Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(Br)=CC=1[O:9]C1C=CC=CC=1.[Mg].C(OCC(F)=C[C:24]1([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34](F)F)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)(=O)C>O1CCCC1>[CH2:34]1[O:33][C:30]2[CH:29]=[CH:28][C:27]([CH:24]3[CH2:25][CH2:26]3)=[CH:32][C:31]=2[O:9]1
Reactant: Fc1ccc(Br)cc1Oc1ccccc1
Reactant: CC(=O)OCC(F)=CC1(c2ccc(OC(F)F)cc2)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: c1cc2c(cc1C1CC1)OCO2
Yield: 143.3 %

Procedure:
The method of Example 25 was repeated using a Grignard reagent, prepared from 4-fluoro-3-phenoxyphenyl bromide (0.31 g), tetrahydrofuran (2 ml) and magnesium (20 mg) and 1-(3-acetoxy-2-fluoroprop-1-enyl)-1-(4-difluoro-methoxyphenyl)cyclopropane (Example 24) (0.155 g). The residue after evaporation was purified by preparative thin layer chromatography (solvent: diethyl ether/hexane; 1:9) and then preparative high performance liquid chromatography (column: C18; solvent: methanol; flow rate: 8 ml/min) to afford 1-(4-difluoromethoxyphenyl)-3-(4-fluoro-3-phenoxyphenyl)prop-1-enyl)-1-(3,4-methylenedioxyphenyl)cyclopropane (120 mg, 54%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15](#[N:18])[CH:16]=[CH2:17].N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:17][CH2:16][C:15]#[N:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: C=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OB(c2cnn(CCC#N)c2)OC1(C)C
Reaction time: 2 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.00 g, 25.8 mmol) in acetonitrile (50 mL) was added acrylonitrile (3.4 mL, 52 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.94 mL, 12.9 mmol). After about 2 hours, the reaction mixture was concentrated under reduced pressure. The crude material was then dissolved in a minimal amount of dichloromethane and purified via silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in heptane to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (s, 1H), 7.64 (s, 1H), 4.40 (t, J=6.4 Hz, 2H), 3.06 (t, J=6.4 Hz, 2H), 1.26 (s, 12H). MS (ESI+) m/z 247.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([Br:26])[CH:17]=3)[C:11]=1[C:12]([NH:14][OH:15])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=21.[O:31]1CCC[CH2:32]1>O>[NH2:1][C:2]1[O:3][C:4]2[C:9]([CH:10]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([Br:26])[CH:17]=3)[C:11]=1[C:12]1[NH:13][C:32](=[O:31])[O:15][N:14]=1)=[CH:8][CH:7]=[C:6]1[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=21
Reactant: C1CCOC1
Reactant: COc1cc(C2C(C(=N)NO)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Solvent: O
Product: COc1cc(C2C(c3noc(=O)[nH]3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-hydroxy-4H-benzo[h]chromene-3-carboxamidine (21), (118 mg, 0.25 mmol) and diimidazole carbonyl (40.5 mg, 0.25 mmol) are suspended in 10 ml tetrahydrofuran at room temperature and then is stirred under LC-MS control under heating. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1)=[CH2:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][S:24]([O:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH:1]=[CH2:2])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1)(=[O:26])=[O:25]
Reactant: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](CO)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C[C@H]1CC[C@H]([C@H]2CC[C@H](COS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
15.1 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethanol, 8.2 mL of pyridine, and 0.41 g of 4-dimethylaminopyridine were dissolved in 50 mL of dichloromethane. A dichloromethane (6 mL) solution containing 6.3 mL of methanesulfonyl chloride was added dropwise to the above solution on ice for 30 minutes. The solution was heated to room temperature, then stirred for 6 hours, and was left over night. The reaction solution was poured into 10% hydrochloric acid, and the organic phase was fractioned. The water phase was extracted with dichloromethane. The organic phase was collected and washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silicagel/toluene) and recrystallization (hexane/toluene) three times, to thereby obtain 9.8 g of trans-4-(trans-4-vinylcyclohexyl)cyclohexylmethyl methanesulfonate in the form of colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=2)[C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g, 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), dry potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were stirred in refluxing dry acetone (600 mL) for 12 h. After cooling, the acetone was evaporated, and the solution was dissolved in water (250 mL). The water phase was extracted with diethyl ether (4×100 mL), the organic phase was washed with brine (2×50 mL), dried (MgSO4) and the solvent was removed in vacuo. Recrystallisation from petroleum ether and ethyl acetate gave the titled compound as white crystals, m.p. 102-103° C. Yield: 121.4 g (89%). Spectroscopic data were in accordance with the literature (J. Barbera, R. Iglesias, J. L. Serrano, T. Sierra, M. R. de la Fuente, B. Palacios, M. A. Perez-Jubindo, J. T. Vazquez, J. Am. Chem. Soc. 1998, 120, 2908).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][OH:20])=[N:9][N:10]=2)[CH:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH2:19][O:20][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: OCCSc1ccccc1-c1nnc2ccc(F)cn12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Fc1ccc2nnc(-c3ccccc3SCCOC3CCCCO3)n2c1
Yield: 73.9 %

