Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8])[CH3:2].Cl.[NH2:26]O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:8][N:26]=1)=[O:24])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1ccccc1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Yield: 92.1 %

Procedure:
To a stirred solution of 4-(2-benzyloxy-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.75 g, 0.01149 mole) in acetic acid (20 mL) was added hydroxylamine hydrochloride (0.878 g, 0.0126 mole) and the resulting mixture was heated to reflux for 3 hours. Volatiles were removed and the resulting residue was diluted with water, basified with sodium bicarbonate solution and extracted with ethyl acetate, washed the ethyl acetate with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 3.42 g (92%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester. LCMS: 324.12 (M+1)+, 78.58%. To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid ethyl ester (1.75 g, 0.00542 mol) in a mixture of THF (30 mL), methanol (15 mL) and H2O (15 mL) was added NaOH (0.651 g, 0.01628 mol) and the resulting mixture was stirred for 2 hours. The reaction mixture was then diluted with cold water. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 1.57 g (98%) of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid. LCMS: 296.08 (M+1)+, 84.73%
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:17][CH:16]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:33]=[N+:34]=[N-:35])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:35][N:34]=[N:33][N:28]=3)=[CH:19][CH:20]=2)[C:7]2[N:8]([CH:10]=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn2cc(C)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Product: CCCCc1nn2cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 31 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5-methyl-3H-imidazo[1,2-b][1,2,4]triazole (from Steps B and C) with trimethyltin azide according to the procedure of Example 1, Step G, gave a 31% yield of the title compound as a light brown solid, mp 124°-125° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][CH2:14][C:15]([CH3:18])([OH:17])[CH3:16].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH2:14][C:15]([OH:17])([CH3:18])[CH3:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: CC(C)(O)CN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNS(=O)(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (2.0 g, 7.3 mmol) was dissolved in tetrahydrofuran. 3-Amino-2-methyl-2-propanol (1.0 g, 8 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl-N-(2-hydroxy-2-methylpropyl)benzenesulfonamide. The resulting oil was dried in vacuo (1.9 g, 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][C:24]([CH3:26])=[N:23][CH:22]=3)=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][C:10]1[O:11][C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][C:24]([CH3:26])=[N:23][CH:22]=3)=[C:17]([O:27][CH3:28])[CH:16]=2)=[N:13][N:12]=1
Reactant: COc1cc(C(=O)NNC(=O)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(-c2nnc(Cc3ccc(F)c(F)c3)o2)ccc1-c1cnc(C)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A mixture of N′-[(3,4-difluorophenyl)acetyl]-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (4.69 g), carbon tetrachloride (2.24 mL) and triphenylphosphine (12.3 g) in acetonitrile (117 mL) was stirred at 80° C. for 2 hr. The mixture was allowed to cool to room temperature, the precipitate was filtered off, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Ethyl acetate was added to the obtained crude product, the precipitate was filtered off, and the filtrate was concentrated. Acetonitrile was added to the obtained residue, and the resultant precipitate was collected by filtration to give the title compound (2.41 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:10][NH:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+].F[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=1[N+:40]([O-:42])=[O:41]>CN(C)C=O>[N+:40]([C:31]1[CH:32]=[C:33]([C:36]([F:37])([F:38])[F:39])[CH:34]=[CH:35][C:30]=1[N:11]1[N:10]=[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:7][C:6]2[CH:18]=[CH:19][CH:20]=[C:4]([O:3][C:2]([F:1])([F:21])[F:22])[CH:5]=2)=[N:12]1)([O-:42])=[O:41]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)c1n[nH]nc1Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2[N+](=O)[O-])nc1Oc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 5-[3-(trifluoromethoxy)phenoxy]-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step E, 0.55 g, 1.7 mmol) in N,N-dimethylformamide (5 mL) was added anhydrous potassium carbonate (0.48 g, 3.5 mmol) and 4-fluoro-3-nitrobenzotrifluoride (0.29 mL, 2.1 mmol). The mixture was heated to 80° C. with stirring for 90 min. The reaction mixture was concentrated to dryness under reduced pressure. The resulting residue was diluted with water (10 mL) and extracted with ethyl acetate (30 mL, 15 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude product. The crude material was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to obtain the title compound (0.76 g) as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)=[N:9][N:10]3[CH2:14][CH2:13][S:12][C:11]=23)=[CH:3][CH:2]=1.[F:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.CN1CCOCC1>C(Cl)Cl>[F:22][C:23]1[CH:24]=[C:25]([S:29]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:8]3[C:7]([C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[C:11]4[S:12][CH2:13][CH2:14][N:10]4[N:9]=3)[CH:16]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(-c2nn3c(c2-c2ccncc2)SCC3)c1)c1cccc(F)c1
Reaction time: 1 h
Yield: 58.5 %

