Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:5]=1[CH:6]=O)C=C.[C:16]([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])(=[O:29])[CH2:17][C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19].[C:39]1(C)[CH:44]=CC=C[CH:40]=1.N1CCCCC1>C(O)(=O)C>[CH2:44]([C:11]1[CH:4]=[C:5]([CH:8]=[C:9]([O:14][CH3:15])[C:10]=1[O:12][CH3:13])[CH:6]=[C:17]([C:18]([O:20][CH2:21][CH:22]([CH2:27][CH3:28])[CH2:23][CH2:24][CH2:25][CH3:26])=[O:19])[C:16]([O:30][CH2:31][CH:32]([CH2:37][CH3:38])[CH2:33][CH2:34][CH2:35][CH3:36])=[O:29])[CH:39]=[CH2:40]
Reactant: Cc1ccccc1
Reactant: CCCCC(CC)COC(=O)CC(=O)OCC(CC)CCCC
Reactant: C=CCc1cc(OC)c(OC)cc1C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: C=CCc1cc(C=C(C(=O)OCC(CC)CCCC)C(=O)OCC(CC)CCCC)cc(OC)c1OC
Yield: 64 %

Procedure:
A mixture of 3™allyl-4,5-dimethoxybenzaldehyde (10.3 g, 0.05 moles), di-(2-ethylhexyl) malonate (16.4 g, 0.05 moles), toluene (20 ml), acetic acid (0.41 ml) and piperidine (0.77 ml) is heated to reflux using a Dean Stark. After cooling, washing the toluene phase with water, drying and evaporation of the solvent, an orange-coloured oil is obtained, which is purified by chromatography on a column of silica 60 (eluent: 90:10 heptane/ethyl acetate) to give di-(2-ethylhexyl) 3-allyl-4,5-dimethoxybenzalmalonate (colourless oil, 15 g, yield=64%), which has the following characteristics:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15](Cl)=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH3:35]>N1C=CC=CC=1.ClCCl>[NH2:35][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(Cl)c23)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NS(=O)(=O)c1ccccc1

Procedure:
5-(4-Amino-3-methoxyphenyl)-4-chloro-7-cyclopentylpyrrolo[2,3-d]pyrimidine (0.50 g, prepared in a similar manner to Example 32) was reacted with benzenesulphonyl chloride (0.31 g) in pyridine (5 ml) and dichloromethane (1 ml) at 0° C. and the product obtained after work-up was reacted with ammonia in a similar manner to Example 32 to give N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]benzenesulphonamide, m.p. 113-115° C. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][C:31]=1[Cl:32]>C(Cl)Cl>[Cl:25][C:26]1[CH:27]=[C:28]([S:33]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:10][CH2:11][C:12](=[O:15])[CH2:13][CH2:14]3)=[CH:5][CH:4]=2)(=[O:34])=[O:35])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(Cl)c(Cl)c3)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a stirred solution of 0.5 g (1.9 mmol) of the hydrochloride salt of 1-(4-amino-phenyl)-piperidin-4-one (which was obtained in Example 224) in 10 mL of anhydrous methylene chloride was added 0.99 mL (5.7 mmol) of diisopropylethyl amine. After 10 minutes of stirring, 0.51 g (2.1 mmol) of 3,4-dichlorobenzene sulfonyl chloride was added and the mixture was allowed to stir overnight. The reaction mixture was quenched with water and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed twice with water, twice with brine, dried over sodium sulfate and then concentrated in vacuo. The residue was then purified by flash chromatography (10% EtOAc in hexanes to 50% EtOAc in hexanes) and the title compound was collected as 0.25 g of a yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.55 (t, J=6.09 Hz, 4H), 3.58 (t, J=6.03 Hz, 4H), 6.33 (s, 1H), 6.60–6.88 (m, 2H), 6.95–7.00 (m, 2H), 7.50 (d, J=1.47 Hz, 2H), 7.78–7.79 (m, 1H); MS (ES) m/z: 398.8 (MH+); HRMS found for C17H16Cl2N2O3S: 398.0227.
Reaction SMILES: [CH:1]1([CH:4]=O)[CH2:3][CH2:2]1.[CH3:6][C:7]([S@@:10]([NH2:12])=[O:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]1([CH:4]=[N:12][S@:10]([C:7]([CH3:9])([CH3:8])[CH3:6])=[O:11])[CH2:3][CH2:2]1
Reactant: O=CC1CC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)N=CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
The title compound was prepared according to a general procedure described by G. Liu, D. A. Cogan, T. D. Owens, T. P. Tang, and J. A. Ellman J. Org. Chem. 1999, 64, 1278: A mixture of cyclopropanecarboxaldehyde (35.0 g, 0.5 mol), (S)-(−)-2-methyl-2-propanesulfinamide (30 g, 0.25 mol) and anhydrous CuSO4 (120 g, 0.75 mol) in CH2Cl2 (1500 mL) was stirred at room temperature overnight. The reaction mixture was filtered and evaporated to give the title compound (39 g, yield 95%), which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH2:5])=[O:4].[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)[CH2:19][CH2:18]2)[CH2:7]1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.CC(=O)CC>[ClH:1].[ClH:1].[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([N:20]3[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][C@H:8]4[C:9]5[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=5)[N:6]([CH2:2][C:3]([NH2:5])=[O:4])[CH2:7]4)[CH2:18][CH2:19]3)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: c1ccc2c(c1)NC[C@H]2CCN1CCN(c2ccc3[nH]ccc3c2)CC1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCC(C)=O
Product: Cl
Product: NC(=O)CN1C[C@@H](CCN2CCN(c3ccc4[nH]ccc4c3)CC2)c2ccccc21
Yield: 67.6 %