Procedure:
A solution of 2-[2-(6-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-phenylsulfanyl]-ethanol (400 mg, 1.38 mmol), 4-methylbenzenesulfonic acid (65 mg, 0.345 mmol) and 3,4-dihydro-2H-pyran (251 μL, 2.76 mmol) in DCM (5 mL) was stirred at RT under a nitrogen atmosphere for 36 h. The reaction mixture was diluted with DCM and extracted with sat. NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC using MeOH in DCM (0 to 5%) to give the title compound as a pale yellow oil (381 mg, 74%). LCMS (Method 3): Rt 3.10 min, m/z 374 [MH+]. 1H NMR (400 MHz, CDCl3): 1.49 (6 H, m), 3.01-3.02 (2 H, m), 3.42-3.59 (2 H, m), 3.80-3.80 (2 H, m), 4.52 (1 H, m), 7.34-7.35 (2 H, m), 7.55-7.55 (2 H, m), 7.67-7.68 (2 H, m), 7.90 (1 H, dd, J 9.97 and 4.82).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(O)(=O)[CH2:18][C:19]([OH:21])=[O:20].C(OCC)(=O)C>N1C=CC=CC=1.C(O)C>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[CH:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(/C=C/c2ccncc2)cc1
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)C=Cc1ccc(/C=C/c2ccncc2)cc1
Yield: 46.6 %

Procedure:
To a solution of 4-[(E)-2-(4-pyridyl)vinyl]benzaldehyde (50 mg) in pyridine (0.025 ml) and ethanol (0.075 ml) was added malonic acid (27.4 mg), and the mixture was refluxed for 7 hours. After cooling, ethyl acetate was added thereto, the resulting precipitates were collected by filtration to give 4-[(E)-2-(4-pyridyl)vinyl]cinnamic acid (28 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[O:6].[CH:13]([Mg]Br)=[CH2:14]>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]([CH:13]=[CH2:14])[OH:6]
Reactant: C=C[Mg]Br
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: C1CCOC1
Product: C=CC(O)c1cc(OC)ccc1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2,5-dimethoxybenzaldehye (12.0 g, 0.072 mole) in 50 ml of dry THF was added dropwise to 100 ml of 1M solution of vinyl magnesium bromide in THF while keeping the reaction mixture at room temperature with cooling. The mixture was stirred for 4 hours at room temperature and then quenched with saturated NH4Cl solution. The layers were separated and the aqueous portion was extracted with diethyl ether. The combined organic portion was washed with water, dried (MgSO4), and concentrated. The resulting oil, 13.4 g, was sufficiently pure for the next reaction; IR (neat) 3500 cm-1); NMR (CDCl3) δ6.7-7.0 (m,3H); 6.0-6.2 (m, 1H); 5.1-5.3 (m,3H); 3.75 (two singlets, 6H); 3.16 (br,1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[N:6]1[C:19](=[O:20])[C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)[C:7]1=[O:25].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O.[Ag]=O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[N:6]1[C:19](=[O:20])[C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][N:8]([C@@H:9]2[O:16][C@H:13]([CH2:14][O:15][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:11]([OH:12])[CH2:10]2)[C:7]1=[O:25]
Reactant: O=c1c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reactant: BrCc1ccccc1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: O=c1c(C(F)(F)F)cn([C@H]2C[C@H](O)[C@@H](COCc3ccccc3)O2)c(=O)n1C1CCCO1
Reaction time: 5 h

