Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]>O.C(O)C>[CH2:3]([C:6]1[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)[CH2:4][CH3:5]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1nc2cnc3ccccc3c2n1CCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
A solution of sodium hydroxide (2.23 g, 55.9 mmol) in water (100 mL) was added to a solution of ethyl 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoate (14.6 g, 43.0 mmol) in ethanol (100 mL). The reaction mixture was stirred at room temperature overnight, then the ethanol was removed under reduced pressure. The remaining aqueous solution was washed with dichloromethane and adjusted to pH 5 with 10% aqueous hydrochloric acid. The aqueous layer was extracted with dichloromethane (2×). The later organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to yield 11.5 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentanoic acid as yellow solid.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=C)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.CC(C)=[O:28].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=[O:28])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:24][CH:25]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C=Cc1cc(C)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-methyl-2-vinylbenzoate (0.31 g) in a mixed solvent of acetone (6.20 mL)-acetonitrile (6.20 mL)-water (6.20 mL) were added osmium oxide (fixed catalyst I) (0.12 g) and sodium periodate (1.00 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.16 g) as a crude product. This compound was used in the next step without an additional purification.
Reaction SMILES: [OH-].[K+].C([O-])C.C[O:7][C:8]([C:10]1[N:11]([CH3:33])[C:12](=[O:32])[N:13]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[N:16][CH2:15][C:14]=12)=[O:9]>O.CO>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[N:13]3[C:12](=[O:32])[N:11]([CH3:33])[C:10]([C:8]([OH:9])=[O:7])=[C:14]3[CH2:15][N:16]=[C:17]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:18]=2[CH:23]=1
Reactant: COC(=O)c1c2n(c(=O)n1C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: CC[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(C(=O)O)c2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
Potassium hydroxide, 1.3 g (0.02 mole), was dissolved in 1 ml of water and added to a suspension of 4 g (0.0097 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-2-methyl-1-oxo-4H-imidazo [1,5-a][1,4]benzodiazepin-3-carboxylic acid methyl ester ethanolate in 200 ml of methanol. The solution was refluxed under argon for 3 hrs, concentrated at reduced pressure, diluted with cold water and acidified with acetic acid to give an off-white solid. The solid was washed with water and air dried on the funnel overnight to give crude end product. Recrystallization from ethanol/methylene chloride gave white crystals with mp 265°-267° (dec).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:11]=1[CH3:12])[C:5](OC)=[O:6].CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:11]=1[CH3:12])[CH:5]=[O:6]
Reactant: COC(=O)c1cc(Br)c(C)c(Cc2cccc(F)c2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(Br)cc(C=O)cc1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a dichloromethane (0.1 M) solution of methyl 3-bromo-5-(3-fluorobenzyl)-4-methylbenzoate (1 eq.) from the previous step was added DIBAL-H (1.5 M solution in toluene, 2.2 eq.). The resulting solution was stirred at RT for 1.5 h and then carefully quenched with 10% aq. HCl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. The crude alcohol thus obtained was taken up again in dichloromethane (0.1M) and then added Dess-Martin periodinane (1.0 eq.) and sodium bicarbonate (1.2 eq.). After stirring at RT for 40 min, the reaction mixture was diluted with ether and washed sequentially with sat. aq. NaHSO3, 1 N aq. NaOH, water and brine. The organic extract was dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=2)[C:5]=1[C:6]#[N:7])([O-])=O.CC(C)=O.[Cl-].[NH4+]>[Zn].O>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]=1[C:6]#[N:7]
Reactant: COc1cccc(COc2cccc([N+](=O)[O-])c2C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1c(N)cccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a mixture of 2-nitro-6-(3-methoxybenzyloxy)benzonitrile (Example 193c) (480 mg, 1.69 mmol) in 5:1 acetone:water (9 mL) was added zinc (552 mg, 8.44 mmol) and ammonium chloride (911 mg, 16.9 mmol). The reaction was stiffed at room temperature for 30 minutes, then filtered and concentrated. The residue was purified by flash chromatography (55:45 EtOAc:Hexane) to provide 2-amino-6-(benzyloxy)benzonitrile (337 mg, 78%). 1H NMR (400 MHz, d-DMSO) δ 3.73 (s, 3H), 5.04 (s, 1H), 6.27 (d, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 7.06-6.97 (m, 3H), 7.27 (t, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.55 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].Br[CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].C([O-])([O-])=O.[Cs+].[Cs+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:13][CH2:14][CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccccc1C(F)(F)F
Temperature: 60 °C
Reaction time: 16 h
Yield: 90.9 %

