Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5]1.[ClH:22].O1CCOCC1>CCO.[Pd].CCOC(C)=O>[ClH:22].[CH3:21][C:2]([OH:1])([CH3:20])[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]1
Reactant: CC(C)(O)CN1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(O)CN1CCNCC1
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of benzyl 4-(2-hydroxy-2-methylpropyl)piperazine-1-carboxylate (0.54 g, 1.847 mmol) in EtOH (10 mL) was added 10% palladium on carbon (0.1 g, 0.094 mmol). The reaction was stirred overnight under a hydrogen atmosphere. After 16 hours, the reaction was filtered through Celite® brand filter aid (rinsed with MeOH and DCM). The filtrate was concentrated to a clear oil, the oil was diluted with EtOAc, and 4 N HCl/dioxane (0.5 mL; 2 mmol) was added dropwise. The white precipitate was collected by vacuum filtration, washed with diethyl ether, and dried in vacuo, to generate 2-methyl-1-(piperazin-1-yl)propan-2-ol hydrochloride as a brown powder (0.31 g, 86% yield).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[O:7])=[CH:4][C:3]=1[O:34][CH3:35].[H-].[Na+].[N+:38]([C:41]1[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=1[CH2:43]Br)([O-:40])=[O:39]>CN(C)C=O>[CH3:35][O:34][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:2]=1[O:1][CH2:43][C:42]1[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=1[N+:38]([O-:40])=[O:39])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1O
Reactant: O=[N+]([O-])c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1OCc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of 4-hydroxy-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-benzamide (320 mg) in N,N-dimethylformamide (8 ml) was treated with sodium hydride (29.1 mg, 60% w/w in mineral oil) at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes and then at ambient temperature for 10 minutes. o-Nitrobenzyl bromide (143 mg) was added, and the reaction mixture was stirred for 2.5 hours. The reaction was quenched with water and the mixture was diluted with ethyl acetate. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, and brine. The organic solution was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography (SiO2 15 g, 3% methanol in dichloromethane) to give 3-methoxy-4-(2-nitrobenzyloxy)-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (210 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1>[C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Ic1ccccc1
Agent: CC(C)(C)O[K]
Solvent: Cc1ccccc1
Product: c1ccc(N2CCOCC2)cc1
Temperature: 100 °C
Yield: 62 %

Procedure:
To a toluene solution (3 ml) containing iodobenzene (110 mg), morpholine (73.2 mg), and tert-butoxypotassium (110 mg) the mesh catalyst precursor (12 mm by 14 mm, wire diameter of 0.1 mm, opening of 0.154 mm) prepared in Example 3 was added to be heated for 24 hours at 100° C. The reaction mixture was cooled to room temperature, and the mesh catalyst precursor was washed with ethanol to be taken off from the mixture. The solvent was distilled away from the reaction mixture under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give an intended product, 4-phenylmorpholine with 62% yield. The mesh catalyst precursor taken off from the mixture was recycled in the same reaction to give the intended product, 4-phenyl-morpholine with respective yields of 61%, 57%, 58%, 54%, 58%, 58%, 53%, 53%, 53% from the second to the tenth reaction.
Reaction SMILES: [CH2:1]([O:8][N:9]1[CH:13]=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]=[O:23])[CH3:20]>C1COCC1>[CH2:1]([O:8][N:9]1[C:13]([CH:22]([OH:23])[CH:21]([CH2:24][CH3:25])[CH2:19][CH3:20])=[CH:12][CH:11]=[N:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C=O)CC
Reactant: c1ccc(COn2cccn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ccnn1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 72 %

