Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.C([C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[O:13][C:12](=[O:18])[CH:11]=[C:10]2[OH:19])C.[CH:20](Cl)(Cl)Cl>>[CH3:17][C:16]1[C:15]([CH3:20])=[C:14]2[C:9]([C:10]([OH:19])=[CH:11][C:12](=[O:18])[O:13]2)=[CH:8][CH:7]=1
Reactant: CCc1cc2c(O)cc(=O)oc2cc1C
Reactant: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Product: Cc1ccc2c(O)cc(=O)oc2c1C

Procedure:
Fuming nitric acid (16 ml) was added to a stirred suspension of 6-ethyl-4-hydroxy-7-methylcoumarin (m.p. 234°-7° ; 3.17g) in chloroform (250 ml) at room temperature over 1 hour. After standing for a further hour, the solvent was removed in vacuo at room temperature and 6N hydrochloric acid (60 ml) added to the residue. Filtration gave the product, m.p. 170°-2°(d), (C12H11NO5 requires C, 57.83; H, 4.45; N, 5.62. Found: C, 58.07; H, 4.54; N, 5.76).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:5]=[C:6]([C:15]([O:17]C)=[O:16])[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1>CO.O>[CH3:3][C:4]1[N:5]=[C:6]([C:15]([OH:17])=[O:16])[S:7][C:8]=1[C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(C)c(-c2ccncc2)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(C(=O)O)sc1-c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
Potasium hydroxide (1 g) was added to a stirred solution of methyl 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylate (2 g) in methanol (50 ml) at room temperature and the mixture was stirred at room temperature for 1.5 hours, diluted with water (150 ml), and washed with chloroform. Then the solution was adjusted to pH 3 to 4 by addition of 2N hydrochloric acid aqueous solution. The resulting precipitate was collected by filtration, and air-dried to give 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxylic acid (1.8 g, 96%) as colorless powder.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH2:9]=[O:10]>C(N(CC)CC)C>[OH:10][CH2:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CO)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
To a 2 liter, round bottomed flask fitted with a nitrogen inlet were added 500 grams (3.6 mole) of diethyl phosphite (Aldrich), 120 grams (3.8 mole) of paraformaldehyde (Baker) and approximately 6 milliliters of triethylamine. The mixture was stirred overnight at room temperature but no visible reaction had occurred so approximately 10 milliliters more of triethylamine was added and the mixture was slowly warmed to 90° C. The solution was heated for approximately an additional hour, filtered hot and distilled. 320 grams of a liquid product corresponding to a 60% yield was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]1[CH2:15][C:14](=[O:16])[C:13]([C:17](=O)[CH2:18][CH3:19])=[C:12]([OH:21])[CH2:11]1.Cl.[CH2:23]([O:25][NH2:26])[CH3:24]>>[CH3:9][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]1[CH2:15][C:14](=[O:16])[C:13]([C:17](=[N:26][O:25][CH2:23][CH3:24])[CH2:18][CH3:19])=[C:12]([OH:21])[CH2:11]1
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O
Agent: Cl
Product: CCON=C(CC)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O

Procedure:
5-(2,6-Dimethyl-4-hydroxyphenyl)-2-[1-(ethoxyimino)propyl]-3-hydroxycyclohex-2-en-1-one (31) was prepared from 5-(2,6-dimethyl-4-hydroxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv). The product was characterized by proton nuclear magnetic resonance spectroscopy and the spectroscopic data is reported in Table 5, Example 37.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[F:22])=[CH:7][C:8]([C:12]#N)=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH3:24][OH:25].C[OH:27]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[F:22])=[CH:7][C:8]([C:12]([O:25][CH3:24])=[O:27])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: COc1ccc(-c2cc(C#N)nc3cc(Cl)ccc23)c(F)c1
Agent: Cl
Product: COC(=O)c1cc(-c2ccc(OC)cc2F)c2ccc(Cl)cc2n1
Temperature: 60 °C
Yield: 90 %

Procedure:
7-Chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carbonitrile (4.4 g, 14.07 mmol) was suspended in MeOH (70.3 ml), added 200 ml sat HCl/MeOH and then heated to 60° C. for 4 hours. The reaction was allowed to cool to ambient temperature and then was concentrated. The residue was dissolved in EtOAc and then washed with 1:1 1N NaOH/sat NaHCO3, brine, dried (MgSO4) and concentrated to afford methyl 7-chloro-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (4.4 g, 12.73 mmol, 90% yield) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@H:35]3[CH3:40])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[NH4+:42]>CCO>[NH2:42][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[C@@H:13]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][C@@H:35]3[CH3:40])[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc(N)nc2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 140 °C

