Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][C@:10]1([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:14]([CH3:33])[C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To a solution of tert-butyl (3S)-3-{[tert-butyl (dimethyl) silyloxy]methyl}-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylate (8.65 g, 19.9 mmol) and iodomethane (1.37 mL, 21.9 mmol) in tetrahydrofuran (173 mL), lithium bistrimethylsilyl amide (21.9 mL, 21.9 mmol, 1M solution in tetrahydrofuran) was added in an ice bath, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, saturated aqueous solution of ammonium chloride (300 mL) was added, and the mixture was extracted with ethyl acetate (300 mL×2). The organic layer was washed with saturated aqueous solution of sodium chloride (200 mL), and dried with anhydrous sodium sulfate. After the filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elusion by hexane:ethyl acetate, 7:1→1:1) to obtain 3.72 g (42%) of the title compound (single component) as a colorless oily substance.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([OH:25])[CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2].Cl[C:27]1[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH2:1]([C@@H:3]1[CH2:7][O:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:14]=[C:15]([CH:16]=[C:17]([O:19][C@@H:20]([CH3:24])[CH2:21][O:22][CH3:23])[CH:18]=3)[O:25][C:27]3[CH:32]=[N:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][N:28]=3)=[CH:10][CH:9]=2)=[N:4]1)[CH3:2]
Reactant: CC[C@@H]1COC(c2ccc(-c3cc(O)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Reactant: CS(=O)(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC[C@@H]1COC(c2ccc(-c3cc(Oc4cnc(S(C)(=O)=O)cn4)cc(O[C@@H](C)COC)c3)[nH]2)=N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 105.4 %

Procedure:
3-{5-[(4R)-4-Ethyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}-5-{[(2S)-1-methoxypropan-2-yl]oxy}phenol (272 mg, 0.79 mmol) synthesized in Example (108b) was dissolved in acetonitrile (5.0 mL), and 2-chloro-5-(methylsulfonyl)pyrazine (220 mg, 1.14 mmol) synthesized in Example (97c) and cesium carbonate (640 mg, 1.96 mmol) were added at room temperature, followed by stirring at room temperature for 3.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-3%) to afford the desired compound (417 mg, yield ˜100%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([C:21]([CH3:27])([CH3:26])[C:22](OC)=[O:23])=[C:18](O)[N:19]=2)=[N:6]1.P(Cl)(Cl)(Cl)=O.[NH3:37]>C(#N)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]3[C:21]([CH3:26])([CH3:27])[C:22](=[O:23])[NH:37][C:18]=3[N:19]=2)=[N:6]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncncc23)nc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncncc34)nnc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
186 mg (0.438 mmol) of methyl 2-{3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-5-hydroxy-1,2,4-triazin-6-yl}-2-methylpropanoate were admixed with 4 ml (42.913 mmol) of phosphoryl chloride and the mixture was stirred at RT for 2.5 h. The reaction solution was diluted with 20 ml of dry acetonitrile and gradually added dropwise while cooling with ice to 30 ml of a 25% aqueous ammonia solution, and the mixture was stirred at RT overnight. The reaction mixture was concentrated on a rotary evaporator and the precipitate was filtered off. 127 mg of the target compound were obtained (74% of theory).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:11][CH2:10]2)[C:7]2[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:3].[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[NH2:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([NH:1][C@H:2]([C:4]2[N:8]([CH:9]3[CH2:10][CH2:11]3)[C:7]3[C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=[CH:15][C:6]=3[N:5]=2)[CH3:3])[C:26]=1[C:27]#[N:28]
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COC(=O)c1cccc2nc([C@H](C)N)n(C3CC3)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(C3CC3)c12
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-methyl 2-(1-aminoethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate (140 mg, 0.54 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (83 mg, 0.54 mmol) and 1,1′-dimethyltriethylamine (190 μL, 1.1 mmol) in n-butanol (3 mL) was stirred at 120° C. After 18 h, the mixture was cooled to rt and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 0 to 10% gradient of MeOH in DCM-EtOAc (1:1) with 0.2% NH4OH as eluent to give (S)-methyl 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-1-cyclopropyl-1H-benzo[d]imidazole-7-carboxylate: LC-MS (ESI) m/z 378.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]3[CH2:23][C@:13]4([C:21]5[C:16](=[N:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][C:7]=3[CH:8]=2)[N:3]=1.[Se](=O)=[O:25]>O1CCOCC1.O>[O:22]=[C:14]1[NH:15][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[C@:13]21[CH2:12][C:7]1[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=1[CH2:23]2)[N:3]=[C:2]([CH:1]=[O:25])[CH:11]=[CH:10]3
Reactant: Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2-methyl-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (1.30 g, 4.31 mmol) and selenium dioxide (718 mg, 6.47 mmol) in dioxane (50 mL) and H2O (5 mL) was heated at reflux for 4 h. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10. Product-containing fractions were combined, toluene was added, and the mixture was concentrated in vacuo to give the title compound. MS: m/z=316 (M+1).