Procedure:
3.66 Grams of 3-(2-tetrahydrofuranyl)-2'-deoxy-5-trifluoromethyluridine was dissolved in 40 ml of acetone. Thereto were added 5.13 g of benzyl bromide and 5.79 g of silver oxide. The mixture was stirred for 5 hours with refluxing. The reaction mixture was filtered and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (developing solvent : chloroform-methanol=40 : 1). The eluate was recrystallized from dichloromethane-petroleum ether to obtain 0.19 g yield: 4.1%) of 3-(2-tetrahydrofuranyl)-2'-deoxy-5'-O-benzyl-5-trifluoromethyluridine (compound 21) having the melting point of 145° to 147° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[C:18](OC)=[O:19].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[C:24]=1[OH:31]>>[F:17][C:14]([F:15])([F:16])[C:11]1[CH:10]=[CH:9][C:8]([C:6]2[S:5][C:4]([CH2:18][OH:19])=[C:3]([CH2:2][O:31][C:24]3[C:23]([CH3:22])=[CH:28][CH:27]=[C:26]([CH3:29])[C:25]=3[CH3:30])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(C)c(O)c1C
Reactant: COC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)cc1CBr
Product: Cc1ccc(C)c(OCc2cc(-c3ccc(C(F)(F)F)cc3)sc2CO)c1C

Procedure:
The title compound was prepared using methyl 3-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-carboxylate (intermediate 132) and 2,5,6-trimethylphenol.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([S:26][CH3:25])[CH:32]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(Br)n2)n1
Reactant: CSc1cccc(B(O)O)c1
Product: CSc1cccc(-c2cccc(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C)n3)n2)c1

Procedure:
The title compound was prepared from 6′-bromo-6-methyl-4-(4-trifluoromethylphenyl)-[2,2′]bipyridinyl (example E.26) (0.39 g, 1.1 mmol) and commercially available 3-(methylthio)phenylboronic acid (0.183 g, 1.1 mmol) according to the general procedure VI. Obtained as a white solid (0.150 g, 31%). MS (ISP) 437.1 [(M+H)+]; mp 144° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[N:6]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=1)#[N:2]>CCO.[Pd]>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:4]([CH2:3][C:1]#[N:2])=[CH:5][N:6]2[CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18]
Reactant: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)Cn1cc(CC#N)c2c(N)cccc21
Reaction time: 4 h

Procedure:
A mixture of tert-butyl [3-(cyanomethyl)-4-nitro-1H-indol-1-yl]acetate (700 mg, 2.22 mmol, described in Intermediate 11) and 10% Pd/C (65 mg) in EtOH (20 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 4 h, the reaction was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=286 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](OCC)(=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][C:17]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:4][C:3]=1[S:13](=[O:14])(=[O:15])[NH2:16])=[O:24])[CH3:23]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Product: CCOC(=O)CC(=O)Nc1ccc(NS(C)(=O)=O)cc1S(N)(=O)=O
Temperature: 160 °C
Yield: 72 %

