Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:4]=2[CH:3]=1.C(O)(=O)/C=C\C(O)=O.ClC1[N:36]=[N:35]C2CCNCC=2C=1.C1(CCC(Cl)=O)C=CC=CC=1>C(O)C>[NH:35]([C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:4]=2[CH:3]=1)[NH2:36]
Reactant: O=C(CCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: Clc1cc2c(nn1)CCNC2
Agent: O=C(Cl)CCc1ccccc1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCO
Product: NNc1cc2c(nn1)CCN(C(=O)CCc1ccccc1)C2

Procedure:
The 3-chloro-5,6,7,8-tetrahydro-6-(3-phenylpropionyl)pyrido[4,3-c]pyridazine, required as starting material, may be obtained in a manner analogous to that described in Example 8(g), from 28.6 g of 3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine maleate and 31.5 g of 3-phenylpropionyl chloride. M.P. 134°-137° from 95% ethanol.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[NH:10]1[CH2:15][CH2:14][CH:13]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][C:2]([NH2:1])([CH3:9])[CH3:8])[CH2:12][CH2:11]1
Reactant: CC(C)(N)CNCCN
Reactant: O=C1CCNCC1
Product: CC(C)(N)CNCCNC1CCNCC1

Procedure:
In a manner analogous to that described immediately hereinabove, by reacting N-(2-amino-2-methylpropyl)-1,2-ethanediamine with piperidin-4-one, it is reductively alkylated to yield N-(4-piperidyl)-N'-(2-amino-2-methyl-propyl)-1,2-ethanediamine; and, 2,2,6,6-piperidin-4-one is reductively alkylated to yield N-(2,2,6,6-tetramethyl-4-piperidyl)-N'-(2-amino-2-methylpropyl)-1,2-ethanediamine having the structure: ##STR15##
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[C:16]([C:20]1[C:29]2[C:24](=[CH:25][C:26]([O:34][CH3:35])=[C:27]([C:30](=O)[CH2:31][CH3:32])[CH:28]=2)[O:23][C:22]([CH3:37])([CH3:36])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[F:7]/[C:6](=[C:30](/[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:34][CH3:35])[O:23][C:22]([CH3:37])([CH3:36])[CH:21]=[C:20]2[C:16]([CH3:17])([CH3:19])[CH3:18])\[CH2:31][CH3:32])/[C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCC(=O)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/CC)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (431 mg, 1.78 mmol) and 1-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-propan-1-one (Compound 59, 107 mg, 0.35 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 5% ethyl acetate in hexanes)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9](=O)[C@@H:10]([NH2:21])[CH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][CH3:14]>O1CCCC1>[NH2:21][C@@H:10]([CH2:11][C@@H:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][CH3:14])[CH2:9][OH:8]
Reactant: CC[C@@H](C[C@H](N)C(=O)OC)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](C[C@H](N)CO)c1ccccc1
Reaction time: 16 h

