Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:7][C:6]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([CH:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([CH3:38])=[CH:21][N:20]=1)([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC(O)=O>C1COCC1>[C:12]([C:8]1[C:9]([CH3:11])=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([NH:18][C:19]2[N:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([CH:35]([CH3:36])[CH3:37])(=[O:34])=[O:33])[C:22]([CH3:38])=[CH:21][N:20]=2)[CH:7]=1)#[CH:13]
Reactant: Cc1cc(OC(C)C)c(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C#Cc1cc(Nc2ncc(C)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)c(OC(C)C)cc1C

Procedure:
A solution of N2-(2-Isopropoxy-4-methyl-5-trimethylsilanylethynyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine from the previous step (0.102 g, 0.18 mmol) in 2.5 mL THF is treated with TBAF (0.5 mL, 1M in THF) and 30 μL AcOH at 22° C. for 2 hrs. The reaction mixture is concentrated and the residue is purified using a 4 g SiO2 column (ISCO), affording N2-(5-Ethynyl-2-isopropoxy-4-methyl-phenyl)-5-methyl-N4-[2-(propane-2-sulfonyl)-phenyl]-pyrimidine-2,4-diamine (257). MS (ES+): 479.2 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1.C(N(CC)C(C)C)(C)C>CCCCO>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:24]=1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (100 mg, 0.36 mmol), 2-Amino-6-chloropurine (compound 5401) (60.9 mg, 0.36 mmol) and N,N-diisopropylethyl amine (69 μL, 0.40 mmol) were suspended in n-BuOH (4 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 48 h and then at 120° C. for 24 h. The mixture was allowed to cool to room temperature and concentrate in vacuo to remove n-BuOH. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was triturated with anhydrous ethyl ether and further purified by flash column chromatography on silica gel (eluting with 0-8% MeOH/DCM) to afford the desired product, (S)-3-(1-(2-amino-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one as a off white/yellow solid (5402, compound 323 in Table 4), (28 mg, 20%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)C>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:7]=1
Reactant: Clc1cc(N2CCCC2)nc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: Clc1cc(N2CCCC2)nc(N2CCNCC2)n1

Procedure:
A solution containing 2.0 g (9.17 mmoles) of 2,4-dichloro-6-pyrrolidinopyrimidine and 3.95 (45.9 mmoles) of piperazine in ethanol is boiled under reflux for 1 hour and then evaporated. The evaporation residue is distributed between 100 ml of chloroform and 100 ml of 1% sodium hydroxide solution. After separation the organic phase is washed twice with 50 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column. By using a 9:1 mixture of chloroform/methanol as eluent and recrystallizing the obtained product from hexane, the title compound is obtained in a yield of 1.66 g (67.6%), m.p.: 77°-92° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]2[N:9]([CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:10]([CH2:12][C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].CO.[OH-].[Na+].Cl>C1COCC1>[CH2:19]([CH:18]([N:9]1[C:8]2[CH:23]=[CH:24][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[CH2:12][C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(CC)n1c(Cc2ccco2)nc2cc(C(=O)OC)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)n1c(Cc2ccco2)nc2cc(C(=O)O)ccc21
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To 5.30 g of 1-(1-Ethyl-propyl)-2-furan-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester 12 ml of methanol and 22 ml THF 22 ml of 1 M aqueous sodium hydroxide solution were added and the reaction was stirred for 16 h. The reaction mixture was adjusted to pH 5 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. 4.83 g (85%) of 1-(1-Ethyl-propyl)-2-furan-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid were obtained.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]1([CH3:32])[C@H:26]2[CH2:27][C@@H:22]1[CH2:23][CH2:24][C@H:25]2[CH2:28][C:29](O)=[O:30]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C@@H:25]3[CH2:24][CH2:23][C@H:22]4[CH2:27][C@@H:26]3[C:21]4([CH3:20])[CH3:32])[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Nn3nc(-c4ccc(Cl)cc4)c4ccccc4c3=O)[C@@H]1C2

Procedure:
The product of Example 86A and 2-[(1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid (Eigenmann, G. W.; Arnold, R. T. JACS 1959, 81, 3440-2) were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.38-11.39 (bs, 1H), 8.39-8.42 (m, 1H), 7.90-8.03 (m, 2H), 7.70-7.75 (m, 1H), 7.61-7.67 (m, 4H), 2.20-2.43 (m, 3H), 1.73-2.06 (m, 6H), 1.36-1.69 (m, 1H), 1.20 (s, 3H), 1.07 (s, 3H), 0.91 (d, J=9.5 Hz, 1H); MS (ESI+) m/z 436 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][NH:13][CH2:14][CH2:15][CH2:16][P:17](=[O:20])([OH:19])[OH:18].[OH-].[Na+]>CC(C)=O>[OH:12][N:13]([CH2:14][CH2:15][CH2:16][P:17](=[O:18])([OH:20])[OH:19])[C:9](=[O:10])[CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=P(O)(O)CCCNO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(COc1ccccc1)N(O)CCCP(=O)(O)O
Yield: 3.6 %

