Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[O:16][CH3:17])[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(O)C>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([O:16][CH3:17])=[C:9]([C:4]2[N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Cl:18])=[CH:20][CH:21]=3)[N:7]=[C:6]([NH2:8])[CH:5]=2)[CH:14]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(Cl)n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(Cl)cc2)n1

Procedure:
To a stirred suspension of the hydrochloride salt of 2-chloro-6-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.023 g, 0.075 mmol) in ethanol (7.0 ml) was added 4-chloroaniline (0.025 g, 0.20 mmol). The mixture was stirred under reflux for 6 hours. After evaporation of the solvent under reduced pressure, the residue was treated with hydrochloric acid (1.0 M, 10 ml) and stirred for 30 minutes. Filtration provided the hydrochloride salt of 6-(5-chloro-2-methoxy-phenyl)-N*2*-(4-chloro-phenyl)-pyrimidine-2,4-diamine which was treated with methanol (10 ml) and stirred while a solution of sodium carbonate in water (1.0 M, 1 ml) was added. After stirring for 1 hour, solvents were evaporated under reduced pressure. The residual solid was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.019 g, 70% yield) as a white powder. 1H NMR (CDCl3) δ 4.80 (s, 2H, NH2), 6.62 (s, 1H, Ar), 6.94 (d, 1H, J=8.8 Hz, Ar), 6.98 (s, 1H, NH), 7.27-7.30 (m, 2H, Ar), 7.36 (dd, 1H, J=8.8 Hz, J=2.8 Hz, Ar), 7.61-7.63 (m, 2H, Ar), 7.93 (d, 1H, J=2.8 Hz, Ar),
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]2)[NH:20][C:19]3=[O:29])=[CH:34][CH:33]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc(Cl)cc4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 4-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.02 (s, 1H), 12.95 (s, 1H), 8.99 (s, 1H), 8.28 (s, 2H), 8.05 (d, J=8.5 Hz, 1H), 7.81 (s, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.49 (tdd, J=7.1, 5.1, 1.7 Hz, 1H), 7.40-7.34 (m, 2H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]([CH3:22])([CH3:21])[C:11](=[O:20])[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.O>CS(C)=O>[C:10]([C:11]1([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:4][O:20]1)([CH3:22])([CH3:21])[CH3:9]
Reactant: CC(C)(C)C(=O)COC1CCCCO1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)C1(COC2CCCCO2)CO1
Temperature: 10 °C
Yield: 93.1 %

Procedure:
880 ml of absolute dimethylsulphoxide are added dropwise to a mixture of 38.2 g (1.27 mols) of sodium hydride (80% strength) and 271.5 g (1.23 mols) tri-methyl-oxosulphonium iodide at 10° C. under a nitrogen atmosphere, with stirring. The mixture is subsequently stirred for a further hour at room temperature and is then cooled to 10° C., and a solution of 219 g (1.1 mols) of 3,3-dimethyl-1-(tetrahydro-2H-pyran-2-yloxy)-butan-2-one in 250 ml of absolute dimethylsulphoxide is added dropwise at this temperature. The reaction mixture is stirred at room temperature for 48 hours and then poured into water. The mixture is extracted with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by stripping off the diluent under reduced pressure. 219.4 g (94% of theory) of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxymethyl) oxirane are obtained in this manner.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3ccccc3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=0.92 min; [M+H]+=393.99.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14](=[O:16])[N:13]=[CH:12][NH:11][C:10]=3[S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([C:7]2[C:15]3[C:14]([O:16][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1nc[nH]c2scc(-c3ccccc3)c12
Reactant: CC(=O)Nc1cccc(OCCCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(OCCCOc2ncnc3scc(-c4ccccc4)c23)c1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of 5-phenylthieno[2,3-d]pyrimidin-4(1H)-one (0.023 g, 0.10 mmol), N-[3-(3-bromopropoxy)phenyl]acetamide (0.0274 g, 0.10 mmol), potassium carbonate (0.0418 g, 0.30 mmol) and N,N-dimethylformamide (1.0 mL) was heated to 90° C. for 6 h. The reaction was then allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate (30 mL), water (30 mL) was added, and the organic layer was separated, Concentration, followed by followed by silica gel column chromatography purification (using 1.50% methanol in 1:1 ethyl acetate/hexane and ammonia (0.03%) as eluent) afforded N-(3-{3-[(5-phenylthieno[2,3-d]pyrimidin-4-yl)oxy]propoxy}phenyl)acetamide in 66% yield. N-{4-[3-(4-oxo-5-phenylthieno[2,3-d]pyrimidin-1(4H)-yl)propoxy]phenyl}acetamide was also formed in 12% yield during the reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=3[Cl:18])[NH2:14])=[N:8][C:5]2=[N:6][CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:14][C:24]([C:20]4[O:19][CH:23]=[CH:22][CH:21]=4)=[O:25])[CH:15]=[CH:16][C:17]=3[Cl:18])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a suspension of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (15 g, 46.36 mmol, 1.00 equiv) in dichloromethane (150 mL) was added furan-2-carbonyl chloride (9.1 g, 69.72 mmol, 1.50 equiv) in a bath of ice and stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of methanol and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2) to give 8.9 g (46%) of N-(3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide (I-2) as a light yellow solid. 1H-NMR: (DMSO, 300 MHz): 13.09-13.79 (m, 1H), 10.53 (s, 1H), 8.51 (s, 1H), 8.36 (brs, 2H), 7.98-8.02 (m, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.40 (d, J=3.3 Hz, 1H), 6.74 (dd, J=3.3, 1.8 Hz, 1H). MS M/Z=419 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.[NH2:10][NH2:11]>C(O)(C)C>[F:1][C:2]1[N:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(F)n1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1cccc(F)n1
Yield: 76.8 %