Procedure:
3-(7-Pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenylamine (prepared as described in Example 1) (30 mg, 0.102 mmol) was dissolved in dry DCM (1 mL). At room temperature 3-fluorobenzensulfonylchloride (0.014 mL, 0.107 mmol, 1.05 eq) was added followed by NMM (0.012 mL, 0.107 mmol, 1.05 eq) and the mixture was stirred for 1 hour. It was then diluted with DCM and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluant DCM/MeOH 96:4) to give 27 mg of 3-fluoro-N-[3-(7-pyridin-4-yl-2,3-dihydro-pyrazolo[5,1-b]thiazol-6-yl)-phenyl]-benzenesulfonamide.
Reaction SMILES: [C:1]([C@:4]1([OH:22])[CH2:13][C:12]2[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:6]2([S:21][CH2:20][CH2:19][S:18]2)[CH2:5]1)(=[O:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.O>O1CCCC1.C(OCC)C>[OH:22][C@@:4]1([CH:1]([OH:3])[CH3:2])[CH2:13][C:12]2[C:7](=[C:8]([O:16][CH3:17])[CH:9]=[CH:10][C:11]=2[O:14][CH3:15])[C:6]2([S:18][CH2:19][CH2:20][S:21]2)[CH2:5]1
Reactant: COc1ccc(OC)c2c1C[C@@](O)(C(C)=O)CC21SCCS1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1C[C@@](O)(C(C)O)CC21SCCS1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.0 g of (S)-3'-acetyl-1',2',3',4'-tetrahydro-3'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] in 250 ml of dry tetrahydrofuran was cooled to -78° C. and a solution of 1.12 g of lithium aluminium hydride in 75 ml of diethyl ether was added over a period of a few minutes. The mixture was stirred at -78° C. under nitrogen for 30 minutes and then a further 1.12 g of lithium aluminium hydride in 75 ml of diethyl ether were added. After a total reaction time of 45 minutes, 250 ml of 2M hydrochloric acid were added cautiously to the mixture and then 750 ml of water were added. The mixture was extracted with three 600 ml portions of dichloromethane and the combined extracts were washed with 300 ml of water, dried over magnesium sulphate and evaporated to give (3'S)-1',2',3',4'-tetrahydro-3'-hydroxy-3'-[1-(hydroxy)ethyl]-5', 8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] is a mixture of isomers in the form of a colourless gum which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:15]1[CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCCC(C)C2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)N2CCCC(C)C2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-(3-methylpiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][OH:18])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[C:27]1([CH2:33][C:34]([O:36]C(=O)CC2C=CC=CC=2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[C:27]1([CH2:33][C:34]([OH:36])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][OH:18])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: O=C(Cc1ccccc1)OC(=O)Cc1ccccc1
Agent: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CO)n1-2
Solvent: O
Product: O=C(O)Cc1ccccc1

Procedure:
In a manner similar to Example 12, a mixture of 8-nitro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and phenylacetic anhydride was heated on the water bath to give 8-nitro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine phenylacetate (ester).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][CH2:9][N+:10]([O-:12])=O)([CH3:4])([CH3:3])[CH3:2].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].C(N(CC)CC)C.C1(N=C=O)C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:13])[CH2:7][CH2:8][C:9]1[CH2:16][CH:15]([C:14]([O:18][CH3:19])=[O:17])[O:12][N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)CCC[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(CCC(=O)OC(C)(C)C)=NO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 18.9 g of 4-nitrobutyric acid t-butyl ester, 8.6 g of methyl acrylate, 0.2 g triethyl amine in 200 ml of toluene is stirred and treated dropwise with 27.4 g of phenyl isocyanate. The mixture is stirred for 72 hours at room temperature and heated at 90° C. for two hours. The mixture is cooled, filtered to remove the diphenyl urea, and concentrated under reduced pressure. The resulting oil is chromatographed on SiO2 (elution with hexane:ethylacetate; 75:25) to yield 4,5-dihydro-5-(methoxycarbonyl)-3-isoxazolepropanoic acid t-butyl ester as a colorless oil. NMR (CDCl3) and 5.00 (t, J=9 Hz, 1H), 3.77 (s, 3HO, 3.28 (d, J=9 Hz, 2H), 2.58 (s, 4H), 1.42 (s, 9H). IR (cm-1) 2955, 2910, 1728, 1545, 1437, 1385, 1370, 1340, 12155, 1215.
Reaction SMILES: [OH:1][CH2:2][N:3]([N+:5]([O-:7])=[O:6])[CH3:4].FC(F)(F)C(O[CH2:13][N:14]([N+:16]([O-:18])=[O:17])[CH3:15])=O>C(#N)C>[N+:5]([N:3]([CH3:4])[CH2:2][O:1][CH2:13][N:14]([N+:16]([O-:18])=[O:17])[CH3:15])([O-:7])=[O:6]
Reactant: CN(COC(=O)C(F)(F)F)[N+](=O)[O-]
Reactant: CN(CO)[N+](=O)[O-]
Solvent: CC#N
Product: CN(COCN(C)[N+](=O)[O-])[N+](=O)[O-]
Reaction time: 2 h

