Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)/[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: CCCCC/C(=C/C=C/C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC/C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
As in Example 115, (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid (2.8 g) and 4-nitrophenol (1.71 g) in 20 mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (2.1 g). The mixture was stirred at room temperature for 18 hours and the usual work up furnished 4.0 g of (2E,4Z)-5-(4-methoxyphenyl)-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]([CH2:18][CH3:19])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>O>[CH2:21]([C:3]([N:2]([CH3:20])[CH3:1])([CH2:18][CH3:19])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1)=[O:5])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: CCC(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(N2CCOCC2)cc1)N(C)C
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
In a 2.5 1 sulfonation flask, 900 ml of a solution (1 mol) of 2-dimethylamino-1 -(4-morpholino-phenyl)butan-1 -one according to b) above are heated again to 50° C. 179.7 g (1.05 mol) of benzyl bromide are then added dropwise over 20 minutes. The mixture is stirred for 3 to 4 hours at 50° C. until the thin layer chromatogram shows that there is no educt left. The temperature is raised to 60° C. and then 80 g (2 mol) of sodium hydroxide powder are added in increments over 45 minutes. The mixture is then stirred for another 1 to 2 hours at 50° C. until the thin layer chromatogram shows that there is no educt left. The reaction mixture is charged with 150 ml of water and stirred. The water phase is separated and the organic phase is concentrated on a vacuum rotary evaporator. 378.3 g of the yellowish crude product of 2-benzyl-2-dimethylamino-1 -(4-morpholinophenyl)butan-1 -one having a melting point from 102° C. to 110° C. remain in the flask. The crude product is dissolved hot in 600 ml of ethanol, cooled, crystallised, filtered and then washed with cold ethanol. The crystals are dried. They melt at 114° C. to 115° C., and gas chromatogram as well as thin layer chromatogram show them to be pure. The yield is 299.0 g of 2-benzyl-2-dimethylamino-1-(4-morpholinophenyl)butan-1-one. A further 22.4 g of pure product can be isolated from the mother liquor. The 1H-NMR spectrum of the pure product corresponds to that of the indicated structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH2:8][CH2:7]1.[OH-].[Li+:26]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:20])[CH2:14][CH2:15][C:16]([O-:18])=[O:17])[CH2:10][CH2:11]1.[Li+:26]
Reactant: COC(=O)CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])CCC(=O)NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 48 h
Yield: 96.2 %

Procedure:
To a solution of methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.72 g) in methanol (30 ml) was added lithium hydroxide (0.41 g) in water (10 ml) which was stirred under nitrogen for 48 hours. The solvent was removed under reduced pressure, the residue was triturated with ether and filtered to leave lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.50 g).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH:32]([F:34])[F:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.C(OCC)(=O)C>[F:33][CH:32]([F:34])[O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:9]2[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:26][CH:27]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2ccc(OC(F)F)cc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.60 g) in DME (12.0 mL) were added 1-(bromomethyl)-4-(difluoromethoxy)benzene (0.47 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.16 g) and 2 mol/L aqueous sodium carbonate solution (1.96 mL), and the mixture was stirred overnight at 80° C. under argon atmosphere. Water and ethyl acetate were added thereto, the mixture was allowed to be cooled to room temperature, and the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.60 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([F:12])=[CH:4][C:3]=1[O:14][CH2:15][CH:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: COC(=O)c1cc(Cl)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(OCC2CN(C(=O)OC(C)(C)C)C2)cc1F
Temperature: 30 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A mixture of methyl 5-chloro-2,4-difluorobenzoate (2.2 g, 10.7 mmol), tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (2.0 g, 10.7 mmol) and potassium carbonate (4.43 g, 32.1 mmol) in DMF (30 mL) was stirred at 30° C. for 16 h. The mixture was quenched by water and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column (eluting with petroleum ether/ethyl acetate, from 20/1 to 3/1) to give tert-butyl 3-((2-chloro-5-fluoro-4-(methoxycarbonyl)phenoxy)methyl)azetidine-1-carboxylate (1.2 g, 30%) as a pale yellow oil. LCMS (ESI) m/z: 318.0 [M-56+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:28]([CH2:27][C:26]([O:31][CH2:32][CH3:33])=[O:30])[CH2:29][N:13]=1)=[CH:8]2
Reactant: CC#CC(=O)OCC
Reactant: COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(OC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a stirred solution of 7-methoxy-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carbothioamide (0.69 g), ethyl 2-butynoate (0.43 mL), tetrahydrofuran (15 mL) and toluene (25 mL) was added tributylphosphine (0.54 mL) at room temperature under argon atmosphere. After the mixture was stirred at 40° C. for 4 h, ethyl 2-butynoate (0.22 mL) and tributylphosphine (0.27 mL) were added thereto. After stirring at 40° C. for 2 h, the reaction mixture was concentrated to give a light brown oil, which was purified by silica gel chromatography (ethyl acetate:hexane=30:70 to 75:25, volume ratio) to give the title compound (684 mg, 72%) as a light yellow oil. MS 489 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>[Pd].CO>[CH3:1][CH:2]([CH3:22])[CH2:3][C:4]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)=Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CC(C)Cc1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Yield: 95.7 %