Procedure:
A solution of 2-(trifluoromethyl)phenol (250 mg, 1.54 mmol), tetrabutyl ammonium iodide (114 mg, 1.31 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione (455 mg, 1.70 mmol) was stirred in THF (10 mL) at rt. Cs2CO3 (904 mg, 2.78 mmol) was added. The resulting mixture was stirred at 60° C. for 16 h. H2O was added to the reaction mixture and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by triturating with Et2O to yield Intermediate 6A (0.50 g, 1.4 mmol, 93% yield) as a white powder. LC-MS (ESI) 350 (M+H), RT=3.41 min (Method B).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:18](Cl)(=[O:20])[CH3:19].Cl>O.C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: Clc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 0 °C

Procedure:
To a cooled, stirred suspension containing 154 gms. of anhydrous aluminum chloride, 800 ml. of carbon tetrachloride and 200 gms of p-chlorobiphenyl add (dropwise) 91 gms of acetyl chloride. When the reaction temperature of the mixture reaches 10° C., add 60 ml of methylene chloride and allow the reaction mixture to slowly reach room temperature. Stir the mixture overnight. Pour the resulting mixture into 1 liter of crushed ice and water containing 100 ml. of conc. hydrochloric acid. Separate the organic phase, dry over anhydrous sulfate, filter, concentrate, and triturate the solid residue with 600 ml. of hexane to yield 1-(4'chloro[1,1']biphenyl-4-yl) ethanone, m.p. 100°-101° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([CH:27]([S:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:11][C:12]([NH:15]CC2C=CC(OC)=C(OC)C=2)=[N:13][CH:14]=1.C(=O)(O)[O-].[Na+]>CCCCCC>[Cl:8][C:9]1[C:10]([CH:27]([S:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[C:28]2[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=2[F:35])=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: COc1ccc(CNc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: Nc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Yield: 77.4 %

Procedure:
A trifluoroacetic acid (5 ml) solution of the 5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]-2-(3,4-dimethoxybenzylamino)pyridine (1.89 g, 3.45 mmol) obtained in Example 185 was stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added a saturated aqueous solution of sodium bicarbonate, followed by extraction with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to yield a white solid. The resulting white solid was washed with hexane-ether, and collected by filtration to give the title compound (1.06 g, 2.67 mmol, 77%) as a white powder.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=O)[C:5]=2[O:4][CH2:3][CH2:2]1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCC1>N1C=CC=CC=1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10](/[CH:11]=[CH:14]/[C:15]([OH:17])=[O:16])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1cccc2c1OCCO2
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNC1
Product: O=C(O)/C=C/c1cccc2c1OCCO2
Temperature: 0 °C

Procedure:
A mixture of 2,3-dihydrobenzodioxin-5-carboxaldehyde (Morishima, et al., Eur. Pat. Appl. 309,766, 5 Apr 89) (9.25 g, 56.4 mmol), malonic acid (11.73 g, 112.8 mmol), pyrrolidine (1 mL), and pyridine (25 mL) was heated to reflux for 2 hr, cooled, and then poured into ice water (300 mL). The white precipitate was filtered, washed with 1N HCl, and air dried (9.83 g, 84.6%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CS(C)=O.C(OCC)(=O)C.[NH4+].[Cl-]>[CH2:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.2 %