Procedure:
To a clear solution of 2-chloroacetamide (17.7 g, 0.19 mol) in N-methylpyrrolidin-2-one (500 mL) was slowly added a solution of 5-{4-[(S)-2-(2,3-dihydro-1H-indol-3-yl)-ethyl]-piperazin-1-yl}-1H-indole (52.6 g, 0.15 mol) in butanone (600 mL). Potassium iodide (29.0 g, 0.17 mol) and potassium carbonate (31.4 g, 0.15 mol) was added and the resulting mixture was boiled under reflux for 1 h, filtered and poured onto a mixture of ice and brine. The aqueous phase was extracted with ethyl acetate, and the combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate/ethanol/triethylamine 70:5:5) to give crude title compound (30.6 g). This was precipitated from methanol by addition of hydrochloric acid in diethyl ether until pH was approximately 3. The compound was collected by filtration as a powder (7.7 g). Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7](C)=[C:6](I)[C:5]=1[O:13][CH3:14].[N+:16]([C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.CCOCC>[CH3:1][O:2][C:3]([C:4]1[C:5]([O:13][CH3:14])=[C:6]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:24]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:15]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(Cl)c(C)c(I)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc(Cl)cc(-c2cccc([N+](=O)[O-])c2)c1OC

Procedure:
To a solution of methyl,5-chloro-3-iodo-2-methoxybenzoic acid methyl ester (0.80 g, 2.5 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.085 g, 0.074 mmol) in toluene (12 mL) was added 3-nitrobenzene-boronic acid (0.45 g, 2.7 mmol) dissolved in 1 mL of ethanol. Aqueous 2 N K2CO3 (2.7 mL, 5.4 mmol) was added and the mixture was heated to reflux for 18 h. The mixture was diluted with ether, washed with 3:1 saturated NaHCO3/conc. ammonium hydroxide, 0.1 M EDTA, saturated NaCl, and dried (Na2SO4). The solvent was removed under reduced pressure, and the crude material was purified by silica gel chromatography employing a gradient elution of 60 to 75% CH2Cl2/hexane. 5-Chloro-2-methoxy-3′-nitro-biphenyl-3-carboxylic acid methyl ester 43 was obtained as an amber waxy solid (0.59 g, 75% yield).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and p-anisoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methoxy-benzamide (0.8 g, 90%) as a white solid: mp 289-291° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.32-2.65 (m, 2H), 2.86-3.00 (m, 1H), 3.81 (s, 3H, OCH3), 4.40-4.60 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 7.02 (d, J=8.6 Hz, 2H, Ar), 7.46-7.64 (m, 3H, Ar), 7.85 (d, J=8.7 Hz, 2H, Ar), 8.93 (t, J=5.3 Hz, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.58, 31.17, 46.28, 51.59, 55.32, 113.51, 121.57, 126.25, 128.27, 129.06, 130.64, 131.58, 134.93, 140.07, 161.63, 165.81, 168.07, 170.98, 172.81; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.51; H, 5.04; N, 10.09.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)cc(C)cc21
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2c1cc(C)c([N+](=O)[O-])c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4,6-dimethylindoline (2.6 g) was dissolved in acetic anhydride (35 ml), and nitric acid (d=1.5, 0.92 ml) dissolved in acetic anhydride (15 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for one hour and poured into ice water. Saturated aqueous sodium hydrogencarbonate was added to neutralize the mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent:chloroform-methanol=1:0-100:1) to give 2.4 g of the title compound (2).
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of adenine (5) (5.00 g, 37.0 mmol) in dry DMF (120 mL) was added NaH (1.77 g, 44.4 mmol) at room temperature. The reaction mixture was stirred for 30 min and the resulting white suspension was warmed to 60° C. for an additional 30 min. Benzyl bromide (7.59 g, 44.4 mmol) was added and the mixture was stirred for 24 h at 60° C. TLC of the reaction mixture indicated the formation of two products. DMF was distilled off under reduced pressure and the resulting residue was treated with water (20 mL). The white solid that separated out, was filtered and dried under vacuum. Separation and purification was through flash column chromatography using CHCl3::MeOH (9:1) for elution. 9-Benzyladenine: yield 5.5 g. (66%); mp 231-232° C.; 1H NMR (DMSO-d6,: δ 5.38 (s, 2H, CH2), 7.29-7.33 (m, 7H, Ar—H and NH2), 8.17 (s, 1H, purine C8—H), 8.28 (s, 1H, purine C2—H). 7-Benzyladenine: yield 1.8 g. (21%). Mp 252-255° C. 1H NMR (DMSO-d6): δ 5.53 (s, 2H, CH2), 7.29-7.48 (m, 5H, Ar—H), 7.81 (s, 1H, purine C8—H), 8.0-8.1 (br, 2H, NH2), 8.6 (s, 1H, purine C2—H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>C(OCC)C>[F:12][C:9]1([F:13])[CH2:10][CH2:11][CH:6]([CH2:4][OH:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCC(F)(F)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4,4-difluorocyclohexanecarboxylic acid ethyl ester (0.50 g, 2.6 mmol) cooled to 0° C. in diethyl ether (20 mL) was added dropwise 1.0 M lithium aluminum hydride in tetrahydrofuran (2.6 mL, 2.6 mmol). The reaction was stirred for 30 min. The reaction was carefully quenched with water (2.0 mL) followed by the addition of 1.0 N NaOH (2 mL). The reaction mixture was stirred for 10 min, filtered through a pad of celite and washed with diethyl ether (20 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound as a crude oil (465 mg) which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CS(C)=O.[OH-].[Na+].[CH:16]([O:18][CH2:19][CH2:20]Cl)=[CH2:17]>O>[CH:16]([O:18][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)=[CH2:17]
Reactant: OCc1ccc(O)cc1
Reactant: C=COCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=COCCOc1ccc(CO)cc1
Yield: 55 %