Procedure:
A solution of tert-butyl 9-(2-methylpropa-1-ene-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (270 mg, 0.890 mmol) and 10% palladium on carbon (50.0 mg) in methanol (6 ml) was stirred under a hydrogen atmosphere for 12 hr. The reaction mixture was filtered, and the filtrate was concentrated. The residue was poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (260 mg, 95.6%) as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:7]1[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccccc1CNc1cccnc1Cl
Solvent: C1CCOC1
Product: COc1ccccc1CNc1cccnc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
To a 22 L three neck round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel, and nitrogen inlet, were added 3.84 L of tetrahydrofuran, 91.6 grams (0.17 moles) of bis(diphenylphosphino)ethanenickel (II) chloride, and 96 grams (0.39 moles) of 2-chloro-3-(2-methoxybenzylamino)pyridine. The orange slurry was stirred at 25° C. for about 30 minutes. Phenylmagnesium bromide (3M in ether, 231.6 mL, 0.69 moles) was added over a 4 hour period and the resulting black slurry was stirred for 22 hours at 25° C. During this time, the reaction was monitored by thin layer chromatography assay, and a total of 86 mL (0.26 moles) of additional phenylmagnesium bromide solution was added to the system. The reaction mixture was cooled to 10° C. and the reaction was quenched with 3.84 L of 20% aqueous HCl over 30 minutes. Ethyl acetate (3.84 L) was added and the reaction mixture was stirred an additional 10 minutes. The layers were separated and the organic layer was washed with 4 L of 25% aqueous HCl. The pH of the aqueous layer was, adjusted from 0.98 to 11.6 with 1.6 L of 50% aqueous sodium hydroxide. Diatomaceous earth (Celite®) (1 kg) and 7 L of ethyl acetate were added. The mixture was stirred for 15 minutes, filtered through diatomaceous earth (Celite®) and the cake was washed with about 1 L of ethyl acetate. The layers were separated, the aqueous layer washed twice with 2 L of ethyl acetate, and the organic layers were combined and dried with sodium sulfate. The drying agent was removed by filtration, the cake was washed with ethyl acetate, and the filtrate was vacuum concentrated to about 2 L volume. This solution was treated with 510 g of silica gel for 30 minutes at 20°-25° C., filtered, and the silica gel was washed twice with 2 L of ethyl acetate. The filtrate was vacuum concentrated to a yellow slurry and displaced with 1 L of isopropanol to a final volume of about 275 mL. The slurry was granulated at 0°-5° C. for 30 minutes, filtered, washed with cold isopropanol, and dried giving 83.8 g (74.8%) of crude material (Mp 122°-125° C). A portion (48.3 g) of this material was purified by chromatography to give 38.6 g of the title compound as a yellow solid. Mp 124°-128° C. Spectral data for this compound are identical to the data reported in step 1 of Example 4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](Br)[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B1OC(C([O-])=O)C=CO1)#[N:17].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:9]1[C:10]([O:13][CH3:14])=[N:11][CH:12]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:8]=1)#[N:17]
Reactant: N#Cc1ccccc1B1OC=CC(C(=O)[O-])O1
Reactant: COc1ncc(-c2ccccn2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ncc(-c2ccccn2)cc1-c1ccccc1C#N
Temperature: 140 °C
Reaction time: 5 h

Procedure:
Tetrakistriphenylphosphine palladium (0.15 g) was added to a mixed solution of 0.50 g of 5-(2-pyridyl)-3-bromo-2-methoxypyridine, 0.42 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 0.82 g of cesium carbonate and 20 ml of dimethylformamide and the mixture was stirred at 140° C. in a nitrogen atmosphere for 5 hours. After cooling to room temperature, ethyl acetate was added thereto, the mixture was washed with water and a saturated saline solution and dried over magnesium sulfate. The solvent was concentrated in vacuo and the residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3) to give 0.36 of the title compound as pale yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]1[C@@H:13]2[CH2:14][NH:15][CH2:16][C@@H:12]2[CH2:11][N:10]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)C(C)C)(C)C>CS(C)=O.O>[Cl:8][C:4]1[N:3]=[C:2]([N:15]2[CH2:14][C@@H:13]3[CH2:9][N:10]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][C@@H:12]3[CH2:16]2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(Cl)n3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 89.4 %

Procedure:
2,6-dichloropyrazine (1.02 g, 6.85 mmol) was dissolved in DMSO (7 mL). The product from Example 1C (1.61 g, 7.58 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.61 mmol) were added to the reaction mixture. The reaction was stirred at ambient temperature for 23 h. The reaction was diluted with water (200 mL) and extracted with CH2Cl2 (4×100 mL). The organic extracts were combined and washed with and brine (150 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc, Rf=0.38) to afford the title compound as a white solid (1.99 g, 89%). MS (DCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: C(O)C.Cl.[NH2:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[C:8]2[CH:14]=[C:13]([Cl:15])[S:12][C:9]2=[N:10][CH:11]=1.O1CCCC1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[N:36]=[C:37]=[O:38]>C(N(CC)CC)C>[Cl:15][C:13]1[S:12][C:9]2=[N:10][CH:11]=[C:6]([NH:5][C:37]([NH:36][C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])=[O:38])[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])=[C:8]2[CH:14]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cc1ccccc1-c1c(N)cnc2sc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccccc1-c1c(NC(=O)Nc2ccc(F)cc2F)cnc2sc(Cl)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.9 %

