Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6](COCC[Si](C)(C)C)[C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl>C(O)C>[CH2:1]([C:5]1[NH:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CCC(=O)OCC)n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Product: CCCCc1nc(CCC(=O)OCC)c[nH]1
Temperature: 60 °C
Yield: 50 %

Procedure:
A solution of ethyl 3-[2-n-butyl-1-{(trimethylsilyl)ethoxymethyl}1H-imidazol-5-yl]propanoate (0.992 g, 2.8 mmol) in ethanol (10 mL) was treated with 5N aqueous hydrochloric acid solution (20 mL), and then the reaction mixture was heated at 60° C. for 3.5 hours. The ethanol was evaporated, and the cooled aqueous solution was basified to pH 8 with 10% aqueous sodium hydroxide solution. The product was extracted into ethyl acetate, and the organic extracts were washed with brine, dried with anhydrous sodium sulfate and concentrated to give 0.314 g (50%) of ethyl 3-(2-n-butyl-imidazol-4-yl)-propanoate. This was dissolved in methanol (15 mL) and di-tert-butyldicarbonate (2.44 g, 11.2 mmol) and triethylamine (1.56 mL, 11.2 mmol) were added. The mixture was stirred for 18 hours at ambient temperature, the solvent was evaporated, and the residue was dissolved in hexane and applied to a flash column packed with silica gel. Elution with 8:2 hexane/ethyl acetate afforded 0.285 g (31%) of ethyl 3-[2-n-butyl-1-t-butoxycarbonyl-1H-imidazol-4-yl]propanoate as an oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[CH:4]([O:6][Si](C(C)(C)C)(C)C)[CH3:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.C(OCC)(=O)C>C1COCC1>[Cl:1][CH2:2][C@@:3]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[F:22])([OH:14])[C@H:4]([OH:6])[CH3:5]
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)[C@](O)(CCl)c1ccc(F)cc1F
Reaction time: 1.5 h
Yield: 15 %

Procedure:
A solution of 0.45 g (1.28 mmol) of 1-chloro-2-(2,4-difluorophenyl)-3-(tert-butyldimethylsilyloxy)butan-2-ol ((2S,3R)/(2R,3R)=91/9) in 5 mL of THF was cooled in ice, and 1.3 mL of a 1.0 M solution of TBAF in THF was added dropwise. After the completion of the dropwise addition, reaction was performed for 1.5 hours and then at room temperature for another 11 hours. Next, 10 mL of water was added to stop the reaction, and extraction was performed with 20 mL of ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product as a colorless oil. A quantitative analysis was performed by HPLC (under the same HPLC measurement conditions as those in Example 6). Thereby, the title compound was obtained in a yield of 15% ((2S,3R)/(2R,3R)=91/9).
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:24][C:25]1[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[C:44]([CH3:50])[C:26]=1[CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:39]=[CH:38][O:37][C:36]=2[C:40]([NH:42][NH2:43])=[O:41])[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:17]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[OH:16])[C:9]([NH:43][NH:42][C:40]([C:36]1[O:37][CH:38]=[CH:39][C:35]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:27][C:26]2[C:44]([CH3:50])=[C:45]([CH3:49])[CH:46]=[C:47]([CH3:48])[C:25]=2[CH3:24])[CH:30]=1)=[O:41])=[O:8])#[N:18]
Reactant: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NN)c2)c1C
Reactant: N#Cc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NNC(=O)c3ccc(O)c(C#N)c3)c2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A mixture of 3-cyano-4-hydroxybenzoic acid pentafluorophenyl ester (compound of Reference Example 63; 0.45 g) and 3-[3-(2,3,5,6-tetramethylbenzyloxy)phenyl]-2-furancarboxylic acid hydrazide (compound of Reference Example 4; 0.50 g) in DMF (5 ml) was stirred at 70° C. overnight. The reaction solution was then diluted with ethyl acetate, washed with 1 M hydrochloric acid and water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0%→10% methanol/chloroform gradient) and recrystallized from ethyl acetate, thereby giving 0.31 g of the desired compound. Melting point: 210-211° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[CH:36]=[C:35]1[C:43](O)=[O:44].Cl.CN(C)CCCN=C=NCC>CC#N>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43]([C:35]3[O:34][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[CH:36]=3)=[O:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cc5ccccc5o4)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 2-benzofuran carboxylic acid (0.39 g, 2.4 mmol) were added. To the reaction, was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 30% EtOAc in CH2Cl2 for 10 min, then 40% EtOAc in CH2Cl2 for 10 min) to afford benzofuran-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a white solid (0.59 g, 63%): mp, 292-295° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.3 min. (98%); 1H NMR (DMSO-d6): δ 2.09-2.10 (m, 1H), 2.55-2.65 (m, 2H), 2.84-2.93 (m, 1H), 4.97 (d, J=6.0 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.33-7.84 (m, 8H), 9.40 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.97, 30.92, 37.90, 48.87, 109.90, 111.79, 121.95, 122.81, 123.74, 126.96, 127.09, 127.15, 131.54, 133.02, 134.83, 138.71, 148.71, 154.27, 158.52, 166.94, 167.51, 169.82, 172.74. Anal Calcd for C23H17N3O6+0.2H2O: C, 63.51; H, 4.03; N, 9.66. Found: C, 63.45; H, 3.76; N, 9.52.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7](Cl)=[O:8].N1C=CC=CC=1.[C:16]1([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:8])=[O:28].[C:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cnccn1
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(O)c1cnccn1
Product: c1ccc(-c2ccccc2)cc1
Yield: 45.3 %

