield ratio was 56 mol %.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:24]>[Cu]Br>[Br:24][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Br
Reactant: COC(=O)c1cc(C)c(F)cc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)c(F)cc1Br
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To the suspension of methyl 2-amino-4-fluoro-5-methylbenzoate (2.2 g, 12 mmol) in 48% hydrobromic acid (80 mL) was added an aqueous solution (32 mL) of sodium nitrite (828 mg, 12 mmol) at 0° C., and the resulting solution was stirred for 30 min. Copper (I) bromide (1.72 g, 12 mmol) was added to the solution at 0° C. and the resulting reaction mixture was stirred at r.t for 1 h. After addition of ethyl acetate (200 mL), the reaction mixture was washed with water (200 mL×2), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE-EA (10:1) to give methyl 2-bromo-4-fluoro-5-methylbenzoate (2.2 g, yield 74%) as colorless oil. 1H NMR (500 MHz, CDCl3) δ 7.655 (d, J=8.0 Hz, 1H), 7.257 (d, J=8.5 Hz, 1H), 3.837 (s, 3H), 2.177 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](OC)=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:24](=[O:25])[NH2:30])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C#N)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 49 %

Procedure:
A solution of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (114 mg, 0.32 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 7 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 40 mg (49%) of the 9-[(3-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (d, 1H, J=8 Hz), 7.7 (d, 1H, J=8 Hz), 7.6 (s, 1H), 7.5-7.4 (m, 3H), 7.3 (t, 1H, J=8 Hz), 7.25 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), and 5.75 (s, 2H). IR (KBr, cm−1) 3430, 3347, 2231, 1628, and 1601. MS (ES) m/e 340, 342.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[S:16]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][C:30](O)=[O:31])=[CH:20]1)(=[O:18])=[O:17])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:11])[CH3:12])[CH:7]=[C:6]([CH:13]([CH3:14])[CH3:15])[C:5]=1[S:16]([N:19]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:30](=[O:31])[CH2:29][CH2:28][C:21]([C:22]=23)=[CH:20]1)(=[O:17])=[O:18])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc(CCC(=O)O)c3ccccc32)c(C(C)C)c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)n2cc3c4c(cccc42)C(=O)CC3)c(C(C)C)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
To a solution of 1-(2,4,6-triisopropylphenylsulfonyl)-indole-3-propionic acid (76.22 g) in chloroform (500 ml) was added dropwise thionyl chloride (28.9 ml) at room temperature taking about 10 minutes. The mixture was stirred for one hour at 60° C. After completion of the reaction, the solvent was distilled off under reduced pressure. To the residue was again added chloroform, followed by concentration under reduced pressure. The concentrate was dissolved in dichloroethane (900 ml). To the solution was gradually added, under ice-cooling, crushed aluminum chloride (58.4 g). The mixture was stirred for 30 minutes, and was added to a mixture of 1N hydrochloric acid (1000 ml) and ice (200 g), followed by extraction with chloroform (900 ml). The extract solution was washed with water (900 ml), dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The concentrate was purified by means of a column chromatography (eluted with ethyl acetate:n-hexane=1:4), followed by recrystallization from ethyl acetate-hexane to afford the title compound (43.86 g, m.p.124°-130° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH:7][CH2:8][CH2:9]O)=[CH:4][CH:3]=1.O=S(Cl)[Cl:15]>>[Cl-:1].[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][NH2+:7][CH2:8][CH2:9][Cl:15])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCNCc1ccc(Cl)cc1
Product: ClCC[NH2+]Cc1ccc(Cl)cc1
Product: [Cl-]

Procedure:
2-Hydroxyethylamine was reacted with 4-chlorobenzyl bromide according to Method B2a to give N-(4-chlorobenzyl)-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-(4-chlorobenzyl)-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-chloro-4-cyanophenyl isothiocyanate to give 2-(2-chloro-4-cyanophenylimino)-3-(4-chlorobenzyl)-1,3-thiazolidine.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].O.O.Cl[Sn]Cl.[OH-].[Na+]>CCOC(C)=O>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[N:7][CH:8]=1
Reactant: CC(C)(C#N)c1ccc([N+](=O)[O-])cn1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C#N)c1ccc(N)cn1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
The mixture of 2-methyl-2-(5-nitropyridin-2-yl)propanenitrile (I-1d, 2 g, 10.4 mmol) and SnCl2.2H2O (9.3 g, 41.6 mmol) in EtOAc (10 mL) was stirred at reflux for 4 h. After cooling to room temperature, aqueous 2 M NaOH (80 mL) was added to adjust the pH to 8˜9, the solid was filtered off, and the filtrate was extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated to afford 2-(5-aminopyridin-2-yl)-2-methylpropanenitrile (I-1) (1.7 g, 65.3% yield).
Reaction SMILES: [OH:1][C:2]1[C:9]([I:10])=[CH:8][C:7]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:6][C:3]=1[CH:4]=O.C(N(CC)CC)C.[F:23][C:24]([F:33])([F:32])/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28].O>CN(C=O)C>[I:10][C:9]1[CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=[C:3]2[C:2]=1[O:1][CH:25]([C:24]([F:23])([F:33])[F:32])[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:4]2
Reactant: CCOC(=O)/C=C/C(F)(F)F
Reactant: O=Cc1cc(OC(F)(F)F)cc(I)c1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Temperature: 85 °C
Yield: 69.1 %

