Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CCC[CH2-].[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[I:22]I>C1COCC1>[Cl:6][C:7]1[N:8]=[C:9]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:10]2[S:15][C:14]([I:22])=[CH:13][C:11]=2[N:12]=1
Reactant: II
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
N-Butyllithium (9.4 mL, 22.48 mmol, 2.5 M in hexane solution) was added to a mixture of 2-chloro-4-morpholinothieno[3,2-d]pyrimidine (3.0 g, 11.74 mmol) in 60 mL of THF at −78° C. The reaction mixture was allowed to warm to −40° C. and stirred for 30 min. A solution of iodine (6.0 g, 23.48 mmol) in 10 mL of THF was added dropwise. After the addition was completed. The reaction mixture was brought to room temperature and stirred for 2 h. The mixture was quenched by diluting with dichloromethane (300 mL) and extracting with H2O (2×100 mL). The organic layer was washed with Na2S2O3 (2×100 mL), H2O (2×100 mL), dried over MgSO4, filtered and evaporated to afford 2-chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine (3.4 g, 75%).
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].[CH:7]1([NH:10][NH2:11])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(O)C>[CH:7]1([N:10]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:11]2)[CH2:9][CH2:8]1
Reactant: C/C(N)=C/C#N
Reactant: NNC1CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N)n(C2CC2)n1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-amino-2-butenenitrile (903 mg, 11.00 mmol), cyclopropylhydrazine (1194 mg, 11 mmol) and triethylamine (3.07 mL, 22.00 mmol) were suspended in ethanol (100 mL) and heated to 70° C. for 16 hours. The solvent was removed in vacuo. The residue was suspended in 50 mL of saturated NaHCO3 and stirred for 10 minutes. The contents were extracted with DCM, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent: 0% to 100% gradient EtOAc:Hex). The product was collected as 310 mg. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.13 (m, 4 H), 2.13 (s, 3 H), 3.06 (m, J=6.95, 6.95, 3.79, 3.54 Hz, 1 H), 3.76-3.88 (m, 2 H), 5.24 (s, 1 H). LCMS(ES) [M+H]+ 138.1
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C@@H:29]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:30][CH2:31][N:32]([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH:23]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)C.[ClH:49]>ClCCl.C(OCC)C>[ClH:49].[ClH:49].[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C@@H:29]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:30][CH2:31][N:32]([CH:36]([CH3:37])[CH3:38])[CH:33]([CH3:34])[CH3:35])[CH:23]=2)=[CH:14][CH:15]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCNC(=O)OC(C)(C)C)cc2)ccc1O)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: ClCCl
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCCCCOc2ccc(CCN)cc2)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl(2-{4-[(5-{3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-hydroxyphenyl}pentyl)oxy]phenyl}ethyl)carbamate (Preparation 58, 1.66 g, 2.69 mmol) was dissolved in dichloromethane (20 ml) and ethanol (3 ml) and hydrochloric acid (12 ml of a 2M solution in diethyl ether) was added, and the mixture stirred overnight at room temperature. Solvent was removed in vacuo and the residue dissolved in dichloromethane and solvent removed in vacuo again to furnish the title compound as a yellow foam, 1.6 g
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.O1CCCC1.[Ni]>[NH2:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)cc1F
Yield: 99.4 %

Procedure:
141 g of methyl 2-fluoro-4-nitrobenzoate was dissolved in 1000 ml of methanol and 400 ml of tetrahydrofuran, 20 g of Raney nickel was added to it, and stirred overnight in a hydrogen atmosphere. The catalyst was removed through filtration, and the solvent was evaporated away under reduced pressure to obtain 119 g of methyl 4-amino-2-fluorobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH3:16][I:17]>CO>[IH:17].[CH3:16][S:10][C:9](=[NH:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:13])[F:14])[CH:4]=1
Reactant: NC(=S)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CI
Solvent: CO
Product: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Product: I
Temperature: 25 °C
Yield: 100.8 %