Procedure:
To 3.5 g (25 mmol) of pyrazinoyl chloride dissolved in methylene chloride (20 mL) and pyridine (2 mL) cooled to 0° C. in a 50 mL round bottom flask was added 4-phenyl-phenol (5.0 g, 30 mmol). Upon completion of the reaction and isolation as described above recrystallization from hexanes yielded 3.15 g (39% yield) of the crystalline title compound; m.p: 95°-98° C. Elemental Analysis: C17H12N2O2Calcd: C:73.90, H:4.38. Found: C:73.68, H:4.28.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=1.Cl.[CH3:33][NH:34][CH3:35].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:29]([C:27]1[O:28][C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[CH:25][CH:26]=1)=[O:31]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Yield: 76.2 %

Procedure:
A solution of 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (0.42 g, 1.00 mmol), dimethylamine hydrochloride (0.17 g, 2.04 mmol), N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (0.26 g, 1.35 mmol), 1-hydroxybenzotriazole hydrate (0.21 g, 1.54 mmol) and 4-methylmorpholine (0.30 mL, 2.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken up into ethyl acetate (75 mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL), water (50 mL) and brine (50 mL). The organic phase was further diluted with dichloromethane until all the material was in solution, then was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (29:1) afforded N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide (0.34 g, 77%) as a colorless solid: mp 224-226° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.32 (dd, J=7.5, 7.5 Hz, 1H), 7.22-7.14 (m, 2H), 7.05 (dd, J=7.8, 7.5 Hz, 1H), 6.96 (m, 1H), 6.62 (m, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.06 (d, J=16.4 Hz, 1H), 4.97 (d, J=16.4 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.22-4.14 (m, 2H), 4.14-4.06 (m, 2H), 3.05 (br s, 3H), 2.94 (br s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 158.9, 154.6, 150.8, 147.2, 144.2, 141.8, 137.8, 131.6, 128.8, 123.6, 123.3, 121.2, 116.5, 111.0, 109.9, 109.4, 98.8, 79.3, 64.2, 63.6, 57.2, 37.7, 36.7, 35.8; MS (ES+) m/z 446.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.[CH2:16](C1C=CC(C=O)=CC=1)[CH3:17].FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9]([CH2:16][CH3:17])=[CH:8][CH:7]=1
Reactant: CCc1ccc(C=O)cc1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Product: CCc1ccc(C(Cl)C(=O)C(=O)OC)cc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methylester but using 4-ethylbenzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[S:16][C:15]([CH3:17])=[C:14]([C:18](=O)[CH2:19]Br)[CH:13]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC>O1CCCC1>[Br:11][C:12]1[S:16][C:15]([CH3:17])=[C:14]([C:18]2[N:1]=[C:2]3[C:7]4[CH:8]=[CH:9][O:10][C:6]=4[CH:5]=[CH:4][N:3]3[CH:19]=2)[CH:13]=1.[CH3:17][C:15]1[S:16][CH:12]=[CH:13][C:14]=1[C:18]1[N:1]=[C:2]2[C:7]3[CH:8]=[CH:9][O:10][C:6]=3[CH:5]=[CH:4][N:3]2[CH:19]=1
Reactant: Nc1nccc2occc12
Reactant: Cc1sc(Br)cc1C(=O)CBr
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1sc(Br)cc1-c1cn2ccc3occc3c2n1
Product: Cc1sccc1-c1cn2ccc3occc3c2n1