Procedure:
To a suspension of lithium aluminum hydride (121 mg, 3.18 mmol) in tetrahydrofuran (8 ml) was added a solution of (2S,4S)-2-amino-4-phenyl-hexanoic acid methyl ester (320 mg, 1.45 mmol) in tetrahydrofuran (10 ml) and the mixture was stirred for 16 hours. The reaction was quenched by dropwise addition of ethyl acetate, then acidified to pH 5 by addition of hydrochloric acid and then made basic by addition of saturated aqueous sodium bicarbonate solution. The mixture was taken up in ethyl acetate/tetrahydrofuran (1:1), the phases were separated and the organic phase was washed sequentially with water and with saturated brine. The organic phase was then dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/MeOH) to yield a yellow oil, (116 mg, 42%); MS (ISP): 194.4 ([M+H]+).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:34])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: BrC(Br)(Br)Br
Reactant: CCCc1ccc(CCCO)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
3-(4-Propylphenyl)propanol (s3) (11.0 g) and triphenylphosphine (24.3 g) were dissolved in methylene chloride (200 ml). Carbon tetrabromide (24.5 g) in methylene chloride (100 ml) solution was slowly added dropwise to the solution, and the mixture was stirred at room temperature for another 3 hours. The reaction mixture was treated with a saturated aqueous solution of sodium hydrogencarbonate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a residue, pale yellow solids. The residue was purified by column chromatography with heptane as an eluent and silica gel as a stationary phase powder to give 3-(4-propylphenyl)bromopropane (s4) (14.5 g). The yield based on the compound (s3) was 97.4%.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:21][C:22]1([CH3:27])OCC[O:23]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[C:5]1[CH2:18][CH2:19][CH3:20].Cl>>[NH2:17][C:8]1[C:7]2[N:6]=[C:5]([CH2:18][CH2:19][CH3:20])[N:4]([CH2:3][C:2]([CH3:28])([CH3:1])[CH2:21][C:22](=[O:23])[CH3:27])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Agent: Cl
Product: CCCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)CC(C)=O

Procedure:
By the general method of Example 11, 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine was hydrolyzed with aqueous hydrochloric acid to provide 5-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one as a light brown solid after recrystallization from aqueous acetonitrile, mp 178-180° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:4]=1[C:11]1[N:16]2[N:17]=[C:18]([S:28][CH3:29])[C:19]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:15]2[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1.O>CN(C)C=O.C(OCC)(=O)C>[CH:34]1([CH2:33][N:20]([C:19]2[C:18]([S:28][CH3:29])=[N:17][N:16]3[C:11]([C:4]4[C:5]([CH3:10])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=4[O:2][CH3:1])=[CH:12][CH:13]=[CH:14][C:15]=23)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:36][CH2:35]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NC(=O)OC(C)(C)C)c(SC)nn12
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C(=O)OC(C)(C)C)c(SC)nn12
Temperature: 40 °C
Reaction time: 1 h

Procedure:
After dissolving tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (400 mg) in N,N-dimethylformamide (5 mL), sodium hydride (60%, 58 mg) was added while cooling on ice, and then (bromomethyl)cyclopropane (111 μL) was added and the mixture was stirred for 1 hour at 40° C. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure to obtain crude tert-butyl N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate. This was dissolved in ethyl acetate (10 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (20 mL) was added, and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled off under reduced pressure to obtain the title compound (368 mg) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].Cl.[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)CC)C>O1CCOCC1>[ClH:1].[CH3:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:26][CH2:25]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: CN(C)C1CCNCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1
Yield: 19.8 %

Procedure:
First, 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one (7.0 g, 0.0243 mol) is suspended in anhydrous dioxan (150 ml) and refluxed for 3 hours after the addition of 4-(dimethylamino)piperidine hydrochloride (4.9 g, 0.0298 mol) and triethylamine (10.0 g, 0.099 mol). Then the mixture is concentrated in vacuo. The residue is made alkaline with sodium hydroxide and extracted exhaustively with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated. The highly viscous residue is taken up in dioxan, clarified with activated charcoal and mixed with ethereal hydrochloric acid solution. The colorless crystals (2.0 g) obtained melted 258° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)O)[S:8][C:6]=2[N:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:5]2[N:10]=[C:9]([CH:11]=[CH:12][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[S:8][C:6]=2[N:7]=1
Reactant: OC(Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1nc(N2CCOCC2)c2nc(C=Cc3ccccc3)sc2n1
Temperature: 120 °C
Reaction time: 24 h