Reaction SMILES: [CH:1]([P:5]([CH2:10][CH2:11][CH2:12][OH:13])[CH2:6][CH2:7][CH2:8][OH:9])([CH2:3][CH3:4])[CH3:2].[OH:14]CCCP(C(CC)C)C(CC)C.OO.C=CCC>C(O)(C)C.C(=S)=S>[CH:1]([P:5](=[O:14])([CH2:6][CH2:7][CH2:8][OH:9])[CH2:10][CH2:11][CH2:12][OH:13])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)P(CCCO)CCCO
Reactant: CCC(C)P(CCCO)C(C)CC
Agent: C=CCC
Agent: OO
Solvent: S=C=S
Solvent: CC(C)O
Product: CCC(C)P(=O)(CCCO)CCCO

Procedure:
The residual product is believed to contain both s-butyl bis(3-hydroxypropyl) phosphine and 3-hydroxypropyl di-s-butyl phosphine. It is dissolved in an equal volume of isopropanol and oxidized with 30% hydrogen peroxide in an equal volume of isopropanol as described above in Example 1 until a negative carbon disulfide reading is obtained. The solution of oxidized phosphine is concentrated under reduced pressure to yield a syrupy yellow liquid weighing 555.6 g (99.2% yield on oxidation or a yield of 62.5% based on the starting butene).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]4=[CH:20][C:19]=3[C:18]2=[O:31])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:33][OH:34]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]4=[CH:20][C:19]=3[C:18]2=[O:31])[CH2:13][C:14]([NH:33][OH:34])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Yield: 77.2 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propanoic acid (2.00 g, 4.77 mmol), N,N′-carbonyldiimidazole (889 mg, 5.48 mmol) and hydroxylamine hydrochloride (419 mg, 6.03 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide as an off-white solid (1.6 g, 77% yield): mp, 197.0-199.0° C.; 1H NMR (DMSO-d6) δ1.33 (t, J=7.0 Hz, 3H, CH3), 3.11-3.28 (m, 2H, CH2), 3.73 (s, 3H, CH3), 4.00 (q, J=7.0 Hz, 2H, CH2), 5.79 (t, J=7.8 Hz, 1H, NCH), 6.87-7.09 (m, 2H, Ar), 7.10 (br s, 1H, Ar), 7.74-7.78 (m, 2H, Ar), 8.23-8.27 (m, 2H, Ar), 8.49 (br s, 1H, Ar), 8.85 (br s, 1H, OH), 10.66 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.69, 34.27, 50.42, 55.45, 63.73, 111.73, 112.45, 119.82, 124.50, 127.04, 129.28, 130.26, 131.20, 135.05, 147.69, 148.58, 166.07, 167.30; Anal Calcd for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.22; H, 5.24; N, 6.08.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][C@@H:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:7]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: BrCc1ccccn1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of (S)-2-methyl-4-N—BOC-piperazine (400 mg, 1.997 mmol) and 2-(bromomethyl)pyridine hydrobromide (505 mg, 1.997 mmol) in anhydrous THF (5 ml) was added triethylamine (0.7 ml, 4.99 mmol) and the resulting mixture stirred at RT for 3 days. The mixture partitioned between water and EtOAc; organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by column chromatography (eluent: 5% MeOH in DCM) to give 320 mg (55%) to afford the title compound as a yellow oil. 1H NMR (CDCl3): 1.14 (d, J 6.2 Hz, 3H), 1.47 (s, 9H), 2.25 (t, J 9.5 Hz, 1H), 2.51 (m, 1H), 2.70 (d, J 11.6 Hz, 1H), 2.84 (brs, 1H), 3.15 (t, J 10.1, 1H), 3.47 (d, J 14.2 Hz, 1H), 3.69 (d, J 13.0 Hz, 1H), 3.75 (brs, 1H), 4.08 (d, J 14.0, 1H), 7.17 (dd, J 7.1 and 5.3, 1H), 7.45 (d, J 7.8, 1H), 7.66 (m, 1H), 8.56 (d, J=4.7 Hz, 1H).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]=[C:33]=[O:34]>CO>[Cl:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[NH:32][C:33](=[O:34])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[N+](C)(C)C[C@@H](CC(=O)[O-])NC(=O)Nc1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