Procedure:
To 1-benzyloxy-1H-pyrazole (prepared as described in JOC 60:4996 1995) dissolved in THF (20 mL) and cooled to −78° C. under a nitrogen atmosphere was added a solution of n-butyllithium (1.6 M in hexane, 2.0 mL, 3.2 mmol) via syringe over 10 min. After stirring at the above temperature for 1.25 h, 2-ethyl-butyraldehyde (0.42 mL, 3.4 mmol) was added dropwise. The mixture was then stirred at −78° C. for 1.5 h and quenched by dropwise addition of saturated aqueous ammonium chloride solution (3 mL). The mixture was warmed to ambient temperature and diluted with EtOAc, washed with saturated aqueous NaCl and the organic phase was dried over MgSO4. Filtration and evaporation of the organic extract produced an oil that was purified on a Biotage column (hexane/EtOAc, 6:1) to give the product as a clear colorless oil (0.565 g, 72%).
Reaction SMILES: CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[OH:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17].Br[CH2:26][CH2:27][Cl:28]>O>[Cl:28][CH2:27][CH2:26][O:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:16]([O:18][CH3:19])=[O:17]
Reactant: ClCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(OCCCl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
To DMF (40 mL) was added potassium carbonate (9.1 g, 65.9 mmol) and methyl 3-hydroxy-4-methoxybenzoate (10.0 g, 54.9 mmol) and the mixture stirred 30 minutes at room temperature 1-bromo-2-chloroethane (11.0 g, 76.8 mmol) was added and the mixture was heated at 60° C. overnight at which point excess 1-bromo-2-chloroethane (5.5 g, 38.4 mmol) was added and heating continued for 8 hours. After cooling to room temperature, the mixture was diluted with H2O, filtered, and the solid washed with EtOAc to give methyl 3-(2-chloroethoxy)-4-methoxybenzoate (4.04 g, 16.6 mmol, 30%). 1H NMR (300 MHz, DMSO-d6) δ 7.63 (d, 1H), 7.47 (s, 1H), 7.11 (d, 1H), 4.29 (t, 2H), 3.95 (t, 2H), 3.86 (s, 3H), 3.81 (s, 3H); LC-MS (ESI) m/z 245 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[O:29])=[CH:23][CH:22]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[O:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:28]([NH:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:15][CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=2)=[CH:26][CH:25]=1)=[O:29]
Reactant: O=C(Nc1ccc(O)cc1)c1ccco1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccc(NC(=O)c3ccco3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and furan-2-carboxylic acid (4-hydroxy-phenyl)-amide via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1) to produce a white solid. MS (ES) for C23H23NO7 [M+H]+: 426.3.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH3:13][C:14]1([CH3:24])[C@@H:16]([CH:17]=[C:18]([Cl:20])[Cl:19])[C@@H:15]1[C:21]([O-:23])=[O:22]>O>[CH3:13][C:14]1([CH3:24])[CH:16]([CH:17]=[C:18]([Cl:20])[Cl:19])[CH:15]1[C:21]([OH:23])=[O:22]
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 30 °C
Reaction time: 20 h

Procedure:
After 100 ml of a liquid medium (pH 6.5, prepared by dissolving 5.0 g of peptone, 10.0 g of glucose, 3.0 g of malt extract and 3.0 g of yeast extract in 1 l of water) was put in a 500 ml flask and sterilized, a loopful of cells of the microorganism each shown in the Table 4 was inoculated from slant culture into the sterilized liquid medium and was subjected to shaking culture at 30° C. for 20 hours. To the cultured solution was added 1.0 g of ethyl (±)-cis, trans-2,2-dimethyl-3(2,2-dichlorovinyl)cyclopropane carboxylate (cis/trans ratio=45/55) and the mixture was reciprocally shaked at 30° C. for 72 hours. Extraction, isolation and analysis of the resulting culture were performed in the same manner as in Example 38 to obtain almost chemically pure 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid (permethric acid). All of the ethyl 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate added were recovered as it was excluding that which has been converted to 2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid. The analytical results of the reaction performed by each bacterial strain are shown in Table 4. In the table, the yield represents the molar yield of (+)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylic acid to ethyl (+)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropane carboxylate contained in the starting material.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][O:13][C:14]=2[N:15]=1)([CH3:3])[CH3:2].[ClH:23].C(OCC)(=O)C>>[ClH:23].[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]=2[N:15]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 3 %

Procedure:
A mixture of the compound obtained in step 1 (0.21 g) and 4N hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane), and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration and recrystallized from ethanol-ethyl acetate to give the title compound (0.0050 g, 3%) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].N1C=CC=CC=1.[CH3:11][NH:12][C:13](=[O:30])[C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CO.[Cl-].[Na+].O>[CH3:2][O:3][N:4]=[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[C:13]([NH:12][CH3:11])=[O:30]
Reactant: CON
Reactant: CNC(=O)C(=O)c1ccccc1COC1CCCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1COC1CCCCO1
Yield: 60.4 %