Procedure:
A solution of phenoxyacetyl chloride (3.4 g.) in dried acetone (10 ml.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (1.51 g.) in mixture of 1 N aqueous sodium hydroxide solution (30 ml.) and acetone (20 ml.) under ice-cooling in the course of 10 minutes, and the mixture was stirred for an hour at the same temperature, and then adjusted to pH 10 with 1 N aqueous sodium hydroxide solution. The acetone was distilled off from the reaction mixture, and the remaining aqueous solution was adjusted to pH 2.0 with 10% hydrochloric acid, washed with ethyl ether, and then adjusted to pH 1.0 with 10% hydrochloric acid and saturated with sodium chloride. This solution was extracted twice with ethyl acetate (each 100 ml. portion) (insoluble materials (0.2 g.) produced at this stage were collected by filtration) and the combined extracts were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 3-(N-hydroxy-N-phenoxyacetylamino)propylphosphonic acid (0.1 g.). Insoluble materials produced above were identified with the same object compound.
Reaction SMILES: [OH-].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].CO.[CH:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:16]>>[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH:14]([OH:15])([CH3:9])[CH3:13].[CH3:16][C:10]1[CH:9]=[C:14]([O-:15])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(O)c1
Agent: C[N+](C)(C)C
Agent: [OH-]
Solvent: CO
Product: CC(C)O
Product: Cc1cccc([O-])c1
Yield: 200 %

Procedure:
To 5.40 ml of a commercially available 10% tetramethylammonium hydroxide-methanol solution (manufactured by TOKYO KASEI; 5.24 mmole equivalents) was added 0.566 g of m-cresol (5.24 mmoles), and about 7 ml of a tetramethylammonium-3-methylphenolate isopropanol solution (containing 5.24 mmoles of m-cresol) was obtained in the same manner as in Operation 1 in Example 4.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[C:12]([F:24])=[C:13]([F:23])[C:14]([F:22])=[C:15]2[C:20](=O)[O:19][C:17](=[O:18])[C:16]=12>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[C:17](=[O:18])[C:16]2[C:15](=[C:14]([F:22])[C:13]([F:23])=[C:12]([F:24])[C:11]=2[F:10])[C:20]1=[O:19]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Solvent: CC(=O)O
Product: O=C1c2c(F)c(F)c(F)c(F)c2C(=O)N1c1ccc(F)cc1F
Yield: 42.3 %

Procedure:
A mixture of about 1 g (about 7.75 mmol) of 2,4-difluoroaniline, about 1.54 g (about 7 mmol) of tetrafluorophthalic anhydride and about 50 mL of glacial acetic acid was refluxed for about 3.5 hours. The solvent was evaporated to dryness under reduced pressure of from about 200 to about 15 mbar. The residue was dissolved in about 75 mL of CH2C12. The solution was washed three times with about 25 mL of about 0.1 M HCl and twice with about 25 mL of water. The residue was then dried with Na2SO4. After removal of the solvent, the residue was recrystallized from ethyl alcohol to yield about 980 mg (about 42%) of 2-(2,4-difluorophenyl)-4,5,6,7-tetrafluoro-1H-isoindole-1,3(2H)-dione with a melting point of about 145° to about 146° C.
Reaction SMILES: C([CH:4]([CH2:32][C:33](=[O:38])[NH:34][CH2:35][CH2:36][CH3:37])[CH:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:10]2[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[O:30][CH3:31])O)(O)=O.C(OC(OC(C)(C)C)N(C)C)(C)(C)C>C(Cl)Cl>[CH3:31][O:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[CH2:19][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:5]=[CH:4][CH2:32][C:33](=[O:38])[NH:34][CH2:35][CH2:36][CH3:37])[CH:8]=2)[N:12]([CH2:16][CH2:17][CH3:18])[CH:11]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCCNC(=O)CC(C(=O)O)C(O)c1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: ClCCl
Product: CCCNC(=O)CC=Cc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2CCC