To a solution of (R)-aminocarnitine (35 mg, 0.22 mmol) and diisopropylethylamine (0.11 mL, 0.65 mmol) in MeOH (2 mL) was added 2-chloro-1-isocyanato-4-(trifluoromethyl)benzene (67 uL, 0.44 mmol) and the reaction stirred at room temperature overnight. The MeOH was removed in vacuo and the residue titurated several times with 1:1 ether/EtOAc, the resulting solid was filtered and dried to give the title compound as a white powder (15 mg, 18%). NMR (300 MHz, CD3OD) δ 8.37 (m, 1H), 7.68 (m, 1H), 7.53 (m, 1H), 4.29 (m, 1H), 3.78-3.48 (m, 2H), 3.25 (s, 9H), 2.70-2.49 (m, 2H); MS ESI 382.1 [M+H]+, calcd for [C15H19ClF3N3O3+H]+ 382.78.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[CH2:13]1[O:21][C:20]2[CH:19]=[CH:18][C:17]([CH:22]3[C:26]4[NH:27][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=5[C:34](=[O:35])[C:25]=4[CH2:24][NH:23]3)=[CH:16][C:15]=2[O:14]1>CN(C=O)C.O>[N:3]1([C:1]([N:23]2[CH2:24][C:25]3[C:34](=[O:35])[C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH:27][C:26]=3[CH:22]2[C:17]2[CH:18]=[CH:19][C:20]3[O:21][CH2:13][O:14][C:15]=3[CH:16]=2)=[S:2])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(C(=S)n1ccnc1)C2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of 1,1′-thiocarbonyldiimidazole (0.192 g, 1.08 mmol) in DMF (5 mL, anhydrous) at 0° C. was added 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (0.30 g, 0.98 mmol) (prepared as in Example 5). The mixture warmed to room temperature and stirred for 20 h. The solution was diluted with water and extracted into ethyl acetate. The organic layers were combined and washed with aq. NaHCO3 and brine, dried with MgSO4 and concentrated in vacuo, to yield the product as a light tan solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[CH3:1][C:2]1[C:6]2[C:7]([OH:15])=[C:8]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:9]=[C:10]([C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([Cl:21])=[CH:23][CH:24]=3)[C:5]=2[O:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1oc2ccc(C(C)(C)C)c(O)c2c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1oc2c(C(=O)c3ccc(Cl)cc3)cc(C(C)(C)C)c(O)c2c1C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 3-methyl-4-hydroxy-5-tert-butylbenzofuran-2-carboxylate, compound 12a (1.00 g, 3.62 mmol) and p-chlorobenzoyl chloride (0.793 g, 4.53 mmol) in 1,2-dichloroethane (40 mL) at 0° C. was added aluminum chloride (0.604 g, 4.53 mmol) and the mixture heated to reflux for two hours. Additional portions of 4-chlorobenzoyl chloride (0.475 g, 2.71 mmol) and aluminum chloride (0.362 g, 2.71 mmol) were added and the reflux continued for an additional 1.5 hours. The reaction mixture was poured into 2N HCl (100 mL) and extracted with methylene chloride (4×25 mL). The combined extracts were washed with water (25 mL), dried (Na2SO4), and concentrated. Flash chromatography using 25% ethyl acetate in hexane as eluant afforded ethyl 3-methyl-4-hydroxy-5-tert-butyl-7-p-chlorobenzoylbenzofuran-2-carboxylate, compound 17 as an oil sufficiently pure for further chemistry. 1H NMR d 1.34 (3H, t, J=6 Hz), 1.50 (9H, s), 2.88 (3H, s), 4.54 (2H, q, J=6 Hz), 7.47 (2H, d, J=8 Hz), 7.78 (2H, d, J=8 Hz), 7.87 (1H, s).