Procedure:
1-Hydroxy-2-nitro-2-azapropane (0.52 g, 4.9 mmol) and acetonitrile (0.5 ml) were stirred under nitrogen at -20° C. as 2-nitro-2-azapropyl trifluoroacetate (1.09 g, 5.4 mmol) was added in one portion. The reaction flask was immediately connected to a vacuum pump and brought to 1-2 mm during several minutes. The reaction temperature was allowed to warm to ambient during 21/2 hours, a precipitate forming at about 10° C. After stirring an additional 11/2 hours, the vacuum was removed and cold ether (5 ml) was stirred with the solid mass 5 minutes before filtering bis(2-nitro-2-azapropyl) ether; yield: 0.83 g (87%); m.p. 30°-38.5° C. Recrystallization from ether gave bis(2-nitro-2-azapropyl) ether; yield: 0.55 g (58%); m.p. 38°-41° C. The analytical sample melted at 40.6°-42° C.
Reaction SMILES: C[CH:2]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:37][CH:36]=1)[C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3](=[O:33])[CH2:2][O:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])=[CH:39][CH:40]=2)=[CH:11][CH:10]=1
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(OCC(=O)COc2ccc(CCCO)cc2)cc1
Temperature: 70 °C
Yield: 97.7 %

Procedure:
A solution of methyl 3-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-1-[4-(tert-butoxycarbonyl)phenoxy]-2-propanone (1.44 g, 2.25 mmol) in tetrahydrofuran (35 ml) was treated at 22° C. with acetic acid (0.8 ml) followed by 5 ml (5 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran. The mixture was then heated at 70° C. for 4 hours. The cooled reaction mixture was then diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate, 7:3) gave 0.88 g (97%) of the title material as oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CC#N.[O-]S([O-])(=O)=O.O=[V+2]>[CH3:6][C:5]([O:4][CH2:1][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccccc1
Agent: O=[V+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CC#N
Product: CC(=O)OCCc1ccccc1
Reaction time: 0.17 h
Yield: 91.9 %

Procedure:
In a dry 50-mL, two-necked, round-bottomed flask, vanadyl sulfate (8.2 mg, 0.05 mmol) in 3 mL of anhydrous CH3CN was placed. To the above mixture, acetic anhydride (153.1 mg, 141.5 μL, 1.5 mmol) was slowly added at ambient temperature. After about 10 min, a solution of 2-phenylethanol (122 mg, 119.3 μL, 1.0 mmol) in CH3CN (2 mL) was slowly added to the above bluish solution with residual suspended vanadyl sulfate, and the reaction mixture was stirred for 24 hours. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with cold, saturated aqueous NaHCO3 solution (5 mL). The resulting separated organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by column chromatography on silica gel to yield 150.9 mg of 2-phenethyl acetate (92%) as colorless oil. The substrate, reaction time, and yield of this test are summarized in Entry 3 of the following Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5](O)=[O:6].P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[CH3:1][O:2][C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([Cl:13])=[O:6]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(F)(F)C(F)(F)C(=O)O
Product: COC(F)(F)C(F)(F)C(=O)Cl
Yield: 95.1 %