Procedure:
4-Chloro-3-trifluoromethyl-phenylthiourea (5.0 g, 19.63 mmol) was dissolved in ca. 80 mL of anhydrous MeOH and methyl iodide (2.93 g, 20.61 mmol) was added via a syringe. The reaction mixture was refluxed for 12 hours. Then it was cooled down to ambient temperature and solvent was removed in vacuo to give colorless oil (7.85 g), which was taken to the next step without further purifications.
Reaction SMILES: [Br-].[F:2][C:3]([Zn+])([F:5])[F:4].I[C:8]1[N:9]=[C:10]([NH2:26])[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu](Br)Br>[F:2][C:3]([F:5])([F:4])[C:8]1[N:9]=[C:10]([NH2:26])[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: FC(F)(F)[Zn+]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Br[Cu]Br
Agent: [Br-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CN(C)C=O
Product: Nc1nc(C(F)(F)F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of trifluoromethylzinc bromide (1.308 g, 6.10 mmol) in DMF (25 mL) and HMPA (10 mL) was added to copper bromide (0.438 g, 3.05 mmol) and the resulting mixture was stirred for 30 min. 2-Iodoadenosine (0.800 g, 2.03 mmol) was added and the solution was warmed at 70° C. for 4 h. The solvents were evaporated and the residue was purified on silica gel with 10% methanol/chloroform to give 2-trifluoromethyladenosine in 63% yield. 2-Trifluoromethyladenosine was converted to IV by using in sequence the following procedures: Procedure A (58% yield), Procedure B (84% yield), Procedure C (51% yield), Procedure D (73% yield), Procedure E (75% yield), and Procedure F (53% yield): mp 173°-175° C.; 13NMR (Me2SO-d6) δ25.7, 31.8, 62.8, 82.1, 84.5, 119.8, 141.1, 148.3, 156.2; 1H NMR (Me2SO-d6) δ2.10 (m, 2 H), 2.40 (m, 2H), 3.51 (m, 2H), 4.13 (m, 1H), 4.88 (m, 1H), 6.25 (m, 1H), 7.85 (br.s, 2H), 8.54 (s, 1H); UV (H2O) λmax 259.5 nm (λ11300); FAB HRMS obsd (M+ +H) 304.0996, calcd for C11H12F3N5O2 304.1021.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([CH:32]1[C:36](=[O:37])[O:35][C:34](Cl)([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:34]2([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=3)=[O:39])[CH2:33][CH:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:36](=[O:37])[O:35]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(Cl)(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1Cc1ccccc1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(Cc3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Yield: 51 %

Procedure:
In 1 ml of dichloromethane were dissolved 55 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 0.07 ml of triethylamine. To the solution was added, under ice-cooling while stirring, 100 mg of the Compound (74) obtained in Example 74. The reaction solution was stirred at room temperature for 30 minutes, to which was added 25 ml of ethyl acetate. The mixture was washed with water, an aqueous solution of sodium hydrogen carbonate and water, successively, which was then dried (MgSO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 70 mg of the subject Compound (75) as a pale yellow oily product. The IR and NMR spectra are in agreement with those of the Compound (75) obtained in Example 75.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]2[C:12]3[C:13](=[CH:23][NH:24][CH:25]=3)[CH2:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH:9]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C)C=O.O>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][N:24]1[CH:25]=[C:12]2[C:13]([CH2:14][N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]3[CH:9]=[C:8]([Cl:7])[CH:27]=[CH:26][C:11]=32)=[CH:23]1)[CH3:34]
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCc1c[nH]cc1-2
Reactant: CCOC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 0.17 h