Procedure:
The resulting product (2.5 g, 7.5 mmol) from step 1, triethylamine (2 mL) and ethyl 4,4,4-trifluorocrotonate (5.1 g, 30 mmol) were mixed in DMF (10 mL), and then the system was heated to 85° C. for reaction for 48 hrs. At the end of reaction, the reaction system was cooled to room temperature, added with water and extracted with ethyl acetate, and the organic phase was dried and evaporated in vacuum to obtain 2.5 g of the product (69%) by column chromatography.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:8]=O.[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1[CH:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]>CO>[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][C:12]=1/[CH:17]=[C:18]1\[C:19](=[O:27])[N:20]([CH2:1][N:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)[C:21]2[C:26]\1=[CH:25][CH:24]=[CH:23][CH:22]=2
Reactant: CN1CCNCC1
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: C=O
Solvent: CO
Product: Cc1cc(C)c(/C=C2\C(=O)N(CN3CCN(C)CC3)c3ccccc32)[nH]1
Temperature: 60 °C
Yield: 67.9 %

Procedure:
N-Methylpiperazine (10 g, 100 mmol) was added to a stirred solution of aqueous formaldehyde (10 g of 38% solution, 100 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one, (2.38 g, 10 mmol) in methanol (100 mL). The solution heated at 60° C. for 1 h, concentrated to a low volume and the precipitate was filtered off, washed with methanol, and dried to give 2.38 g of the title compound, mp 160-164° C. HPLC Rt 4.72 min. 1H NMR (CDCl3) δ2.26 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 2.43 (br s, 4H), 2.70 (br s, 4H), 4.59 (s, 2H), 5.96 (d, 1H), 7.02-7.08 (m, 2H), 7.15 (dd, 1H), 7.38 (s, 1H), 7.48 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C21H26N4O: C, 71.97; H, 7.48; N, 15.99. Found: C, 71.75; H, 7.46; N, 15.87.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:11]([C:17]([OH:19])=[O:18])[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.Cl.[CH2:21](O)[CH3:22]>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:11]([C:17]([O:19][CH2:21][CH3:22])=[O:18])[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1c(C(=O)O)cnn1-c1cccc(Cl)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1S(N)(=O)=O