Procedure:
Methoxyamine hydrochloride (0.33 g, 0.004 mol) was dissolved in methanol (4 ml), and pyridine (0.47 g, 0.006 mol) was added to the solution. To the mixture was added a mixed solution of N-methyl-2-oxo-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.55 g, 0.002 mol) and methanol (2 ml). The mixture was stirred under reflux for 2 hours. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (80 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain an E/Z mixture of 2-methoxyimino-N-methyl-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.37 g, Yield: 60.4%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([OH:29])=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35](=[O:43])([O:39][CH:40]([CH3:42])[CH3:41])[O:36][CH2:37]Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27]([O:29][CH2:37][O:36][C:35]([O:39][CH:40]([CH3:42])[CH3:41])=[O:43])=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CC(C)OC(=O)OCCl
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)OCOC(=O)OC(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 46.8 %

Procedure:
4-((6-(2,4-dichlorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.22 g, 0.4 mmol) was reacted with chloromethyl isopropyl carbonate (0.25 g, 1.64 mmol) according to the procedure as described in Example 79 to give the title compound as yellow oil (0.12 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][C:17](=[O:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17](=[O:19])[CH3:18]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Bromophenol (6.27 g, 36 mmol) and cesium carbonate (20. g, 61.2 mmol) were dissolved in DMF (50 mL) and stirred for 15 minutes at room temperature. Chloroacetone (4.3 mL, 54 mmol) was added and the reaction stirred for 1 hour and was submitted to aqueous workup. Purification by silica gel chromatography (0-50% EtOAc in hexanes) afforded the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][NH:7][C:6]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[N:5]1.C(N(CC)CC)C.[CH3:28][O:29][C:30]([S:32]Cl)=[O:31]>O1CCCC1>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]1[C:9](=[O:10])[CH2:8][N:7]([S:32][C:30]([O:29][CH3:28])=[O:31])[C:6]([C:11]2[CH:12]=[C:13]([Cl:18])[CH:14]=[C:15]([Cl:17])[CH:16]=2)=[N:5]1
Reactant: O=C1CNC(c2cc(Cl)cc(Cl)c2)=NN1CC(F)(F)F
Reactant: COC(=O)SCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)SN1CC(=O)N(CC(F)(F)F)N=C1c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 42.4 %

Procedure:
To a solution of 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one (110 mg, 0.34 mmol) dissolved in 5 mL tetrahydrofuran was added triethylamine (0.06 mL, 0.40 mmol) and methoxy-carbonylsulfenyl chloride (0.04 mL, 0.40 mmol). After 30 min, the reaction was quenched with water and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×5 mL), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was subjected to flash column chromatography (10% ethyl acetate/hexanes) to afford 1-(2,2,2-trifluoroethyl)-3-(3,5-dichlorophenyl)-4-(methoxycarbonylthio)-4,5-dihydro-1,2,4-triazin-6-one (60 mg, 43%) in 80% purity by LC.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[F:15][C:14]([F:17])([F:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH2:7][CH2:6][NH:5][C:4]2=[O:3]
Reactant: CCOC(=O)NCCc1ccccc1C(F)(F)F
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2c1cccc2C(F)(F)F
Temperature: 115 °C
Reaction time: 2 h
Yield: 9.1 %

Procedure:
Using the same procedure and workup as described in Example 1, step 4, [2-(2-trifluoromethyl-phenyl)-ethyl]-carbamic acid ethyl ester (I-22c: 1.2 g, 4.5977 mmol) in POCl3 (13 mL) was reacted with P2O5 (1.3 g, 9.195 mmol). The resulting mixture was stirred at 115° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.090 g of the product (9.1% yield).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([CH3:12])[CH:11]=[CH:10][C:9]([S:1]([OH:3])(=[O:5])=[O:2])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
560 g of 98% sulfuric acid was dropped into 600 g of toluene with stirring. Then, the temperature was raised at 110 to 120° C. while stirring, reacting for 5 hours. After the reaction, the temperature was decreased while distillation water was added, and upon the temperature reached at about 20° C., a small amount of a crystalline of p-toluenesulfonic acid (4-methylbenzenesulfonic acid) in the system, which was provided in advance, was put therein, generating crystalline deposition of p-toluenesulfonic acid. The crystalline as obtained was collected by filtering, into which distillation water was added. Then, the temperature of the liquid was raised into 60° C. again to dissolve. Then, the temperature was gradually decreased, and upon the temperature reached at about 20° C., a small amount of a crystalline of p-toluenesulfonic acid was added to deposit crystalline. The crystalline was collected by filtering to obtain toluenesulfonic acid in which the para compound was included at 99 mole % in the total of the toluenesulfonic acid. Note that the measurement of the concentration of the para compound was carried out by using HPLC (High Performance Liquid Chromatography) manufactured by Shimadzu Corporation. The same measure was used hereinafter.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=[C:6]([Br:14])[CH:5]=1)=[O:3].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[Br:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]2[O:10][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:1][C:2](=[O:3])[C:4]=2[CH:5]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cc(Br)cc([N+](=O)[O-])c1O
Product: CCOC(=O)c1cc(=O)c2cc(Br)cc([N+](=O)[O-])c2o1
Yield: 77 %