Procedure:
To a solution of 1.4 g (12.4 mmole) of potassium t-butoxide in 30 ml of dry dimethylformamide was added 2.4 g (8.2 mmole) of 8-chloro-6-phenyl-2H,4H-pyrrolo[3,4-d][2]benzazepine. The mixture was cooled to 0°, and stirred for 10 min. To the mixture was added 1.3 mol (11.7 mmole) of ethyl bromoacetate. The mixture was stirred at 0° for 45 min, diluted with water, and extracted with ether. The ether solution was washed with water, dried with sodium sulfate, and concentrated at reduced pressure to give a yellow oil. Purification by column chromatography (70 g SiO2, 9:1 methylene chloride/ether) gave as the first major component a yellow oil.
Reaction SMILES: Cl.[C:2]([CH2:7][NH2:8])(=[O:6])[CH:3]([CH3:5])[CH3:4].C(=O)(O)[O-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:14]([NH:8][CH2:7][C:2](=[O:6])[CH:3]([CH3:5])[CH3:4])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C(=O)CN
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)C(=O)CNC(=O)c1ccccc1
Yield: 90.4 %

Procedure:
4.5 g of isobutyrylmethylamine hydrochloride, 11 g of sodium bicarbonate and 4.81 g of benzoyl chloride are treated in the same manner as described in Preparation 1-(4). 6.07 g of N-benzoylisobutyrylmethylamine are thereby obtained. Yield: 90.5%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:24]1CCOCC1.ClC(OCC(C)C)=O.N>CN(C=O)C>[NH2:24][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Reaction time: 0.5 h
Yield: 74 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid and N-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at 0° C. for 20 minutes after which NH3 (g) is passed through the reaction mixture for 30 minutes at 0° C. The reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAc/petroleum ether to provide 2.2 g (74% yield) of the desired product as a white solid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[CH3:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.O>C(O)(=O)C>[CH3:13][CH:14]1[CH2:19][CH2:18][C:17]2[NH:2][C:4]3[C:5]([C:6]([OH:8])=[O:7])=[CH:9][CH:10]=[CH:11][C:12]=3[C:16]=2[CH2:15]1
Reactant: NNc1ccccc1C(=O)O
Reactant: CC1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1CCc2[nH]c3c(C(=O)O)cccc3c2C1
Yield: 87.2 %

Procedure:
A suspension of 2.0 g (10.6 mmol) of 2-hydrazinobenzoic acid hydrochloride in acetic acid (20 ml) was slowly boiled under stirring and 1.2 ml (9.8 mmol) of 4-methylcyclohexanone was dropped thereinto. The obtained mixture was heated under reflux for 8 hours and then allowed to cool. After adding water, the precipitate thus formed was recovered by filtration, washed with water and dried to thereby give 1.96 g of 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylic acid. This product was dissolved in acetone (50 ml) and 2.1 ml (34 mmol) of methyl iodide and 2.35 g (17 mmol) of anhydrous potassium carbonate were added thereto. The reaction mixture was heated under reflux under stirring for 2 hours, then allowed to cool and extracted with water and ethyl acetate. The organic layer was taken up, washed with water, dried over magnesium sulfate and concentrated to dryness. Thus 1.49 g of methyl 6-methyl-5,6,7,8-tetrahydro-9H-carbazole-1-carboxylate was obtained. This product was suspended in diphenyl ether (10 ml) and 890 mg of 10% palladium-carbon was added thereto. The obtained mixture was heated under reflux under stirring in a nitrogen atmosphere for 1 hour. After allowing to cool, It was dissolved by adding tetrahydrofuran. Then the catalyst was filtered off and the filtrate was concentrated. After adding n-hexane, the crystals thus formed were recovered by filtration to thereby give 1.26 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl[CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:18][C:19]1([CH2:22][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:21][O:20]1
Reactant: CC1(CCl)CO1
Reactant: O=C(Nc1ccccc1O)c1ccccc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: O
Product: CC1(COc2ccccc2NC(=O)c2ccccc2)CO1
Temperature: 72.5 °C
Reaction time: 6 h
Yield: 61.3 %