Procedure:
The crude chloropyridine derivative was dissolved in 2 mL of EtOH and 2 mL of 30% aqueous ammonium hydroxide. This solution was heated to 140° C. for 60 min. The mixture was concentrated in vacuo and the crude material was purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (23 mg) as a foamy solid.
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Br.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>CN(C)C=O>[Br:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:11]1[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]2[C:7]1=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrC/C=C/CBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Temperature: 50 °C

Procedure:
A mixture of trans-1,4-dibromo-2-butene (6.4 g, 30 mmol) and potassium phthalimide (5.6 g, 30 mmol) in anhydrous dimethyl formamide (200 ml) was heated at 50° C. for 24 h. Then the reaction mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with brine and the pure title product was obtained by flash chromatography on silica gel (ethyl acetate: hexane; 15:85) (3.2 g, 40%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH2:15](I)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:16][CH3:17]
Reactant: CCCI
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A mixture of 5-nitrovanillin (10 g), propyl iodide (25 g), potassium carbonate (10 g) and N,N-dimethylformamide (200 ml) is stirred at 100° C. for 24 hours. After cooling, water (500 ml) is added to the reaction mixture, followed by extraction with ethyl acetate (200 ml). The extract solution is washed with water, dried and, then, distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=2:1-1:1) to afford 4-propoxy-3-methoxy-5-nitrobenzaldehye (6 g) as a pale yellow oily product. This product is dissolved in acetone (200 ml), and potassium permanganate (18 g) is added to the solution. The mixture is stirred at room temperature overnight. To the reaction mixture are added ethanol (50 ml), water (50 ml) and acetone (200 ml). The whole mixture is stirred for two hours, and filtered off. The filtrate is concentrated under reduced pressure. Precipitating crystals are collected by filtration to give 3-methoxy- 5-nitro-4-propoxy benzoic acid (2.2 g) as colorless crystals. This product is recrystallized from a mixture of ethanol and water to give colorless needles, m.p. 121°-123° C.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:14]2[C:9](=[C:10]([OH:15])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6].[CH2:16]([OH:21])[CH:17]([OH:20])[CH2:18]Cl>CO>[CH3:3][N:4]1[C:14]2[C:9](=[C:10]([O:15][CH2:18][CH:17]([OH:20])[CH2:16][OH:21])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:5]1=[O:6]
Reactant: CN1C(=O)CCc2c(O)cccc21
Reactant: OCC(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)CCc2c(OCC(O)CO)cccc21
Yield: 22 %

Procedure:
2.0 g of potassium hydroxide was dissolved in 80 ml of methanol, and 4.8 g of 1-methyl-5-hydroxy-3,4-dihydrocarbostyril and 4.0 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 4 hours. After allowing the mixture to cool, the precipitated crystals were filtered, and the filtrate was concentrated to dryness. The residue thus obtained was extracted with 120 ml of chloroform, and the extract was washed with a 5% aqueous potassium hydroxide solution and then water and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethyl acetate to give 1.5 g of 1-methyl-5-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a colorless amorphous solid having a melting point of 120° - 121° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH:5]=[C:6]1[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]1=[O:15].[CH:19]1([Mg]Br)[CH2:21][CH2:20]1.Cl.O>C1COCC1>[CH:19]1([CH:5]([C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([OH:1])[CH:3]=2)[CH:6]2[C:7](=[O:15])[O:8][C:9]([CH3:14])([CH3:13])[O:10][C:11]2=[O:12])[CH2:21][CH2:20]1
Reactant: Br[Mg]C1CC1
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(C(c2cccc(O)c2)C2CC2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-(3-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (65.0 g) in THF (1.30 L) was added dropwise a 10% solution of cyclopropylmagnesium bromide in THF (2.20 kg) at −11° C. to −1° C. over 1.6 hr, and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid was added to the reaction mixture at 2° C. to 17° C. to adjust the solution to pH 3. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (76.0 g) as a yellow oil.
Reaction SMILES: [CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[C:6](OCC)=[O:7].[BH4-].[Li+].C1COCC1.Cl>O>[CH:1]1[C:2]2[CH:22]=[CH:21][C:20]3[C:19]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH:13]=[CH:12][C:11]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7]
Reactant: CCOC(=O)c1cc2ccc3c4ccccc4ccc3c2o1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cc2ccc3c4ccccc4ccc3c2o1
Yield: 90.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet tube with bubbler was added ethyl phenanthro(1,2-b]furan-2-carboxylate (H. G. Pars Pharmaceutical Laboratories, Inc., 7.9 g, 27.2 mmol), lithium borohydride (Aldrich, 0.65 g, 30 mmol) and dry THF (400 mL). The mixture was stirred at reflux for 6 h and then poured into H2O (1 L). The reaction mixture was acidified with 1 N HCl and the resulting white solid was filtered, washed with additional H2O (1500 mL) then dissolved in CH2Cl2 (500 mL), dried (Na2SO4), filtered, concentrated to 200 mL and diluted to 500 mL with hexane. The resulting material was filtered, washed with hexane (100 mL) and placed in a vacuum oven overnight. A total of 6.1 g (90.1%) of phenanthro[1,2-b]furan-2-methanol, mp 125°-126° was obtained (C,H).
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][CH:12]=3)[C@@:7]3([CH2:21][CH2:20][O:19][C:18]([NH2:22])=[N:17]3)[C:6]=2[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](O)=[O:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[NH2:22][C:18]1[O:19][CH2:20][CH2:21][C@@:7]2([N:17]=1)[C:6]1[CH:5]=[C:4]([O:23][CH3:24])[CH:3]=[C:2]([F:1])[C:15]=1[O:14][C:13]1[C:8]2=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]2[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][N:30]=2)=[CH:11][CH:12]=1
Reactant: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(N)ccc1O2
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(F)c2c(c1)[C@]1(CCOC(N)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2
Reaction time: 0.03 h
Yield: 46.8 %