Procedure:
In a 500 mL three-neck round-bottom flask equipped with an overhead stirrer and a reflux condenser were placed 21.7 g of 4-hydroxybenzyl alcohol, and 65 mL of dimethyl sulfoxide. To this solution was slowly added 6.99 g of NaOH, while keeping the temperature below 45° C. After the solution was completed, 20.4 mL of 2-chloroethyl vinyl ether was added slowly while keeping the temperature at 60° C. The reaction mixture was heated at this temperature for 2 hours, and the progress of the reaction was followed by GC. After cooling, the reaction product was added dropwise to 500 mL of water. The precipitated product was then filtered and redissolved in 500 mL of diethyl ether. The ether layer was washed one time with 100 mL of 3% aqueous NaOH and two times with 100 mL portions of distilled water. The ether layer was dried with sodium sulfate, filtered and evaporated. A 55% yield of 2-(4-hydroxymethyl-phenoxy)ethyl vinyl ether was obtained.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH:29]1([C:32]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)=O)[CH2:31][CH2:30]1>CCOCC>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[CH:2][O:3][CH3:4])=[CH:35][CH:36]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC=C(c1ccc(Cl)cc1)C1CC1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 59.4 %

Procedure:
A solution of methoxymethyl triphenyl phosphonium chloride (20.5 g, 0.060 mol) in ether is cooled to −60° C., treated with a 2.5 M solution of butyllithium in hexanes (25.2 mL, 0.063 mol), warmed to and stirred at 0-5° C. for 90 minutes, recooled to −60° C., treated with a solution of 4-chlorophenyl cyclopropyl ketone (9.03 g, 0.050 mol) in ether, warmed to and stirred at room temperature overnight, quenched with ethyl acetate and 2 N hydrochloric acid, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:9) gives the title product as an oil (6.2 g, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:20][CH2:21][CH2:22][O:23][C:24]1[C:31]([CH3:32])=[CH:30][C:27]([CH:28]=O)=[CH:26][C:25]=1[CH3:33]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=3)[N:1]=[C:28]2[C:27]2[CH:30]=[C:31]([CH3:32])[C:24]([O:23][CH2:22][CH2:21][OH:20])=[C:25]([CH3:33])[CH:26]=2)=[CH:12][CH:11]=1
Reactant: COc1cccc(C(=O)Nc2ccc(Br)cc2)c1N
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: COc1cccc2c(=O)n(-c3ccc(Br)cc3)c(-c3cc(C)c(OCCO)c(C)c3)nc12