Procedure:
Following the process described in example 1 (point A), starting from 5-bromo-2-hydroxy-3-nitroacetophenone and diethyl oxalate, the title compound was prepared, which was purified by crystallization in tetrahydrofuran:ethanol mixtures (77% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])[N:5]=[N:6][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[F:22].C([O-])([O-])=O.[K+].[K+].Cl.CCOCC>CO.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>[ClH:1].[Cl:15][C:16]1[CH:17]=[C:18]([C:2]2[CH:3]=[C:4]([CH2:8][N:9]3[CH:13]=[CH:12][N:11]=[C:10]3[CH3:14])[N:5]=[N:6][CH:7]=2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CO
Product: Cc1nccn1Cc1cc(-c2ccc(F)c(Cl)c2)cnn1
Yield: 86.7 %

Procedure:
5-Chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine (0.07 g, 0.34 mmol), 3-chloro-4-fluorophenylboronic acid (0.076 g, 0.44 mmol), K2CO3 (0.09 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium (0.04 g, 0.034 mmol) were mixed and degassed dioxane (1.4 ml) was added. The mixture was refluxed for 44 hours and the solvent was removed in vacuo. The residue was taken in MeCl2, filtrated and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (CH2Cl2—MeOH 98:02) to provide a white foam which was dissolved in MeOH (2 ml). HCl-Et2O was added to provide 5-(3-chloro-4-fluoro-phenyl)-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine hydrochloride (0.1 g, 77%) as an offwhite solid, MS: m/e=302.7 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(CCO)(=O)=[O:26].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:26])[C:15]=2[N+:21]([O-:23])=[O:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCO
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(F)c2[N+](=O)[O-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.3 %

Procedure:
To a cooled stirring solution of 4-(3-fluoro-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.50 g, 4.61 mmol), and 2-(methylsulfonyl)ethanol (876 mg, 6.92 mmol) in anhydrous DMF (15 mL), under nitrogen, was added, portionwise, sodium hydride (553 mg, 13.8 mmol, 60% oil dispersion). The solution foamed upon the sodium hydride addition. The resulting dark orange solution was stirred, at 0° C., for 30 minutes upon completion of sodium hydride addition. The reaction solution became viscous and additional DMF (5 mL) was added, via syringe, the ice bath removed and the dark solution stirred at room temperature, under nitrogen, for 2 h. The reaction was cooled in an ice bath, quenched with 0.1N hydrochloric acid solution, and transferred to a separatory funnel with ethyl acetate (100 mL). This organic phase was washed with brine (75 mL×3). The aqueous washings were combined and extracted with ethyl acetate (75 mL×3). The organic extracts were combined and washed with saturated aqueous sodium bicarbonate solution (100 mL), brine (100 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed to give an amber colored oil (2.21 g). This oil was adsorbed onto silica and purified by column chromatography, eluting with 50% ethyl acetate in hexane to afford the product as a light yellow colored solid (1.37 g, 92%). Mass Spectrum (+ESI): 324 [M+H]+, 322 [M−H]−.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl.[OH:14][C:15]1[C:22]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[C:27]([CH3:30])([CH3:29])[CH3:28]>C(O)C>[OH:14][C:15]1[C:22]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:21][C:18]([CH:19]=[N:1][N:2]2[CH:6]=[CH:5][N:4]=[C:3]2[N:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[CH:17][C:16]=1[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Nn1ccnc1N1CCOCC1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(C=Nn2ccnc2N2CCOCC2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.18 g of 1-amino-2-morpholinoimidazole are dissolved in 50 ml of ethanol and treated with 3.5 ml of 2N hydrochloric acid. After the addition of 1.65 g of 4-hydroxy-3,5-di-tert.-butylbenzaldehyde, the reaction mixture is stirred at room temperature overnight. The solvent is subsequently removed by evaporation in a vacuum. The residue is treated with 20 ml of water and saturated sodium carbonate solution is added up to an alkaline reaction. The separated, colorless product is removed by filtration and purified by column chromatography (eluent methylene chloride/methanol 10%). By recrystallization from water/methanol, there is obtained pure 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-morpholinoimidazole of m.p. 185°-187°.