Procedure:
To a suspension of (S)-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthene]-2,7′-diamine (102 mg, 0.310 mmol) and 5-chloropicolinic acid (54 mg, 0.341 mmol) in ethyl acetate (2 mL) was added triethylamine (0.13 mL, 0.929 mmol) and the mixture was stirred for 2 min, followed by addition of 1-propanephosphonic acid cyclic anhydride (T3P) (50 wt. % solution in ethyl acetate) (0.37 mL, 0.619 mmol). After 2 hr at RT, the mixture was quenched with sat NaHCO3 and diluted with 3 ml EtOAc. The organic layer was separated, concentrated in vacuo, and the residue purified by FC on 12 g RediSep Gold column using 10-80% DCM/MeOH/NH4OH (90:10:1) in DCM to afford (S)—N-(2-amino-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]oxazine-4,9′-xanthen]-7′-yl)-5-chloropicolinamide (68 mg, 0.145 mmol, 47% yield).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:12]N)[CH:4]=1.O=[C:15]1[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]1>C(O)(=O)C.CCOC(C)=O>[Br:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:20]1[CH2:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][C:15]=1[NH:12]2
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: NNc1cc(Br)ccc1C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)ccc(Br)c23)C1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
Step 2 A stirred suspension of 4-bromo-2-hydrazinylbenzoic acid hydrochloric acid salt (16.35 g, 58.1 mmol) in acetic acid (171 mL) was treated with ethyl 3-oxocyclohexanecarboxylate (9.88 g, 58.1 mmol) at rt. The mixture was stirred at reflux for 2.5 h, then was cooled to rt and concentrated to afford a brown solid. This was suspended in EtOAc (20 mL) and the precipitate was collected by filtration, washed with EtOAc and air dried to provide 5-bromo-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid (11.46 g). The filtrate was concentrated and the residue was resuspended in EtOAc, the precipitate collected by filtration and dried to provide additional product (0.82 g) for a total of 12.28 g (58%). 1H NMR (400 MHz, DMSO-d6) δ 13.10 (br. s., 1H) 11.06 (s, 1H) 7.50 (d, J=8.13 Hz, 1H) 7.19 (d, J=8.13 Hz, 1H) 4.07-4.15 (m, 2H) 3.08-3.19 (m, 1H) 2.99-3.08 (m, 1H) 2.89-2.99 (m, 2H) 2.79-2.89 (m, 1H) 2.09-2.22 (m, 1H) 1.75-1.89 (m, 1H) 1.20 (t, J=7.14 Hz, 3H). Mass spectrum m/z 366.0, 368.0 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[CH2:14]([CH:17]([C:20]#[N:21])[C:18]#[N:19])[CH:15]=[CH2:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:14]([C:17]([CH2:8][N:6]1[CH:7]=[C:3]([Br:2])[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:5]1)([C:20]#[N:21])[C:18]#[N:19])[CH:15]=[CH2:16]
Reactant: CC(C)(C)c1nn(CCl)cc1Br
Reactant: C=CCC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cc(Br)c(C(C)(C)C)n1
Yield: 40.9 %

Procedure:
1.84 g of 4-bromo-3-t-butyl-1-(chloromethyl)-1H-pyrazole hydrochloride and 0.77 g of allyl malononitrile were dissolved in 21 ml of N,N-dimethylformamide. 2.02 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.84 g of allyl [(4-bromo-3-t-butyl-1H-pyrazole-1-yl)methyl]malononitrile (referred as the compound of the present invention (14), hereinafter) shown by below formula.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10]Cl.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cn1c([N+](=O)[O-])cnc1CCl
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c([N+](=O)[O-])cnc1COc1ccc(S(C)(=O)=O)cc1