Procedure:
Next, the above sulfonamide was introduced in ethanol saturated with hydrogen chloride, and, while stirring, heated under reflux for 7 hours. After solvent was evaporated, water was added, followed by extraction with chloroform. Extract liquid was evaporated to dryness to obtain 0.62 g of the title compound. m.p.: 125° to 128° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)[CH3:2].[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])=[O:23])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (139) (100 mg, 0.25 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([O:25][CH3:26])[CH:16]=2)[O:4][CH2:3]1.[H-].[Na+].[CH3:31]I>CN(C)C=O>[CH3:1][C:2]1([CH3:28])[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]([CH3:31])[C:14](=[O:27])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[C:17]([O:25][CH3:26])[CH:16]=2)[O:4][CH2:3]1
Reactant: CI
Reactant: COC(=O)c1ccc(C(=O)Nc2ccccc2C2=NC(C)(C)CO2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N(C)c2ccccc2C2=NC(C)(C)CO2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[2-(4,4-dimethyl(2,5-oxazolinyl)]-phenyl]-3-methoxy-4-methoxycarbonylbenzamide (1.45 g) in N,N-dimethylformamide (18 ml) was added portionwise sodium hydride (167 mg) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. Methyl iodide (0.283 ml) was added to the mixture and the solution was stirred at 0° C. for 1 hour. The reaction was quenched with water and then the aqueous solution was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give N-[2-[4,4-dimethyl-(2,5-oxazolinyl)]phenyl]-N-methyl-3-methoxy-4-methoxycarbonylbenzamide (1.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: OCCc1ccc(F)cc1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-bromophenol (81.7 g, 472 mmol), 2-(4-fluorophenyl)ethanol (79 g, 567 mmol) and Ph3P (149 g, 567 mmol) in THF (100 mL) cooled in an ice-water bath was added drop wise DEAD (93 ml, 590 mmol) over 20 min. Note: The reaction is exothermic and efficient cooling is highly recommended before initiating large scale reaction. After 1 h, cold bath was removed and stirred overnight (17 h) at rt. Then, the reaction mixture was concentrated, the resulting residue triturated with hexanes, filtered and the filter cake washed with 10% ether/hexanes (2-lit). The filtrate was concentrated and purified by flash chromatography (silica gel column 3″×11″) using 4-lit hexanes and 2-lit 2% EtOAc/Hex to afford 1-bromo-4-(4-fluorophenethoxy)benzene (142 g, 469 mmol, 99% yield) as colorless liquid (contaminated with ˜2.5% Ph3P by 1HNMR). 1H NMR (500 MHz, CDCl3) δ 7.41-7.36 (m, 2H), 7.28-7.22 (m, 2H), 7.05-6.99 (m, 2H), 6.82-6.76 (m, 2H), 4.14 (t, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-])=O)=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH3:9])[C:6]([NH2:10])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: CNc1ccc([N+](=O)[O-])c(C)n1
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(N)c(C)n1
Yield: 100.7 %

Procedure:
A suspension of 0.4 g (2.39 mmol) of 6-methylamino-2-methyl-3-nitropyridine (Prace Naukowe Akedimii Ekonomicznej imienia Oskara Langego we Wroclawiu (1988), 435, 119-28) and 0.1 g of 10% palladium-on-charcoal in 50 ml of methanol is stirred at 20° C. for 6 hours under 4 atmospheres of hydrogen. The reaction mixture is subsequently filtered through a celite plug and then concentrated under reduced pressure. 0.33 g of the expected product is thus isolated in the form of an oil which will be used as is in the continuation of the synthesis.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cccc3ccccc23)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(Cc3cccc4ccccc34)sc3ncccc23)c1Cl
Yield: 63.8 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(naphthylmethyl)thieno [2,3-b]pyridine-3-sulfonamide (58 mg, 0.10 mmoles), methanol (2 ml) and 4N HCl (2 ml). Recrystallization from EtOAc/hexanes provided 30 mg (61%) of the title compound as a yellow crystalline solid, m.p. 165-168° C.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9]1([CH3:24])[CH:14]=[CH:13][C:12]([O:15][C:16]([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])=[O:17])=[CH:11][CH:10]=1.O=O>C(OCC)C>[C:21]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:22])[CH2:20][CH2:19][CH2:18][C:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]([CH3:24])=[CH:14][CH:13]=1)=[O:17]
Reactant: CC(C)(C)OO
Reactant: Cc1ccc(OC(=O)CCCC(=O)Cl)cc1
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: Cc1ccc(OC(=O)CCCC(=O)OOC(C)(C)C)cc1
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a vigorously stirred solution of 4.9 g. (0.045 mole) of 82.0% t-butyl hydroperoxide and 18.0 g. (0.045 mole) of aqueous 10% sodium hydroxide at 10°-14° C. was slowly added 8.2 g. (0.034 mole) of 4-(p-tolyloxycarbonyl)butyryl chloride (prepared from p-tolyl 4-carboxybutyrate and thionyl chloride) in 25 ml. of diethyl ether. The reaction mixture was then stirred for 3.5 hours at 8°-10° C. After a work-up similar to that in Example I 8.2 g. (theory, 10.0 g.) of white solid, m.p. 50°-55° C., was obtained. The assay according to "active oxygen" content was 93.6% and the corrected yield was 76.7%.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[CH:28][N:29]=[C:2]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Reactant: C1CCNCC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(N2CCCCC2)c1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and piperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.28 (d, 1H), 8.22 (m, 1H), 7.88 (m, 1H), 7.59 (m, 2H), 7.42 (d, 1H), 7.40 (s, 1H), 7.15 (m, 1H), 7.05 (d, 1H), 4.35 (broad t, 2H), 3.61 (m, 4H), 3.38 (s, 4H), 2.90 (broad t, 2H), 2.60 (m, 4H), 1.60 (m, 6H). MS: 461.4 (M+1).