Procedure:
2,6-Difluoropyridine (25 g), isopropyl alcohol (100 ml) and hydrazine hydrate (40 ml) were mixed and refluxed with heating for 3 hours. The isopropyl alcohol was evaporated under reduced pressure, and the residue was added with water. The deposited crystals were collected by filtration, washed with water and dried to obtain 6-fluoro-2-hydrazinopyridine (21.2 g, yield: 76.8%). Coloration was observed during drying, and accordingly, the product was used for the next reaction immediately after the drying.
Reaction SMILES: [NH:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22](Cl)=[O:23]>>[CH3:19][C:20]([CH3:26])([CH3:25])[CH2:21][C:22]([N:1]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:23]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: C1COCCOCCOCCOCCOCCN1
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16-pentaoxacyclooctadecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: Cl[C:2]1[N:7]([CH:8]([CH3:10])[CH3:9])[S:6](=[O:12])(=[O:11])[N:5]=[C:4]([O:13][CH3:14])[N:3]=1.C(N(CC)CC)C.[CH2:22]([OH:24])[CH3:23]>>[CH:8]([N:7]1[S:6](=[O:12])(=[O:11])[N:5]=[C:4]([O:13][CH3:14])[N:3]=[C:2]1[O:24][CH2:22][CH3:23])([CH3:10])[CH3:9]
Reactant: COC1=NS(=O)(=O)N(C(C)C)C(Cl)=N1
Reactant: CCO
Solvent: CCN(CC)CC
Product: CCOC1=NC(OC)=NS(=O)(=O)N1C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28.7 parts by weight of 5-chloro-6-isopropyl-3- methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide were added, a little at a time, in the course of 10 minutes, to a stirred mixture of 12.2 parts of triethylamine and 90 parts of absolute ethanol at 20°-25° C. After 3 hours' stirring at 25° C., the reaction mixture was evaporated down under reduced pressure, the residue was taken up in methylene chloride and the solution was washed with 10% strength sodium carbonate solution. After drying over magnesium sulfate, chromatography over alumina and evaporating down under reduced presure, 24 parts of 6-isopropyl-33-methoxy-5-ethoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 81°-85° C. were obtained.
Reaction SMILES: [NH3:1].Cl[C:3]1([C:16]2[C:17]([O:22][CH2:23][CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][C:4]1=[O:15].[Na+].[Cl-]>ClCCl>[NH2:1][C:3]1([C:16]2[C:17]([O:22][CH2:23][CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][C:4]1=[O:15]
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2cc(F)c(C#N)cc21
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ncccc1C1(N)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.4 ml (17.0 mmol) of a 7N methanolic ammonia solution were added dropwise to a cooled solution of 1.13 g (3.41 mmol) of 3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 20 ml of dichloromethane under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was mixed with saturated NaCl solution and extracted with ethyl acetate (3×). The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. The residue was mixed with 20 ml of diethyl ether. After stirring for 5 min, a white solid precipitated and was filtered off and dried in a vacuum oven. 800 mg of the title compound were obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][N:5]=[C:4]2[NH:12][CH:13]=[CH:14][C:3]=12.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Na+]>CO>[C:15]1([N:21]2[C:8](=[O:10])[C:7]3[C:2]([C:3]4[CH:14]=[CH:13][NH:12][C:4]=4[NH:5][CH:6]=3)=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: COC(=O)c1cnc2[nH]ccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1c2c[nH]c3[nH]ccc3c-2nn1-c1ccccc1
Temperature: 90 °C