Procedure:
To a suspension of 2-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-yl)-1-phenyl-ethanol (1.1 g, 2.9 mmol) in toluene (25 mL) was added p-toluenesulfonic acid (0.11 g, 0.58 mmol) and the resulting solution stirred at 120° C. for 24 h. The reaction mixture was concentrated in vacuo to give 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine as a crude yellow solid which was used without purification. To a suspension of 5-chloro-7-morpholin-4-yl-2-styryl-thiazolo[5,4-d]pyrimidine (2.9 mmol) in THF (9 mL), acetonitrile (9 mL) and H2O (3 mL) were added ruthenium(III) chloride (18 mg, 0.081 mmol) and periodic acid (1.3 g, 5.80 mmol). The resulting solution was stirred at RT for 2 h, then partitioned between EtOAc and an aqueous solution of sodium thiosulfate. The aqueous layer was isolated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by column chromatography to give the title compound as a yellow solid (0.34 g, 42%).
Reaction SMILES: C(OC(N1C[C@H](O)C[C@@H]1C(O)=O)=O)(C)(C)C.[CH2:17]([N:20]([CH2:33][CH2:34][CH3:35])[C:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28]C)=[O:27])=[O:22])[CH2:18][CH3:19].COC(C1C=C(C=CC=1)C(O)=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)CC>CN(C=O)C.C(OCC)(=O)C>[CH2:33]([N:20]([CH2:17][CH2:18][CH3:19])[C:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([OH:28])=[O:27])=[O:22])[CH2:34][CH3:35]
Reactant: CCCN(CCC)C(=O)c1cccc(C(=O)OC)c1
Agent: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC(=O)c1cccc(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCNCCC
Product: CCCN(CCC)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step E (1): Methyl 3-(dipropylcarbamoyl)benzoate. To a solution of 3-(methoxycarbonyl)benzoic acid (6.7 g, 37.2 mmol) in DMF (60 mL) was added HATU (17.0 g, 44.7 mmol) and dipropylamine (9.4 g, 93 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (600 mL) was added and the mixture was washed with H2O, dried and concentrated to give the title compound was used in the next step without purification.
Reaction SMILES: [C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[C:11](=[O:12])[CH:10]=[CH:9][CH2:8][CH2:7]1)([O:3][CH3:4])=[O:2].S(C)C.[CH:18]([Mg]Br)=[CH2:19]>C1COCC1>[C:1]([CH2:5][C:6]1([CH2:13][CH3:14])[CH2:7][CH2:8][CH:9]([CH:18]=[CH2:19])[CH2:10][C:11]1=[O:12])([O:3][CH3:4])=[O:2]
Reactant: CCC1(CC(=O)OC)CCC=CC1=O
Reactant: C=C[Mg]Br
Solvent: CSC
Solvent: C1CCOC1
Product: C=CC1CCC(CC)(CC(=O)OC)C(=O)C1
Yield: 69 %

Procedure:
The enone, 6-carbomethoxymethyl-6-ethyl-2-cyclohexen-1-one, prepared by the process of Step (c) (58.1 mmol, 11.4 g), 5.81 mmol (1.194 g) of CuBr.Me2S and 11.7 ml of Me2S were stirred in 176 ml of THF at -40° C. under nitrogen and treated with 58.1 mmol (58.1 ml of 1M solution in THF) of vinylmagnesium bromide added dropwise over 45 minutes. The reaction was then quenched with 200 ml of 1M HCl (aq.) and extracted with 5×100 ml of petroleum ether. Drying (MgSO4) and flash chromatography afforded 8.96 g (39.9 mmol, 69% pale yellow oil) of product as a mixture of diastereomers. The diastereomers (56:44 ratio) were separated by preparative HPLC on a Prep 500A using a brand of silica gel available from Waters Associates, Milford, Ma., and designated "more polar isomer" and "less polar isomer."
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)(=O)=O.[Cl:21][C:22]1[C:23](O)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[Cl:21][C:22]1[C:23]([O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:12]3[N:17]=[CH:16][C:15]([CH2:18][CH2:19][CH3:20])=[CH:14][N:13]=3)[CH2:8][CH2:7]2)=[CH:24][C:25](=[O:28])[NH:26][CH:27]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)[nH]cc3Cl)CC2)nc1
Temperature: 120 °C