Procedure:
To 2-amino-5-methanesulfonylamino-benzenesulfonamide (prepared as described in Examples 1d or 1gc′, 175 mg, 0.66 mmol) was added diethyl malonate (297 mg, 1.66 mmol) and heated at 160° C. for 60 min. After cooling down to 25° C., a 1:1 mixture of ethyl acetate/hexanes (5 mL) was added, upon which as a white solid precipitated out. The solid was collected by vacuum filtration, washed twice with a 1:1 mixture of ethyl acetate/hexanes, and dried under high vacuum to afford the desired product, N-(4-methanesulfonylamino-2-sulfamoyl-phenyl)-malonamic acid ethyl ester (179 mg, 0.47 mmol, 72%) as an off-white solid. 1H NMR (400 MHz, CD3OD) δ: 1.32 (t, 3H, J=7.0 Hz), 3.00 (s, 3H), 3.60 (s, 2H), 4.25 (quartet, 2H, J=6.8 Hz), 7.44 (dd, 1H, J1=3.2 Hz, J2=8.4 Hz), 7.87 (d, 1H, J=5.6 Hz), 7.92 (d, 1H, J=8.4 Hz). LC-MS (ESI+) calcd for C12H17N3O7S2 379.05, found 380.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21]([C:24]1[CH:25]=[C:26]([NH:30][CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH:27]=[CH:28][CH:29]=1)(=O)=O>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:21])[CH:25]=2)[CH2:31][C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2cccc(Cl)c2)[C@@H]1O
Yield: 52.1 %

Procedure:
The title compound (280 mg, 35%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (450 mg, 1.6 mmol) and 3-chloroxyphenyl-1H-imidazol-2-ylmethylamine (232 mg, 1.1 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>O.CCO>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
To a mechanically stirred solution of 5.0 g NaOH in 35 ml H2O and 25 ml EtOH at 15° C. was added 12.0 g (0.100 mole) of acetophenone and 12.4 g (0.100 mole) of 4-fluorobenzaldehyde. After a brief exotherm to 25° C., the temperature returned to 15° C., and the cooling bath was removed. The reaction mixture was stirred at room temperature for 1.5 hour, and the thick slurry was transferred to a beaker to cool overnight at 10° C. This mixture was filtered, and the solids were washed with distilled H2O until the washings were neutral to litmus. Upon drying in vacuo, 20.8 g of a pale yellow solid was obtained, m.p. 86°-87° C.
Reaction SMILES: CC(C)([O-])C.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:21])[CH2:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1.[C:22]1([C:28](=[CH2:33])[C:29]([O:31][CH3:32])=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>C(O)(C)(C)C.ClCCl>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:21])[CH:15]([C:16]1[NH:20][CH:19]=[CH:18][N:17]=1)[CH2:33][CH:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:29]([O:31][CH3:32])=[S:30]
Reactant: C=C(C(=S)OC)c1ccccc1
Reactant: O=C(Cc1ncc[nH]1)c1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: ClCCl
Solvent: CO
Product: COC(=S)C(CC(C(=O)c1ccc(Cl)cc1Cl)c1ncc[nH]1)c1ccccc1
Reaction time: 8 h
Yield: 71 %

Procedure:
A solution (1 M) of tert-butoxide in tert-butanol (54.9 ml) was added to a stirred solution of 1-(2,4-dichlorophenyl)-2-imidazol-2-ylethan-1-one (0.11 M) and methyl 2-phenylthioprop-2-enoate (0.14 M) dissolved in dichloromethane (300 ml) and methanol (200 ml) at room temperature. The reaction, which developed a dark color, was typically stirred overnight (ca. 16 h) under argon. The reaction was monitored by TLC using 5% methanol in dichloromethane as the solvent system. Additional methyl 2-phenylthioprop-2-enoate was added as needed to consume all of the starting 1-(2,4-dichlorophenyl)-2-imidazol-2-ylethan-1-one. The reaction was quenched by the addition of sat. aq. NH4Cl (˜100 ml). The mixture was transferred to a separatory funnel and diluted with ethyl acetate (300 ml). The aqueous layer was removed and the organic layer was washed with sat. aq. NH4Cl (3×100 ml), brine (100 ml), and dried with Na2SO4. After filtration and evaporation, the residue was purified by flash chromatography over silica gel. The column was eluted starting with 100% dichloromethane to remove the non-polar methyl 2-phenylthioprop-2-enoate. The product was eluted with 3% methanol in dichloromethane. After drying overnight in vacuo, methyl 5-(2,4-dichlorophenyl)-4-imidazol-2-yl-5-oxo-2-phenylthiopentanoate as a deep red glass was obtained in 71% yield. A further 10% yield of product could be obtained by resubmitting side product contaminated fractions to a second purification by flash chromatography.
Reaction SMILES: Cl[C:2]1[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>C(Cl)Cl>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: CCOc1ccc(Nc2c(-c3ccccc3)c(Cl)nn3ccnc23)cc1
Solvent: ClCCl
Product: CCOc1ccc(Nc2c(-c3ccccc3)c(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1
Temperature: 25 °C