Procedure:
A solution of 6.1 g of 2-(5-bromo-2-methyl-3-thienyl)furo[3,2-c]imidazo[1,2-a]pyridine, which was prepared by the reaction of 4-aminofuro[3,2-c]pyridine and 5-bromo-3-bromoacetyl-2-methylthiophene in a similar manner to that of aforementioned Preparation 7, in 50 ml of tetrahydrofuran was added dropwise to a solution of 3.5 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. When addition was complete, the mixture was refluxed for 2 hours. After being cooled, excessive lithium aluminum hydride was decomposed by the addition of hydrous ether, and the mixture was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure to give 4.5 g of the title compound as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl[CH2:19][C:20]1[CH:39]=[CH:38][C:23]([O:24][CH2:25][C:26]2[N:27]=[C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[O:29][C:30]=2[CH3:31])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][C:30]1[O:29][C:28]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:27][C:26]=1[CH2:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][O:1][C:2]2[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:3]=2)=[CH:39][CH:38]=1
Reactant: COC(=O)Cc1cn(-c2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A mixture of methyl (3-hydroxy-1-phenyl-1H-pyrazol-4-yl)acetate (464 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-4-yl]acetate (767 mg, yield 75%) was obtained as colorless crystals from a fraction eluted with ethyl-acetate. The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:7]2[CH2:20][CH2:21][N:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:6]12)=O.[Li+].[BH4-].CO.O>C1COCC1>[C:26]([O:25][C:23]([N:22]1[CH:6]2[CH:7]([N:8]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:11])[CH2:9][CH:5]2[CH2:3][OH:2])[CH2:20][CH2:21]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2C1C(CO)CN2C(=O)OCc1ccccc1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
A solution of ester 76 (2.7 g, 6.7 mmol) in THF (15 mL) was cooled to 0° C. and treated with LiBH4 (10 mL, 2M in THF). After 3 h, the solution was slowly treated with MeOH followed by H2O. The solution was then concentrated and diluted with EtOAc. The solution was slowly treated with 1M HCl until gas generation ceased. The solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was absorbed onto SiO2 and purified by flash chromatography (1:1 hexane/EtOAc to 1:2 hexane/EtOAc) to afford alcohol 77 (1.9 g, 75%) as a light yellow-colored oil. 1H NMR (CDCl3, 300 MHz): δ7.39-7.27 (m, 5H), 5.13-5.09 (m, 2H), 4.43-4.41 (m, 1H), 4.13-4.08 (m, 2H), 3.70-3.29 (m, 6H), 2.48-2.46 (m, 1H), 2.53-2.05 (m, 1H), 2.03-1.99 (m, 1H), 1.48 (s, 9H) ppm. Mass spectrum, m/z [377.5] (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:21][CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>C(#N)C>[Si:24]([O:23][CH2:22][CH2:21][N:4]1[C:3]([CH2:1][CH3:2])=[C:7]([N+:8]([O-:10])=[O:9])[C:6]([C:11]([NH2:13])=[O:12])=[N:5]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO, 9849166), (4.9 g, 26.6 mmol), cesium carbonate (21.0 g, 64.5 mmol) and (2-bromoethoxy)-tert-butyldimethylsilane (7.0 g, 29.0 mmol) in acetonitrile (400 ml) was stirred at 80° C. for 20 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (200 ml) and water (100 ml). The layers were separated, the organic phase washed with water (3×50 ml), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate as eluant, and repeated using an elution gradient of pentane:ethyl acetate (50:50 to 0:100), to give some of the desired compound.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([OH:7])C.[C:8]([O:13][CH2:14][CH2:15]O)(=[O:12])[C:9]([CH3:11])=[CH2:10].N1C=CC=CC=1>C(Cl)Cl>[Cl:4][C:1]([OH:2])=[O:7].[C:8]([O:13][CH2:14][CH3:15])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: O=C(Cl)Cl
Reactant: CCO
Reactant: C=C(C)C(=O)OCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCC
Product: O=C(O)Cl
Temperature: -30 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
750 g (6 mols + 25%) of phosgene and 2 liters of dry, ethanol-free methylene chloride were placed in a 10 liter reactor, cooled to -30° C. A solution of 6 mols (780 g) of hydroxyethyl methacrylate and 6 mols (480 g) of pyridine in 1 liter of methylene chloride was added to this mixture over a period of 1 hour 30 minutes, the temperature being kept at between -10° and -15° C. After two hours of stirring at -10° C., the excess phosgene was removed by degassing with nitrogen. After removing the pyridine hydrochloride by filtration, the solution was rapidly washed with 2 liters of ice-cold water. The organic phase was decanted, dried over magnesium sulphate and concentrated under reduced pressure; 1,040 g of ethyl methacrylate chloroformate were thus obtained in a yield of 90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([N:30]2[C:38]3[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH:25]=[C:24]([O:40][CH3:41])[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.CN(C=O)C>[F:39][C:35]1[CH:34]=[C:33]2[C:38](=[CH:37][CH:36]=1)[N:30]([C:28]([C:26]1[CH:25]=[C:24]([O:40][CH3:41])[N:23]=[C:22]([N:17]3[CH2:18][CH2:19][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:20]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:15][CH2:16]3)[CH:27]=1)=[O:29])[CH2:31][CH2:32]2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4CCc5cc(F)ccc54)cc(OC)n3)CC1)C(=O)N2
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 0.633 g (2.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 0.700 mg (2.28 mmol) (2-chloro-6-methoxypyridin-4-yl)-(5-fluoro-2,3-dihydroindol-1-yl)-methanone and 954 mg (6.90 mmol) potassium carbonate in 5.0 mL NMP was stirred for 8 h at 130° C. After cooling the reaction mixture to RT the precipitate formed was filtered off and purified by preparative HPLC. The fractions containing the product were combined and evaporated down i. vac. The residue obtained was digested in DMF and the product remaining as a solid was suction filtered and dried i. vac. The mother liquor was again purified by preparative HPLC, the fractions containing product were combined and evaporated down i. vac. The residue was triturated with ethanol, the solid product was suction filtered and dried i. vac.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].S(=O)(=O)(O)O.[N:25]([O-])=O.[Na+].[NH2:29][C:30]1[C:35]([OH:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=1>O.N1C=CC=CC=1>[NH2:29][C:30]1[N:31]=[C:32]([N:25]=[N:1][C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:33]([Br:37])=[CH:34][C:35]=1[OH:36]
Reactant: Nc1ncc(Br)cc1O
Reactant: O=N[O-]
Reactant: CC(C)(C)OC(=O)c1cc(-c2ccccc2)sc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(-c2ccccc2)sc1N=Nc1nc(N)c(O)cc1Br
Reaction time: 1.5 h
Yield: 103.1 %