Procedure:
A solution of methyl 4-[5-[2-carboxy-1-hydroxy-3-(propylcarbamoyl)propyl]-1-propylindol-3-ylmethyl]-3-methoxybenzoate (0.81 g), and N,N-dimethylformamide di-tert-butyl acetal (1.54 ml, redistilled) in methylene chloride (26 ml) was stirred under a nitrogen atmosphere for 1 hour. The solvent was evaporated, and the product purified by flash chromatography, eluting with 4:1 ethyl acetate: hexane, to give methyl 3-methoxy-4-[1-propyl-5-[3-(propylcarbamoyl)prop-1-enyl]indol-3-ylmethyl]benzoate (0.56 g, 79%, as a separable mixture of olefin isomers) as a white solid: mp 140°-142°; E-olefin partial NMR (300 MHz, DMSO-d6): 0.83(m, 6H, 2×CH3), 3.82(s, 3H, OCH3), 3.92(s, 3H, OCH3). 6.15(d of t, 1H, olefinic-H), 6.47(d, J=15.9 Hz, 1H, olefinic-H), 7.86(t, 1H, NH), Z-olefin partial NMR (300 MHz, DMSO-d6 ): 0.82(m, 6H, 2×CH3), 3.82(s, 3H, OCH3), 3.90(s, 3H, OCH3), 5.70(m, 1H, olefinic-H), 6.57(d, J=11.5 HZ, 1H, olefinic-H), 7.86(t, 1H, NH).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]([CH3:30])[CH:13]([CH2:19][S:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]Cl)[C:22]=1[CH3:29])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[OH-].[Na+]>C(O)C>[CH3:29][C:22]1[C:23]([CH2:27][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)=[N:24][CH:25]=[CH:26][C:21]=1[S:20][CH2:19][CH:13]([N:12]([CH3:30])[CH3:11])[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)C(CSc1ccnc(CCl)c1C)N(C)C
Reactant: Sc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(CSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)N(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Mercaptobenzimidazole (1.5 g) was dissolved in ethanol (20 ml) and thereto were added ethyl 2-dimethylamino-3-(2-chloromethyl-3-methyl-4-pyridylthio)propionate (3.16 g) and an aqueous solution (10 ml) of 1N sodium hydroxide. The mixture was stirred at 50° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The residue was subjected to column chromatography and eluted with chloroform-methanol to give 2-((3-methyl-4-(2-dimethylamino-2-ethoxycarbonylethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as a pale yellow oil.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1)(C)(C)C>CO>[ClH:1].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)=[O:16])[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCC(C(=O)N2CCOCC2)CC1
Agent: Cl
Solvent: CO
Product: NC1CCC(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HCl (2 M aq, 150 mL) was added to a suspension of [4-(morpholine-4-carbonyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.8 g) in MeOH, and the resulting mixture was stirred at RT overnight. The reaction mixture was evaporated under reduced pressure, the oily residue was taken up in EtOAc, and the resulting mixture was sonicated. The solid formed was collected by filtration and dried under reduced pressure to afford 5.2 g of (4-amino-cyclo-hexyl)-morpholin-4-yl-methanone hydrochloride.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[C:14]([C:19]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:46])[CH3:45])[CH:41]=[CH:40][C:20]=1[O:21][CH:22]([CH2:38][CH3:39])[C:23]([N:25]1[C:30]2[CH:31]=[C:32]([OH:36])[C:33]([NH2:35])=[CH:34][C:29]=2[O:28][CH2:27][C:26]1=[O:37])=[O:24])([CH2:17][CH3:18])([CH3:16])[CH3:15]>C1COCC1>[C:14]([C:19]1[CH:43]=[C:42]([C:44]([CH2:47][CH3:48])([CH3:45])[CH3:46])[CH:41]=[CH:40][C:20]=1[O:21][CH:22]([CH2:38][CH3:39])[C:23]([N:25]1[C:30]2[CH:31]=[C:32]([OH:36])[C:33]([NH:35][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=3)=[O:11])=[CH:34][C:29]=2[O:28][CH2:27][C:26]1=[O:37])=[O:24])([CH2:17][CH3:18])([CH3:16])[CH3:15]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc(N)c(O)cc21
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)N1C(=O)COc2cc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c(O)cc21
Reaction time: 1 h

Procedure:
4-Trifluoromethylphenylisocyanate (2.55 g, 0.0136 mole) was added to the amine ((g), 6.56 g, 0.0136 mole) in THF (ml 100). After 1 hour stirring, the solution was evaporated to dryness and the residue crystallized from toluene to give the coupler ((h), 6 g, 67%) as white prisms. The product structure was confirmed by NMR analysis.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][N:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:19]2[CH:18]=[N:17][C:16]([O:15][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: CCCCCCOc1ccc(B(O)O)cn1
Reactant: Clc1ncc(Br)cn1
Product: CCCCCCOc1ccc(-c2cnc(Cl)nc2)cn1