Procedure:
To a solution of 1H-indole-3-carboxaldehyde (300 mg, 2.07 mmol) in 4.1 mL of dry dimethylsulfoxide was added sodium hydride (108 mg, 55%, 2.5 mmol) under nitrogen at 0° C. After the reaction mixture was stirred at room temperature for 30 min, benzyl bromide (0.40 mL, 2.5 mmol) was added with additional stirring for 2 h. The reaction mixture was diluted with 10 mL of ethyl acetate and 10 mL of saturated NH4Cl aqueous solution at 0° C., successively, and extracted with 100 mL of ethyl acetate. The extract was washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound as a pale brown solid (10.8 mg, 31%).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23](=[O:27])[CH:24](Br)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[CH3:2][NH:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:25][CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:27])[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CNC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)N1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a suspension of N-methylpiperazine-1-carboxamide hydrochloride (6 g, 33.52 mmol) and K2CO3 (9.26 g, 67.0 mmol) in acetonitrile (100 mL) was added bromopropionic acid tert-butyl ester (8.4 g, 40.2 mmol). The reaction mixture was stirred at reflux for 12 h, cooled to room temperature and partitioned in ethyl acetate (200 mL) and water (100 mL). Organic layer was separated, dried (MgSO4), and concentrated to give tert-butyl 3-(4-(methylcarbamoyl)piperazin-1-yl)propanoate as an oil which was dissolved in a mixture of dichloromethane (100 mL) and TFA (trifluoroacetic acid) (20 mL) and then stirred overnight. The volatiles were removed under vacuum. The residue was dissolved in methanol, 1N hydrogen chloride in ether was added, and then the solution was concentrated to give 3-(4-(methylcarbamoyl)piperazin-1-yl)propanoic acid as a solid. LCMS 216 (M+1)
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:8])[O:4][CH2:3]1.C(Cl)Cl.[O-:13][Mn](=O)(=O)=O.[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:1][C:2]1([CH3:9])[CH2:7][O:6][S:5](=[O:13])(=[O:8])[O:4][CH2:3]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC1(C)COS(=O)OC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(C)COS(=O)(=O)OC1
Yield: 129.2 %

Procedure:
10 g (0.067 mol) of 5,5-dimethyl-1,3,2-dioxathiane 2-oxide (prepared in accordance with Example 1), 70 ml of methylene chloride, 0.76 g (0.0033 mol) of benzyltriethylammonium chloride and 70 ml of water are placed in a 350 ml four-necked flask which is provided with a stirrer and a thermometer. 7.5 g (0.0475 mol) of KMnO4 are added portion-wise at 5°-10° C. and while stirring vigorously. After the addition the reaction mixture is stirred at room temperature for a further 30 minutes and suction filtered. The organic phase is separated. The residue is washed well on the suction filter with 20 ml of methylene chloride and the aqueous phase is again extracted with this new filtrate. The combined organic phases are extracted with 1 g of NaHSO3 in 20 ml of water and washed with a small amount of water. After drying over Na2SO4 and evaporation there are obtained 10.2 g of 5,5-dimethyl-1,3,2-dioxathiane 2,2-dioxide as a white powder with a m.p. of 80°-82° C.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=12.Cl[C:18]([C:20]1[CH:21]=[CH:22][C:23]([N+:30]([O-:32])=[O:31])=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26])=[O:19]>C(N(CC)CC)C>[CH3:28][O:27][C:25]([C:24]1[CH:29]=[C:20]([CH:21]=[CH:22][C:23]=1[N+:30]([O-:32])=[O:31])[C:18]([C:3]1[N:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]=[CH:6][C:5]2=[CH:1][N:2]=1)=[O:19])=[O:26]
Reactant: COC(=O)c1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)c1ccc2cncn2c1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)c2ncc3ccc(C(=O)OC(C)(C)C)cn23)ccc1[N+](=O)[O-]