Procedure:
A solution of t-butyl 2-amino-5-phenyl-3-thenoate (8.26 g; 0.03 mole) in 2:5 acid (120 ml) (see Example 1) was chilled to -2° C. and concentrated sulfuric acid (5 ml) was added at such a rate that the temperature did not exceed 2° C.; a solution of sodium nitrite (2.16 g) in water (5 ml) was added dropwise below 2° C. The resulting diazonium solution was stirred at -2° C. to +2° C. for 45 minutes, then added in a slow stream with magnetic stirring to a cold (below 5° C.) solution of 2-amino-5-bromo-3-pyridinol (Example 2-L) (5.67 g; 0.03 mole) in pyridine (30 ml) and 2:5 acid (90 ml). The dye solution was stirred at 0° to 5° C. for 1.5 hours, then the cooling bath was removed and the mixture stirred for an additional 30 minutes. After drowning in cold water (2.5 liters), the dye was collected on a filter, washed with water and dried to yield 14.7 g of material with only traces of impurities.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[CH:31]=[C:32]([I:34])[S:33][C:26]=12>CN(C1C=CN=CC=1)C.BrC1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:23])[N:11]([CH3:22])[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:25]1[CH:30]=[CH:29][N:28]=[C:27]2[CH:31]=[C:32]([I:34])[S:33][C:26]=12
Reactant: Clc1ccnc2cc(I)sc12
Reactant: Cn1c(Nc2ccccc2)ncc(-c2ccc(O)c(F)c2)c1=O
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cn1c(Nc2ccccc2)ncc(-c2ccc(Oc3ccnc4cc(I)sc34)c(F)c2)c1=O
Temperature: 150 °C
Reaction time: 168 h

Procedure:
A suspension of 5-(3-fluoro-4-hydroxyphenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.113 g, 0.266 mmol), 7-chloro-2-iodothieno[3,2-b]pyridine (0.075 g, 0.254 mmol; prepared according to the procedure of Ragan, J. A. Org. Proc. Res. 2003, 7, 676) and DMAP (0.003 g, 0.025 mmol) in bromobenzene (3 mL) was stirred under nitrogen. The reaction mixture was allowed to stir for 7 days at 150° C. and then for 2 days at room temperature. The reaction was concentrated in vacuo to remove as much bromobenzene as possible. The resulting gummy brown residue was dissolved in CH2Cl2 and then EtOAc was added to yield a dark brown solid precipitate that was filtered and washed with EtOAc. The filtrate, which contained the desired product, was concentrated and purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. Product containing fractions were pooled and concentrated to yield (0.020 mg) of the desired product. Impure fractions were pooled, concentrated and repurified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product isolated from the two purifications were combined to yield the desired product (39 mg; 27%) as a yellow solid. LRMS (APCI pos) m/e 571 (M+1).