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13](=[O:24])[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1.[H-].[Na+].F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>O>[C:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[C:13]1=[O:24])#[N:31]
Reactant: N#Cc1ccccc1F
Reactant: O=c1[nH]cc(-c2ccccc2)cc1-c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cc(-c2ccccc2)cc(-c2ccccn2)c1=O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
5 ml of a dimethylformamide solution containing 0.26 g of 3-(2-pyridyl)-5-phenyl-2 (1H)-pyridone was incorporated with 0.04 g of sodium hydride. After 15 minutes, the solution was further incorporated with 0.15 g of 2-fluorobenzonitrile and 0.10 g of cuprous iodide, and vigorously stirred at 100° C. for 2 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then saturated saline water, and dried by magnesium sulfate anhydride. The solvent was distilled off under a vacuum. The residue was refined by silica gel chromatography (ethyl acetate/hexane=1:2), to obtain 0.03 g of the light yellow, powdery subject compound.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]([Cl:23])[CH3:22])=[O:19]>C(Cl)(Cl)Cl>[C:18](=[O:19])([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[O:20][CH:21]([Cl:23])[CH3:22]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(Cl)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a ice cooled mixture of 27.8 g of p-nitrophenol, 16.0 g of pyridine and 1 L of chloroform is added, dropwise, 34 g of alpha-chloroethyl chloroformate. After 1 hour, the ice bath is removed and the reaction is stirred for 16 hours at room temperature. The mixture is washed with water, 0.5% sodium hydroxide and water. The organic layer is dried and concentrated in vacuo to give 47.85 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][CH:3]=1.[Br:9]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9]
Reactant: Nc1cccc(O)n1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(O)ccc1Br
Reaction time: 0.33 h
Yield: 52.8 %

Procedure:
To a solution of 6-amino-pyridin-2-ol (5 g, 45.4 mmol) in glacial acetic acid (60 mL) was added bromine (2.33 mL, 45.4 mmol) under Ar atmosphere. The mixture was stirred for 20 minutes, then water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness to obtain crude 6-amino-5-bromo-pyridin-2-ol (4.53 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:45]=[CH:44][C:19]([O:20][C:21]2[CH:22]=[C:23]([CH:32]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[CH:34]=2)[C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])=[CH:18][CH:17]=1)#[N:15]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11]([N:29]1[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]2[CH:22]=[C:21]([O:20][C:19]3[CH:18]=[CH:17][C:16]([C:14]#[N:15])=[CH:45][CH:44]=3)[CH:34]=[C:33]([O:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=3)[CH:32]=2)[CH2:27][CH2:28]1)=[O:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)N3CCNCC3)c2)cc1
Product: CC(C)(C)OC(=O)NCCC(=O)N1CCN(C(=O)c2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 77 %

Procedure:
3-tert-Butoxycarbonylamino-propionic acid (0.206 g, 1.09 mmol) and 4-[3,5-bis-(4-cyano-phenoxy)-benzoyl]-piperazine (0.5 g, 1.09 mmol) and other reagents as described in Example 9(e) were used to afford 0.5 g of the required product. 1H NMR (DMSO-d6): δ 1.38 (9H, s), 2.45 (2H, m), 3.14 (2H, m), 3.52 (8H, m), 6.71 (1H, brs), 7.01 (2H, s), 7.08 (1H, t), 7.28 (4H, d), 7.89 (4H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[C:25](=O)[CH:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[S:17][C:22]3[CH2:21][CH2:20][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=4)[C:23]=3[N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: O=C1C(Br)CCCC1c1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccc(OC(F)(F)F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (48 mg, 0.18 mmol) and of crude 6-bromo-2-(4-trifluoromethoxyl-phenyl)-cyclohexanone (65 mg, 0.19 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (16 mg, 17%) as a pale-brown oil. MS ISP (m/e): 501.0 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.61 (s, 1H), 7.35 (s, 1H), 7.08-7.20 (m, 4H), 6.82 (s, 1H), 6.65 (d, 1H), 4.06 (m, 1H), 3.56 (s, 3H), 2.75 (m, 2H), 2.28 (s, 3H), 2.25 (m, 1H), 1.77-1.98 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:19]1[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=1.Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][O:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:19]2[N:20]=[CH:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[N:23][CH:24]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: COc1ccc(COC(C)(C)CO)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(OCC(C)(C)OCc2ccc(OC)cc2)cn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 2-[(4-methoxybenzyl)oxy]-2-methylpropan-1-ol (0.30 g) in N-methylpyrrolidone (4.5 mL) was added sodium hydride (63 mg) under ice-cooling, followed by stirring at 60° C. for 30 minutes. To the reaction mixture was added methyl 5-chloropyrazine-2-carboxylate (246 mg), followed by stirring at 120° C. overnight. To the reaction mixture was added 1 M hydrochloric acid for neutralization in an ice bath, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20) to obtain methyl 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazine-2-carboxylate (0.20 g) as a colorless oily substance.