Procedure:
This compound is obtained according to the same process as that described in example 9 by benzoylation of tert-butyl imidazo[1,5-a]pyridine-6-carboxylate with methyl 5-(chlorocarbonyl)-2-nitrobenzoate in the presence of triethylamine. A yellow solid is obtained. Melting point: 170° C.; 1H NMR (d6-DMSO): 1.63 (9H, s), 3.89 (3H, s), 7.76 (1H, d), 8.05 (1H, s), 8.12 (1H, d), 8.26 (1H, d), 8.70 (1H, d), 8.77 (1H, s), 10.25 (1H, s)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17](N)=[C:16]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15]([S:25][CH3:26])=[N:14]1.N(OCCC(C)C)=O>CN(C=O)C.C(OCC)C>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[CH:17]=[C:16]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[C:15]([S:25][CH3:26])=[N:14]1
Reactant: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1cnccn1
Agent: CC(C)CCON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1-c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of aminopyrazole 41 (42 mg, 0.1 mmol) in DMF (5 mL) was warmed up to 65° C. and treated dropwise with excess isoamyl nitrite (150 mL). Stirring was continued for 30 min. The reaction was cooled down to room temperature, diluted with ethyl ether (10 mL) and washed with brine (5×15 mL). The organic layer was dried (magnesium sulfate) and the solvents removed at reduced pressure, leaving a dark oil residue. The desired product was obtained upon flash chromatography eluting with ethyl acetate-hexanes (5-10%), to yield 14 mg (35%) of desired product. 1H-NMR (δ, CDCl3): 2.63 (3H, s); 7.78 (2H, s); 8.1 (1H, s); 8.28 (1H, d, J=2.5 Hz); 8.4 (1H, dd, J=1.4; 8.4 Hz); 9.2 (1H, d, J=1.5 Hz). MS: M+1=404 (calculated: 404).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[N:15]=[C:14]([F:16])[N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][NH:11]2.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]([CH3:29])[CH3:28].C(Cl)Cl.CCOCC.CO>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]1[N:15]=[C:14]([F:16])[N:13]=[C:12]2[C:8]=1[N:9]=[CH:10][N:11]2[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)Br
Reactant: Fc1nc(NCc2cccc(Cl)c2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(NCc3cccc(Cl)c3)nc(F)nc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (3-chloro-benzyl)-(2-fluoro-9H-purin-6-yl)-amine (0.6 g, 2.16 mmol) in dimethylformamide (10 ml) at room temperature under an argon atmosphere, was added powdered, anhydrous potassium carbonate (1.47 g, 5 eq, 10.8 mmol), followed by 2-bromopropane (2.2 ml, 10 eq, 21.6 mmol). The reaction mixture was stirred at room temperature for 24 h, when DCM:ether:MeOH (55:40:5), indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous phase was extracted with more ethyl acetate (2×50 ml) and the combined organic phase washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel flash column chromatography, eluted with CHCl3 to afford the title compound as a slightly yellow gum; Yield: 0.45 g (65%). δH (250 MHz, CDCl3) 1.57 (6H, d, J 7.5, CH[CH3]2), 4.81-4.63 (3 H, m, NHCH2Ar and CHMe2), 5.98 (1 H, s, br, NH), 7.29-7.19 (3 H, m, ArH), 7.34 (1 H, s, br, ArH), 7.42 (1 H, d, J 7.5, ArH), 7.51 (1 H, s, br, NH); δC (250 MHz, CDCl3) 161.93 (C), 156.37 (C), 156.05 (C), 141.33 (C), 140.42 (C), 137.75 (CH), 134.49 (C), 129.92 (CH), 127.69 (CH), 125.81 (CH), 125.64 (CH), 47.43 (CH), 43.82 (CH2), 22.56 (2×CH3); m/z 320.3 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:12]2[N:13]=[CH:14][N:15]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH:16]=2)=[CH:9]/[O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30].Cl>ClCCl>[CH2:29]([S:31]([NH:1][C:2]1[CH:3]=[C:4](/[C:8](/[C:12]2[N:13]=[CH:14][N:15]([S:17]([N:20]([CH3:22])[CH3:21])(=[O:18])=[O:19])[CH:16]=2)=[CH:9]/[O:10][CH3:11])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[CH3:30]
Reactant: CCS(=O)(=O)Cl
Reactant: CO/C=C(/c1cccc(N)c1)c1cn(S(=O)(=O)N(C)C)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(/C(=C/OC)c2cn(S(=O)(=O)N(C)C)cn2)c1
Reaction time: 5 h