Procedure:
A mixture of 47.4 g 3-methoxytetrafluoropropionic acid and 67.3 g phosphorous pentachloride was heated and the contents distilled to obtain a pale yellow liquid boiling to 102°. Redistillation of this liquid yielded 49.8 g (95.2%) 3-methoxytetrafluoropropionyl chloride, b.p. 84°-86°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]1>O>[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][C:2]2[CH:3]=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccc([N+](=O)[O-])cc3)c3nccn3n2)CC1
Reaction time: 8 h

Procedure:
In a 2 dram reaction vial was added crude 6-chloro-N-(4-nitrophenyl)imidazo[1,2-b]pyridazin-8-amine (0.42 g, 1.4 mmol) from 1a and trans-1,4-diaminocyclohexane (1.0 g, 8.0 mmol). The mixture was allowed to melt at 160° C. for 8 hrs. The melt was then cooled, diluted with water and extracted with dichloromethane. The organic layer was concentrated to provide crude N6-((trans)-4-aminocyclohexyl)-N8-(4-nitrophenyl)imidazo[1,2-b]pyridazine-6,8-diamine which was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16].C(OCC)C>CN(C)C=O.O.C(OCC)(=O)C>[Si:19]([O:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C1NCCN1CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCN1CCNC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(2-hydroxyethyl)-2-oxoimidazolidine (13 g) in dimethylformamide (50 ml) containing imidazole (7.5 g) was treated with t-butylchlorodiphenylsilane (28.6 ml) and the clear solution stirred for 3 hours at ambient temperature. The white suspension formed was dissolved in water (200 ml) and ethyl acetate (500 ml). The aqueous phase was re-extracted with ethyl acetate (100 ml) and the combined organic phases were washed with 3×100 ml portions of water, 1×100 ml brine, dried and evaporated to give a solid. Trituration of the solid with diethyl ether (100 ml) afforded the title compound as a white solid, (33.7 g).
Reaction SMILES: Br[C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:9]2[C:8]3[C:17]4=[C:16]5[C:5](=[CH:6][CH:7]=3)[CH:4]=[CH:3][CH:2]=[C:15]5[CH:14]=[CH:13][C:12]4=[CH:11][CH:10]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Brc1ccc2ccc3cccc4ccc1c2c34
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Temperature: 130 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixed solution of 59 g of 1-bromopyrene, 40 g of p-chlorophenylboronic acid, 108 g of tripotassium phosphate, g of tetrabutylammonium bromide, 1.15 g of palladium acetate and 1,250 ml of dimethylformamide was heated and stirred under a nitrogen gas stream at 130° C. for 3 hours. The solution was cooled to room temperature and 1,000 ml of water was poured into the solution, followed by filtration. The resulting solid was washed with 200 ml of methanol, dissolved in 1,000 ml of dichloromethane, dried over magnesium sulfate, filtered through Celite and then evaporated. The resulting solid was washed with 200 ml of methanol and then vacuum-dried to obtain 58.2 g of 1-(4-chlorophenyl)pyrene.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18](I)[CH3:19].O>CN(C)C=O>[CH3:1][CH:2]([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:3][C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: CC(=O)CCC(C)CC(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)CCC(C)=O
Reaction time: 2 h

Procedure:
3-Methyl-6-oxoheptanoic acid (2.45 g) was stirred in dry dimethylformamide (60 ml) at 20° C. and anhydrous sodium carbonate (1.64 g) was added. Ethyl iodide (5.4 ml) was added dropwise and the mixture was refluxed with stirring for 2 hours. The mixture was cooled, poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with saturated aqueous sodium thiosulphate solution, water, and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was purified by chromatography on silica, eluting with 1:4 diethyl ether: hexane. Ethyl 3-methyl-6-oxoheptanoate was obtained as an orange oil (2.0 g) Mass spectrum (Chemical Ionisation) M+1 187
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a 250 ml 3-neck flask, 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g, 50.5 mmol) and DMF (80 ml) were added. The solution was cool to −40° C. under nitrogen, sodium hydride (1.5 g, 60.6 mmol) was added in 2 batches. The mixture was stirred at −40° C. for 1 hour. Then SEM-Cl (10.7 ml, 60.6 mmol) in DMF (20 ml) was added dropwise and the resulting mixture was allowed to stir at −40° C. for another 2 hours. The reaction was quenched with saturated NH4Cl (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (14.4 g, 87% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.92 (m, 2H), 3.59 (m, 2H), 5.72 (s, 2H), 6.65 (s, 1H), 7.84 (s, 1H), 8.37 (2, 1H), 8.45 (s, 1H). MS: m/z 327.0 (M+H+).