Procedure:
A suspension of 1 equivalent of compound 15 and 10 equivalents of phenyl hydrazine was heated to 90° C. for 16 hours. Water was added to the reaction mixture at room temperature and decanted to remove the excess phenyl hydrazine. The crude reaction mixture was dissolved in MeOH and 0.1 N NaOH (2:1, 0.033 M) and stirred for 3.5 hours before concentrating to dryness. Purification by column chromatography afforded the title compound 16 as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.43-6.72 (m, 1H) 7.04-7.28 (m, 1H) 7.37-7.56 (m, 4H) 7.84-8.13 (m, 2H) 8.33-8.55 (m, 1H) 11.99 (s, 1H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:5]=1[C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH2:32][CH3:33])=[CH:24][C:23]=2[O:34][CH3:35])=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])=[O:7].Cl>O.O1CCCC1>[F:3][C:4]1[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:5]=1[C:6]([NH:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:23]([O:34][CH3:35])=[CH:24][C:25]([CH2:30][O:31][CH2:32][CH3:33])=[CH:26][C:27]=2[O:28][CH3:29])=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)OCC)cc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(OC)c1
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of sodium hydroxide (2.9 g) in water-tetrahydrofuran (317 ml-159 ml) was added ethyl (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionate (31.7 g) at 15° C. and the mixture was stirred for 4 hours at the same temperature. After neutralizing with 1N HCl, the organic solvent was removed in vacuo. The aqueous layer was cooled, the crystalline precipitates were collected by filtration and recrystallized from ethanol-water to yield (αS)-α-[(2,6-difluorobenzoyl)amino]-4′-ethoxymethyl-2′,6′-dimethoxy(1,1′-biphenyl)-4-propionic acid (28.8 g).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH:8]([CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:6][CH:5]=1)[CH2:19][C:20]([OH:22])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1-benzyl 4-tert-butyl 2-(biphenyl-4-ylmethyl)succinate (90 mg, 0.209 mmol) in DCM (1 ml), TFA (0.322 ml, 4.18 mmol) was added. The reaction mixture was allowed to stir for 1 hour, and then concentrated under reduced pressure to give 4-(benzyloxy)-3-(biphenyl-4-ylmethyl)-4-oxobutanoic acid (78 mg); Retention time=1.48 minutes (condition B); MS (m−1)=373.2.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:26][OH:27])=[C:4]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[F:25])[CH:5]=[N:6][C:7]=1[CH3:8].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1>>[C:36]([C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[C:3]([CH2:26][OH:27])=[C:4]([CH2:9][NH:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:12]=3[F:25])[CH:5]=[N:6][C:7]=2[CH3:8])=[CH:31][CH:32]=1)#[N:37]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2F)c(CO)c1O
Product: Cc1ncc(CNc2ccc(-c3ccc(C#N)cc3)cc2F)c(CO)c1OCc1ccc(C#N)cc1
Yield: 33 %