Procedure:
A solution of Example 46B (0.32 g, 0.99 mmol) in dichloromethane (5 mL) was treated with pyridine (0.24 mL, 3.0 mmol), treated with ethanesulfonyl chloride (0.10 mL, 1.1 mmol), stirred for 5 hours, treated with 1M HCl and extracted with dichloromethane (3×). The combined dichloromethane extractions were dried (Na2SO4) and concentrated to provide the title compound.
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1)[C:3]1[CH:12]=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:13])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN(c1ccc(O)cc1)c1cnc2cc(Cl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cnc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 4-[N-methyl-N-(6-chloro-2-quinoxalinyl)amino]phenol (4 mmole), ethyl 2-bromopropionate (1 ml), potassium carbonate (1.0 g) and butanone (100 ml) was heated under reflux for a period of 12 hr. The solvent was removed by distillation under reduced pressure and the residue was purified by column chromatography over silica gel (eluant dichloromethane/ethanol 98:2) to give ethyl 2-{4-[N-methyl-N-(6-chloro-2-quinoxalinyl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:24])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([F:17])([F:16])[S:11][CH2:12][CH2:13][O:14]C.F[C:26]1[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=1[C:33](O)(CN1C=NC=N1)C(F)(F)SCCO.CI.C(Cl)C1C=CC=CC=1>>[CH2:33]([O:24][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([CH2:18][N:19]1[CH:23]=[N:22][CH:21]=[N:20]1)[C:10]([S:11][CH2:12][CH2:13][OH:14])([F:17])[F:16])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:26]=1
Reactant: COCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: ClCc1ccccc1
Solvent: CI
Product: OCCSC(F)(F)C(Cn1cncn1)(OCc1ccccc1)c1ccc(F)cc1F

Procedure:
In a similar manner to Example 1 except that 2-(2,4-difluorophenyl)-1,1-difluoro-1[(2-methoxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol was replaced with 2-(2,4-difluorophenyl)-1,1-difluoro-1-[(2-hydroxyethyl)thio]-3-(1H-1,2,4-triazol-1-yl)-2-propanol and methyl iodide was replaced with benzyl chloride, the experiment was carried out, whereby 2-{[2-(benzyloxy)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propyl]thio}-1-ethanol was obtained as a colorless oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:17]12CC(C=C1)C=[CH:18]2>O1CCOCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][N:1]3[CH:18]=[CH:17][N:3]=[N:2]3)[O:9][N:8]=2)=[N:11][CH:12]=1
Reactant: C1=CC2C=CC1C2
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)cn2)=NO1
Solvent: C1COCCO1
Product: Brc1ccc(C2=NOC(Cn3ccnn3)C2)nc1

Procedure:
5-Azidomethyl-3-(5-bromo-pyridin-2-yl)-4,5-dihydro-isoxazole (1 g, 3.5 mmol) and bicyclo[2.2.1]hepta-2,5-diene (1 ml) were combined with dioxane (2 ml) and subjected to microwave radiation in a Smith Personal Synthesizer for 900 seconds at 125° C. The reaction mixture was concentrated in vacuo and ethyl acetate (5 ml) was added. The precipitate was filtered and washed with ethyl acetate (2×5 ml) to give the desired product (417 mg).