Procedure:
A reaction of 5-bromo-2-chloropyrimidine and 2-hexyloxypyridine-5-boronic acid is carried out analogously to the procedure indicated for precursor 3. Corresponding purification gives a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=1.[NH2:12][OH:13]>C(O)C>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:12][OH:13])[CH3:10])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1cccc(CO)n1
Reactant: NO
Solvent: CCO
Product: CC(=NO)c1cccc(CO)n1
Reaction time: 8 h

Procedure:
To a solution of 1643 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone in 25 ml of ethanol was added 0.72 ml of a 50% aqueous hydroxylamine solution, followed by stirring overnight. The reaction solution was concentrated under reduced pressure to obtain 1806 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime as an amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[CH3:18][NH:19][CH2:20][CH2:21][CH3:22].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:12]=[C:11]([O:13][CH:14]([CH3:16])[CH3:15])[CH:10]=[C:6]([C:7]([N:19]([CH3:18])[CH2:20][CH2:21][CH3:22])=[O:9])[CH:5]=1
Reactant: CCCNC
Reactant: COC(=O)c1cc(OC(C)C)cc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCCN(C)C(=O)c1cc(OC(C)C)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 5-isopropoxy-isophthalic acid monomethyl ester (3 g, 12.7 mmol), methyl propyl amine (1.3 mL, 12.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.4 g, 12.7 mmol), and 1-hydroxybenzotriazole hydrate (1.7 g, 12.7 mmol) in dichloromethane (50 mL) and stir overnight at room temperature. Dilute with dichloromethane (50 mL), wash with water, 5% aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution, dry (sodium sulfate) and concentrate to give the title product which is used directly without further purification.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([OH:22])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3].[CH2:23](O)[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH3:3]
Reactant: CCCC/C=C\CCO
Reactant: CCCOCCCCCc1ccc(-c2ncc(O)cn2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC/C=C\CCOc1cnc(-c2ccc(CCCCCOCCC)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.5 g of 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-hydroxypyrimidine, 0.3 g of (Z)-3-octen-1-ol, 0.4 g of diethyl azodicarboxylate, 0.6 g of triphenylphosphine and 25 ml of absolute tetrahydrofuran was stirred at room temperature overnight and then concentrated. The residue was suspended with 50 ml of hot hexane and filtered. The filtrate was concentrated. Chromatography of the residue on silica gel with toluene/hexane (vol. 1:1) and recrystallization from methanol gave pure 2-[4-(5-[propyloxy]-1-pentyl)phenyl]-5-([(Z)-3-octenyl]oxy)pyrimidine, m.p. (C-I) 38° C.
Reaction SMILES: [CH2:1]([N:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:4](=[O:24])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[N:8]=1)[CH3:2].C(O)C>[C].[Pd].C(Cl)(Cl)Cl>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:9]2[N:8]=[C:7]([O:6][CH2:5][C:4]([N:3]([CH2:1][CH3:2])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=2)=[CH:16][CH:17]=1
Reactant: CCN(C(=O)COc1nc(-c2ccc([N+](=O)[O-])cc2)nc(C)c1C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCN(C(=O)COc1nc(-c2ccc(N)cc2)nc(C)c1C)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
A mixture of 2-[5,6-dimethyl-2-(4-nitrophenyl)-4-pyrimidinyloxy]-N-ethyl-N-phenylacetamide (2.3 g) obtained in Example 164, 5% palladiumcarbon (0.4 g), ethanol (30 ml) and chloroform (10 ml) is stirred at room temperature for three hours under hydrogen atmosphere, and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure, and recrystallized from acetonitrile to give a 1/10 hydrate of the desired compound (2.1 g), m.p. 183-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (112 mg, 0.31 mmol), N,N-diisopropylethylamine (163 μL, 0.94 mmol) and 1-methyl-1H-pyrazol-3-ylamine (30 μL, 0.31 mmol) were combined in methylene chloride (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the cooling bath was removed. After stirring 16 h, the reaction mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium bicarbonate solution (1.5 mL). The aqueous phase was extracted with chloroform (1.5 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (110 mg, 81%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C19H23ClN4O4S [M+] 438.11, found 439 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.24-1.61 (m, 6H, 3×CH2), 1.71 (m, 2H, 2×CH of CH2), 1.96 (m, 2H, 2×CH of CH2), 3.29 (s, 3 H, SO2CH3), 3.85 (s, 3 H, NCH3), 4.29 (m, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.71 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 9.15 (s, 1 H, NH).
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]([CH3:42])[C:25]([C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1)=[O:26]>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([N:24]([CH3:42])[CH3:23])=[O:26])=[N:28][CH:29]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: CN(C)C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc(C(=O)N(C)C)nc4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (from PepTech Corp. Encyclopedia of Amino Acid Analogs and Boronic Acids). LCMS calculated for C24H26N5O3 (M+H)+: m/z=432.2. Found 432.1.