Procedure:
A mixture of 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate (800 mg, 2.67 mmol), 5-chloro-4-hydroxypyridin-2(1H)-one (389 mg, 2.67 mmol, AK Scientific) and cesium carbonate (2612 mg, 8.02 mmol) in DMF (20 mL) was heated at 120° C. for 6 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and washed with H2O (3×). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The residue was purified by flash chromatography (SiO2, O-10% MeOH/CH2Cl2) to give the desired product as a yellow solid. MS (ESI) 379 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:24])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N:15][C:14]=2[CH:23]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30].CN(C)C=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C:8](=[O:24])[C:9]([C:10]1[CH:11]=[CH:12][C:13]2[O:17][C:16]([CH2:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[N:15][C:14]=2[CH:23]=1)=[CH:28][N:29]([CH3:31])[CH3:30]
Reactant: Cc1nsc(NC(=O)Cc2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nsc(NC(=O)C(=CN(C)C)c2ccc3oc(CC(C)(C)C)nc3c2)c1Cl
Temperature: 110 °C
Yield: 27.3 %

Procedure:
N-(4-Choro-3-methylisothiazol-5-yl)-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (2.5 g, 0.0066 mole) [prepared as in Example 1] and N,N-dimethylformamide dimethylacetal (1.5 g, 0.013 mole) were added to a mixture of N,N-dimethylformamide (5 ml) and toluene (20 ml) and the resulting mixture was heated to 110° C. for 4 hours. The mixture as cooled to room temperature and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and washed sequentially with brine and water, dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo. The residue was further purified by flash column chromatography, eluting with ethyl acetate:hexane at 1:1 by volume. Further flash column chromatography, eluting with ethyl acetate:dichloromethane at 1:9 by volume gave N-(4-chloro-3-methylisothiazol-5-yl)-α-[(dimethylamino)methylene]-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]acetamide (0.78 g) as a single geometrical isomer.
Reaction SMILES: N1(CC2N=CC([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:27]4[C:32]([Cl:33])=[C:31]([O:34][CH3:35])[CH:30]=[C:29]([O:36][CH3:37])[C:28]=4[Cl:38])=[C:21]4[C:26]=3[N:25]=[CH:24][CH:23]=[CH:22]4)=[O:16])=CC=2)CCNCC1.N[C:40]1[N:45]=[CH:44][C:43]([CH2:46][N:47]([CH3:53])[CH2:48][CH2:49][N:50]([CH3:52])[CH3:51])=[CH:42][CH:41]=1>C(Cl)Cl.CO>[CH3:51][N:50]([CH3:52])[CH2:49][CH2:48][N:47]([CH2:46][C:43]1[CH:42]=[CH:41][C:40]([NH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:27]3[C:28]([Cl:38])=[C:29]([O:36][CH3:37])[CH:30]=[C:31]([O:34][CH3:35])[C:32]=3[Cl:33])=[C:21]3[C:26]=2[N:25]=[CH:24][CH:23]=[CH:22]3)=[O:16])=[N:45][CH:44]=1)[CH3:53]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)nc3)c3ncccc23)c1Cl
Reactant: CN(C)CCN(C)Cc1ccc(N)nc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN(C)CCN(C)C)cn3)c3ncccc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 5-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoline-8-carboxylic acid (6-piperazin-1-ylmethyl-pyridin-3-yl)-amide (Exam pie 170), N-(6-amino-pyridin-3-ylmethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (prepared as described in Example 26 but using N,N,N′-trimethyl-ethane-1,2-diamine in Step 26.2), and stirring the reaction mixture for 14 h at rt. Title compound: ESI-MS: 568.0 [M+H]+; TLC: Rf=0.15 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](Cl)=[O:18])[CH3:13]>CN(C)C(=O)C.C(OCC)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[O:9])(=[O:10])[NH2:11])=[O:18])[CH3:13]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CCOC(=O)CC(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-benzenesulfonamide (5 g, 29 mmol) was dissolved in N,N-dimethylacetamide (25 mL) and diethyl ether (25 mL). Ethyl-3-chloro-3-oxo-propionate (4.6 g, 30.45 mmol) was added into the above reaction solution. The reaction mixture was stirred at 25° C. for 3 h. The product started to precipitate and was collected by vacuum filtration. The solid was dissolved in ethyl acetate (200 mL) and extracted with water (200 mL). The aqueous layer was back-extracted with ethyl acetate (200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, N-(2-sulfamoyl-phenyl)-malonamic acid ethyl ester, as a white solid, which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 1.23 (3H, t, J=7.0 Hz), 3.61 (2H, s), 4.14 (2H, quartet, J=7.0 Hz), 7.29-7.33 (1H, m), 7.53 (2H, bs), 7.56-7.60 (1H, m), 7.84-7.86 (1H, m), 7.97-7.99 (1H, m), 9.54 (1H, bs). LC-MS (ESI) calcd for C11H14N2O5S 286.06, found 287.1 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[CH:6]=[CH:7][C:8]3[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:9]=3[C:10](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]=2[CH:3]=1.C1C(=O)N([Br:31])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:21][C:19]1[CH:18]=[CH:17][C:9]2[C:10](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:4]3[CH:3]=[C:2]([F:1])[CH:23]=[CH:22][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:20]=1
Reactant: CCOC(=O)C=C1c2ccc(C)cc2C=Cc2ccc(F)cc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=C1c2ccc(CBr)cc2C=Cc2ccc(F)cc21