Procedure:
6-chloro-N-(4-ethoxyphenyl)-7-phenylimidazo[1,2-b]pyridazin-8-amine (0.0201 g, 0.058 mmol) from 1d and (trans)-cyclohexane-1,4-diamine (0.1702 g, 1.49 mmol) were heated at 165° C. for 6 d. After cooling to room temperature, the mixture was taken up in CH2Cl2 and water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using preparative HPLC. The appropriate fraction was collected, and NaHCO3 (solid) was added to it. It was concentrated in vacuo not to dryness, and extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give the above titled compound (1.5 mg, 4.0% yield). LC/MS, m/e 443.40 (M+1). HPLC RT, 2.29 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH:5](O)[CH3:6])[CH3:2].[OH-].[K+].C(N(CC(O)C)C(=O)C)C.C(N(CC(Cl)C)C(=O)C)C.[CH3:30][C:31]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:32]=1[NH2:33].N>Cl>[CH2:1]([NH:3][CH2:4][CH:5]([NH:33][C:32]1[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:31]=1[CH3:30])[CH3:6])[CH3:2]
Reactant: CCNCC(C)O
Reactant: Cc1cccc(C)c1N
Agent: CCN(CC(C)Cl)C(C)=O
Agent: CCN(CC(C)O)C(C)=O
Agent: Cl
Product: CCNCC(C)Nc1c(C)cccc1C

Procedure:
1-Ethylamino-2-propanol is diacetylated according to the method of W. J. Bailey and C. N. Bird [J. Org. Chem. 23, 996 (1958)], and then the ester group of the product is hydrolyzed to free hydroxy group in a 10% ethanolic potassium hydroxide solution at room temperature. The resulting 1-(N-ethyl-acetamido)-2-propanol, bp.: 100°-110° C./53.3 Pa, is chlorinated as described in Step b) of Example 31 under boiling the mixture for 3 hours, and the resulting 1-(N-ethylacetamido)-2-chloro-propane, b.p.: 102°-110° C./53.3 Pa (6.0 g, 36.7 mmoles), is reacted with 9.3 ml (9.1 g, 75 mmoles) of 2,6-dimethyl-aniline for 3 hours at 140°-145° C. under nitrogen atmosphere with stirring. The mixture is cooled, dissolved in 40 ml of a 10% aqueous hydrochloric acid solution, and the solution is rendered alkaline (pH=9) with concentrated aqueous ammonia. The alkaline mixture is extracted thrice with 30 ml of chloroform, each. The chloroform solutions are combined, washed thrice with 30 ml of water, each, dried over magnesium sulfate, and the solvent is evaporated. The oily residue is distilled under reduced pressure. First the excess of 2,6-dimethyl-aniline is recovered (4.6 g, 98% of the excess; b.p.: 52°-62° C./53.3 Pa), and then the crude 1-(N-ethyl-acetamido)-2-(2,6-dimethylphenyl-amino)-propane distils at 120°-140° C./53.3 Pa. The resulting crude product, weighing 1.9 g (21%), is purified by chromatography on 80 g of silica gel; a 1:2 mixture of benzene and ethyl acetate is applied as eluant. A pure product, melting at 58°-60° C., is obtained.