Procedure:
To a mixture of 5-amino-2-chloro-4-(2-methylphenyl)thieno[2,3-b]pyridine hydrochloride ethanol solvate (160 mg) and tetrahydrofuran (3 ml) were added dropwise triethylamine (0.07 ml) and 2,4-difluorophenyl isocyanate (0.12 ml). The mixture was stirred at room temperature for 5 hours and the solvent was distilled off. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over MgSO4 and the solvent was distilled off. To the residue was added isopropyl ether to obtain N-[2-chloro-4-(2-methylphenyl)thieno[2,3-b]pyridin-5-yl]-N'-[2,4-difluorophenyl)urea (133 mg, 68.9%) as crystals. crystals were recrystallized from ethanol to obtain colorless prisms, mp; 225°-226° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:20][CH2:21][CH2:22]C.ICCC.O>O1CCCC1.CCCCCC>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH2:20][CH2:21][CH3:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Solvent: CCCCCC
Solvent: CCCI
Solvent: O
Product: CCCc1cc2cccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridine (400 mG, 1.55 mmol) in tetrahydrofuran (15 mL) at -78° C. was added n-BuLi (0.74 mL of a 2.5M solution in hexane, 1.86 mmol) dropwise. The mixture was stirred 1 h at -78° C. then warmed to rt for 5 min. The mixture was again cooled to -78° C. then iodo propane (0.45 mL, 4.65 mmol) was added and the mixture was stirred 1 h at rt. Water was added, and extractive workup (EtOAc) and purification (SiO2, 20% EtOAc/hexane) gave 1-(benzenesulfonyl)-2-propyl-1H-pyrrolo[2,3-b]-pyridine.
Reaction SMILES: O.[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[C:4]=1[C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:11][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:3]=2)[CH:6]=[C:5]([OH:10])[C:4]=1[C:11](=[O:13])[CH3:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1c(O)cc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2′,4′,6′-trihydroxyacetophenone monohydrate (5 g) and potassium carbonate (7.42 g) in N,N-dimethylformamide (100 mL) was added benzyl bromide (6.39 mL) under ice-cooling, 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 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=10/1-5/1) to give 2′,4′-dibenzyloxy-6′-hydroxyacetophenone (5.71 g). This material was suspended in ethanol (45 mL)-water (15 mL). To the suspension was added potassium hydroxide (11.0 g), and the mixture was stirred at room temperature for 10 minutes. Benzaldehyde (2.51 mL) was added to the mixture, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was acidified by addition of concentrated hydrochloric acid, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 2′,4′-dibenzyloxy-6′-hydroxychalcone (4.85 g). This material was dissolved in N,N-dimethylformamide (40 mL)-acetone (12 mL). To the solution were added potassium carbonate (2.3 g) and methyl bromoacetate (1.1 mL), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (30 mL). To the solution was added 10% palladium-carbon powder (0.5 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1-2/1) to give the title compound (2.26 g).
Reaction SMILES: COC1C=C(C=CC=1OC)C[N:7]1[CH:12]=[CH:11][C:10](=O)[C:9]([C:14]#[N:15])=[CH:8]1.[Li+].[Cl-].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:10]1[C:9]([C:14]#[N:15])=[CH:8][N:7]=[CH:12][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(Cn2ccc(=O)c(C#N)c2)cc1OC
Agent: [Cl-]
Agent: [Li+]
Product: N#Cc1cnccc1Cl

Procedure:
Alternatively, as shown in Scheme 3 below, the bisdimethylaminemethylene intermediate iii obtained by reaction of 3-oxo-butyronitrile ii with DMF-DMA can be reacted with 3,4-dimethoxybenzylamine at reflux in a solvent such as toluene to give 1-(3,4-dimethoxybenzyl)-4-oxo-1,4-dihydro-pyridine-3-carbonitrile viii. Reaction of viii with excess LiCl in refluxing POCl3 results in removal of the dimethoxybenzyl group and conversion to the corresponding 4-chloro-nicotinonitrile v.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[CH3:14][C:15]1C=CC(S(OCCC=C)(=O)=O)=[CH:17][CH:16]=1>>[CH2:17]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13])[CH2:16][CH:15]=[CH2:14]
Reactant: COc1ccc2c(c1)CCNC2=O
Reactant: C=CCCOS(=O)(=O)c1ccc(C)cc1
Product: C=CCCN1CCc2cc(OC)ccc2C1=O

Procedure:
The title compound 49 is prepared according to the procedure reported in step B of Example 8 with amide 42 (0.32 g, 1.8 mmol) and but-3-enyl 4-methylbenzenesulfonate (1.63 g, 4 equiv) as reactants. Yellow oil. (Yield 0.29 g, 69%).