Procedure:
17.6 Grams (0.1 mole) of 1-methyl-2-chloromethyl-5-nitro-imidazole were heated for 2 hours at a temperature of from 50° to 60° C, while stirring thoroughly, as has been described in detail in Example 2 above, together with 17.2 g (0.1 mole) of 4-methylsulfonylphenol in 50 ml of dimethylacetamide, in the presence of 13.8 g (0.1 mole) of potassium carbonate. According to the processing method described in Example 1 above, 22.5 g (= 73% of the theory) of 1-methyl-2-(4-methylsulfonyl-phenoxymethyl)-5-nitro-imidazole were obtained in the form of white crystals having a melting point of 157° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12])=O.[NH2:14][C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CC(C)=O>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[CH:2]=1)([O-:13])=[O:12]
Reactant: Nc1ncccn1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1-c1cn2cccnc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
2-Bromo-2′-nitroacetophenone (5.0 g, 20.4 mmol) and 2-aminopyrimidine (1.94 g, 20.4 mmol) were dissolved in acetone (50 ml) and brought to reflux. After 60 minutes a light white precipitate developed. Refluxing was continued for 5.5 hours and cooled to room temperature. The volume was reduced ½ by evaporation and the intermediate solids were collected by filtration, washed with acetone (20 ml) and air dried (2.84 g of intermediate). A second crop was collected by concentration of the combined mother liquors, and refluxing the residue in fresh acetone (20 ml) for 1.5 hours. Upon cooling, and reducing the volume by ½ by evaporation, 3.11 g of solids were collected. The combined solid intermediate (5.95 g) was dissolved in MeOH (70 ml) with 5 drops of conc. HBr and refluxed for 2 hours. After cooling the volume was reduced by ½, water (40 ml) was added solution was made basic (pH=10) with 1N NaOH. Roto-evaporation to remove methanol resulted in the product crystallizing. The product was filtered, washed with water and air dried to obtain 5.03 g of the desired product. (MS, M++H=241.0)
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH3:13][CH:14]1[NH:18][C:17](=[O:19])[CH2:16][CH2:15]1>>[CH3:13][CH:14]1[CH2:15][CH2:16][C:17](=[O:19])[N:18]1[C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1
Reactant: CC1CCC(=O)N1
Reactant: CCOC(=O)c1ccc(I)cc1
Product: CC1CCC(=O)N1c1ccc(C(=O)O)cc1

Procedure:
Using ethyl 4-iodobenzoate (1.70 mL) and 5-methylpyrrolidin-2-one (0.98 g) and by the reaction and treatment in the same manner as in Preparation Example 15, the title compound (1.80 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29](OC)=[O:30].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:29](=[O:30])[C:28]([F:34])([F:33])[C:27]([F:36])([F:35])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: COC(=O)C(F)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)C(F)(F)F
Temperature: -73 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (3.0 g) in tetrahydrofuran (80 ml) at -80° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -73° C., n-butyllithium (2.78 ml of a 2.5M solution in hexanes). The mixture was stirred at -73° C. for 10 minutes and then a solution of methyl pentafluoropropionate (0.89 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture allowed to warm to room temperature over a period of 1.5 hours. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (80 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a pale yellow solid which was purified by column chromatography on silica gel (150 g) eluted with dichloromethane:hexane (9:1). Combination and evaporation of suitable fractions gave a yellow oil which was further purified by column chromatography on silica gel (50 g) eluted with dichloromethane:hexane (9:1). Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 120° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=2[CH:4]=1.[Br:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:14][C:15]1[N:16]=[CH:17][N:18]([CH2:2][C:3]2[CH:13]=[CH:12][C:6]3[N:7]=[C:8]([S:10][CH3:11])[S:9][C:5]=3[CH:4]=2)[CH:19]=1
Reactant: Brc1c[nH]cn1
Reactant: CSc1nc2ccc(CCl)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.2 %

Procedure:
To a stirred mixture of 6-(chloromethyl)-2-(methylthio)benzo[d]thiazole (0.2 g, 0.9 mmol) from Step 4 of this Example and 4-bromo-1H-imidazole (0.2 g, 1.3 mmol) in anhydrous DMF (3.0 mL) was added K2CO3 (0.37 g, 2.7 mmol). After stirred for 3 h at rt, the reaction mixture was partitioned between EtOAc (100 mL) and water (50 mL). The EtOAc layer was separated, washed with brine (50 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 30% EtOAc in hexanes to 100% EtOAc to afford 6-((4-bromo-1H-imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (160 mg, 54%) as a yellow oil. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J=8.3 Hz, 1H), 7.54 (d, J=1.1 Hz, 1H), 7.45 (d, J=1.3 Hz, 1H), 7.24 (dd, J=1.7, 8.5 Hz, 1H), 6.88 (d, J=1.5 Hz, 1H), 5.17 (s, 2H), 2.80 (s, 3H). LCMS (ESI) m/z 340 and 342 (M+H)+.