Procedure:
The coupling of 4′-[(5-hydroxy-4-hydroxymethyl-6-methyl-pyridine-3-ylmethyl)-amino]-3′-fluoro-biphenyl-4-carbonitrile (61) (250 mg, 0.69 mmol) and α-bromo-p-tolunitrile (149 mg, 0.76 mmol), as described in Example 1, gave 4′-{[5-(4-cyano-benzyloxy)-4-hydroxymethyl-6-methyl-pyridin-3-ylmethyl]-amino}-3′-fluoro-biphenyl-4-carbonitrile (62) (109 mg, 33% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.Cl[CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(C(C)=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: Cc1nccn1-c1ccc(OCCO)cc1

Procedure:
4-(2-Methyl-1H-imidazol-1-yl)phenol (10.0g, 0.057 mole), 2-chloroethanol (13.88 g, 0.172 mole) and potassium carbonate (23.74 g, 0.172 mole) were combined in methyl ethyl ketone (200 ml) and heated at reflux temperature for four days. The solution was cooled and the solid filtered and rinsed with acetone. The filtrate was concentrated to a residue and the residue triturated with hot acetone (2×50 ml). The remaining solid (1.5 g) was dissolved in methylene chloride. Insoluble materials were removed by filtrateion, and the filtrate concentraed to obtain 0.50 g (4%), mp 125°-127° C. Proton NMR indicates that methylene chloride is present in the sample.
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:24]1[CH:25]=[C:26]([CH:40]=[CH:41][C:42]=1[CH3:43])[C:27]([NH:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.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>[CH3:43][C:42]1[CH:24]=[CH:25][C:26]([C:27]([NH:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[CH:32][N:31]=2)=[O:28])=[CH:40][C:41]=1[C:2]#[C:1][C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[C:6]2=[N:5][CH:4]=1
Reactant: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1I
Reactant: C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cc(C(F)(F)F)ccn2)cc1C#Cc1cnc2c(Nc3ccc(S(C)(=O)=O)cc3)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
A mixture of 3-ethynyl-N-(4-(methylsulfonyl) phenyl)imidazo[1,2-a]pyridin-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.170 mmol) of 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide, 0.009 g (0.008 mmol) of Pd(PPh3)4, 0.002 g (0.012 mmol) of Cul, and 0.04 mL (0.23 mmol) of diisopropylethylamine in 0.8 mL of DMF was stirred at ambient temperature overnight under an atmosphere of N2. The reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (triethylamine-treated silica gel; eluted with 10% EtOAc/hexanes to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](O)=[O:31]>>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:11]3[C:6]4[CH2:5][CH2:4][O:3][C:7]=4[CH:8]=[CH:9][CH:10]=3)[CH2:13][CH2:14]2)[CH2:25][CH2:24]1)=[O:31]
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1Cl

Procedure:
The title compound, white solid (97 mg, 78%), MS (ISP) m/z=501.1 [(M+H)+], mp 188° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 2,4-dichloro-benzoic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.C[S-:13].[Na+].Cl>CN(C)C(=O)C.C(OCC)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([SH:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Sc1ccc2ncccc2c1
Temperature: 150 °C

Procedure:
To a solution of 6-bromoquinoline (0.81 g, 3.89 mmol) in N,N-dimethylacetamide (4 mL) was added sodium methyl mercaptide (2.0 g, 28.5 mmol). The mixture was heated at 150° C. for 2 h. After cooling, the mixture was diluted with ethyl acetate, and neutralized with aqueous 1N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was directly used in the next step without further purification. (0.50 g, 79%) LCMS: (M+H)+=161.9.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:3]1[OH:26].[CH2:27](O)[CH3:28]>>[OH:26][C@H:3]1[C@H:2]([O:1][CH2:27][CH3:28])[C:11]2[C:10]([CH2:12][O:13][CH3:14])=[CH:9][N:8]3[C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCO
Reactant: COCc1cn2c(C)c(C)nc2c2c1[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N2
Product: CCO[C@@H]1c2c(COC)cn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O

Procedure:
Analogously to Example 15, 350 mg of the title compound [Rf=0.45 (methylene chloride/methanol=13/1)] of melting point 184-6° C. (decomp.) are obtained by reaction of (7R,8R,9R)-7,8-dihydroxy-6-methoxymethyl-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with ethanol and purification on silica gel (mobile phase: methylene chloride/methanol=100/3).