Procedure:
To a solution of 2-amino-N-(4-bromo-phenyl)-3-methoxy-benzamide (0.600 g, 1.86 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.360 g, 1.86 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.750 g, 5.58 mmol). The reaction mixture was stirred at reflux for 16 hours under nitrogen. The solvent was removed and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). After separation, the organic phase was further backwashed with water (100 mL), then brine (100 mL), dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give the title compound as a white solid. Yield: 250 mg (27%). MP 100-102° C. 1H-NMR (400 Hz, CDCl3): δ 7.90 (d, 1H), 7.47 (m, 3H), 7.25 (m, 1H), 7.03 (d, 2H), 7.00 (s, 2H), 4.02 (s, 3H), 3.91 (m, 2H), 3.80 (t, 2H), 2.15 (s, 6H), 2.06 (t, 1H). MS (ES+) m/z: 497.41 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10]NC.[C:30]([Cu])#[N:31].O.[CH3:34][N:35](C=O)C>>[OH:29][C:26]1[CH:27]=[CH:28][C:23]([C:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][NH:31][CH3:30])=[C:2]([CH:3]=2)[C:34]#[N:35])=[C:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:15][CH3:16])=[CH:24][CH:25]=1
Reactant: N#C[Cu]
Reactant: CN(C)C=O
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)c(Br)c1)c1ccccc1
Solvent: O
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)c(C#N)c1)c1ccccc1
Temperature: 120 °C
Yield: 6 %

Procedure:
To a stirred solution of 4-(1-(3-bromo-4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-1-enyl)phenol (150 mg, 1.0 eq) in 5 mL DMF was added CuCN (36 mg, 1.2 eq) at rt. The mixture was then heated at 120° C. overnight, poured into water, and the resulting mixture was extracted with EtOAc. The extract was washed with water and brine, dried, concentrated, and purified by column chromatography with CH2Cl2:MeOH(NH3)=1:1 to give the desired product (10 mg, 6% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 6.99-7.21 (m, 7H), 6.90 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.49 (d, J=8.8 Hz, 1H), 4.32 (t, J=5.6 Hz, 1H), 4.20 (t, J=5.2 Hz, 1H), 3.46 (t, J=5.6 Hz, 1H), 3.30 (t, J=5.2 Hz, 1H), 3.29 (s, 3H), 2.40-2.50 (m, 2H), 0.90 (t, J=5.6 Hz, 3H); m/z=399 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[C:16]3[N:17]([N:21]=[C:22](Cl)[N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]2[C:16]3[N:17]([N:21]=[C:22]([NH:38][C:35]4[CH:34]=[CH:33][C:32]([N:29]5[CH2:28][CH2:27][N:26]([CH3:25])[CH2:31][CH2:30]5)=[CH:37][CH:36]=4)[N:23]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2cccn3nc(Cl)nc23)C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2ccc(Nc3nc4c(NCC5CCN(C(=O)OC(C)(C)C)C5)cccn4n3)cc2)CC1

Procedure:
3-[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and 3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (475.0 mg, 2.372 mmol) in a manner analogous to Example 2d. Product isolated as pale yellow viscous oil (0.544 g, 72%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.88 (d, J=6.6 Hz, 1H), 6.89 (t, J=7.3 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 4.98 (br s, 1H), 3.65-3.08 (m, 6H), 2.64-2.51 (m, 1H), 2.15-2.05 (m, 1H), 1.80-1.65 (m, 1H), 1.47 (s, 9H). 163 b) 3-({2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from 3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (500.0 mg, 1.421 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (300.0 mg, 1.568 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (78.0 mg, 0.143 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.284 g, 39%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (d, J=6.5 Hz, 1H), 7.46 (d, J=8.9 Hz, 2H), 6.96 (d, J=8.9 Hz, 2H), 6.71 (t, J=7.3 Hz, 1H), 6.59 (s, 1H), 6.35 (d, J=7.7 Hz, 1H), 4.75 (br s, 1H), 3.66-3.05 (m, 10H), 2.63-2.52 (m, 5H), 2.36 (s, 3H), 2.15-2.04 (m, 1H), 1.80-1.65 (m, 1H), 1.46 (s, 9H). MS=507 (MH)+.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])[CH:28]=[CH:29][C:30]=1[C:31]([O:33][CH3:34])=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][C:28]([Br:1])=[C:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=2[F:42])[CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2F)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Br)c(-c2ccc(F)cc2F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 141.6 %

Procedure:
Dibromoisocyanuric acid (15.9 g) was added at room temperature to a DMF (150 mL) solution of methyl 3-(benzyloxy)-2′,4′-difluorobiphenyl-4-carboxylate (28.0 g), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (34.0 g)