Procedure:
Compound 4-a (0.24 g) was dissolved in 20 ml of carbon tetrachloride, and 0.14 g of NBS and catalytic amount of benzoyl peroxide were added to the solution, followed by heating under reflux for 4 hours. After cooling, insoluble matters were filtered off and the filtrate was diluted with dichloromethane. The dilution of the filtrate was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained product was unstable and subjected to the subsequent reaction without particular purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:22]2[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(Cl)n1
Reactant: N#Cc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccnc1-c1cccc(Cl)n1
Yield: 71.9 %

Procedure:
To a degassed solution of 2-chloro-6-tributylstannylpyridine (prepared according to S. Choppin et al. in Org. Lett., 2000, 2, 803-5) (600 mg, 1.49 mmol) and 2-chloro-3-cyanopyridine (412 mg, 2.98 mmol) in THF was added tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.05 mmol) and the mixture heated at reflux for 96 hours. The solvent was removed under reduced pressure and the crude product chromatographed on silica, on a gradient of dichloromethane to 2% methanol in dichloromethane, to afford 6′-chloro-2,2′-bipyridinyl-3-carbonitrile as a white solid (231 mg): δH (400 MHz, d6-DMSO) 7.71-7.74 (2H, m), 8.11 (1H, t, J 7.8), 8.20-8.23 (1H, m), 8.48 (1H, dd, J 1.8, 8.0), 8.97 (1H, dd, J 1.8, 4.9); m/z (ES+) 216, 218 (M++H).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]1=[O:13].[NH3:14]>O1CCCC1>[OH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:4](=[N:3][O:2][CH3:1])[C:5]([NH2:14])=[O:13]
Reactant: N
Reactant: CON=C1C(=O)Oc2ccccc21
Solvent: C1CCOC1
Product: CON=C(C(N)=O)c1ccccc1O
Yield: 36.4 %

Procedure:
5 g (0.028 mol) of benzofuran-2,3-dione 3-(O-methyl-oxime) (WO-A 9524396) in 100 ml of tetrahydrofuran are stirred with 20 ml of 25% strength aqueous ammonia solution at 20° C. for 2 hours. The solvent is then distilled off under reduced pressure, the residue is poured onto water and extracted with ethyl acetate, the organic is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethanol, affording 2 g (36.4% of theory) of 2-(2-hydroxy-phenyl)-2-methoxyimino-acetamide.