Procedure:
A mixture of N-(2-hydroxyphenyl)benzamide (159 mg; 0.75 mmol), 2-(chloromethyl)-2-methyloxirane (1.60 g, 15 mmol), and benzyltriethylammonium chloride (27 mg, 0.12 mmol) was stirred at 70-75° C. for 6 h After cooling to room temperature, water (2 ml) was added and the mixture was vigorously shaken. It was extracted with dichloromethane (2×5 ml), and the combined organic extracts were washed with aq. NaOH (2M, 5 ml) and water (10 ml). Drying with Na2SO4, evaporation of the solvent and flash chromatography on silica gel with n-heptane/ethyl acetate (ethyl acetate from 25 to 50%) afforded title compound as yellowish solid (131 mg, 0.46 mmol, 62%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][N:10]1[C:15](=[O:16])[C:14]2=[CH:17][N:18]([CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[N:19]=[C:13]2[N:12]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:11]1=[O:35].CC1C=CC([S:43](OCCCO[Si](C)(C)C(C)(C)C)(=O)=S)=CC=1.[O:58]1C[CH2:61][CH2:60][CH2:59]1>>[OH:58][CH2:59][CH2:60][CH2:61][S:43][C:17]1[N:18]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[N:19]=[C:13]2[C:14]=1[C:15](=[O:16])[N:10]([CH3:9])[C:11](=[O:35])[N:12]2[CH2:31][CH:32]([CH3:33])[CH3:34]
Reactant: Cc1ccc(S(=O)(=S)OCCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: C1CCOC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3cccc4ccccc34)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCO)n(Cc3cccc4ccccc34)nc21
Temperature: -78 °C

Procedure:
Lithium diisopropylamide (3.3 mmol) was added to a solution of 5-methyl-7-(2-methylpropyl)-2-(1-naphthalenylmethyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)dione (600 mg) and 3-{[dimethyl(1,1-dimethylethyl)silyl]oxy }propyl 4-methylphenylthiosulfonate (J. Med. Chem. 1995, 38, 2557) (720 mg) in tetrahydrofuran (20 ml) cooled to -78° C. After 2 hours the reaction mixture was warmed to ambient temperature and after a further hour quenched with water. The reaction mixture was diluted with ethyl acetate and was washed twice with dilute hydrochloric acid, twice with saturated sodium hydrogen carbonate solution, once with brine, and then dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (20 ml) and tetrabutylammonium fluoride (1 M in tetrahydrofuran, 2 ml) was added. After 18 hours the reaction mixture was quenched with saturated sodium hydrogen carbonate solution and extracted with ether. The ether extract was washed once with water and once with brine, then dried over magnesium sulfate, filtered and concentrated. Chromatography of the residue on silica gel (isohexane:ethyl acetate 1:1-1:2) followed by preparative reverse phase HPLC and recrystallisation from isohexane : ethyl acetate gave the title compound (156 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.O[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[N:12][CH:11]=1.CC[O:22]C(C)=O>C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:22][C:18]2[C:19]3[CH:10]=[CH:11][N:12]=[CH:13][C:14]=3[CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1cncc2ccccc12
Reactant: CCOC(C)=O
Solvent: C1CCCCC1
Product: Clc1cncc(Oc2cccc3cnccc23)n1
Yield: 61 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (250 mg, 1.69 mmol) and 4-hydroxyisoquinoline (270 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (263 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 7.72-7.78 (m, 3H, Harom 3+6+7), 8.11 (d, 1H, Harom 5, J=7.8 Hz), 8.53 (d, 1H, Harom 2, J=5.9 Hz), 8.55 (s, 1H, HPz 5), 8.75 (s, 1H, HPz 3), 9.43 (s, 1H, Harom 8).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[NH:18])([O-:17])=[O:16]
Reactant: NCCSCc1nccs1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCSCc1nccs1)N[N+](=O)[O-]

Procedure:
Reaction of 2-[(2-aminoethyl)thiomethyl]thiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(2-thiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[Cl:12][CH2:13][C:14](O)=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:12][CH2:13][C:14]1[O:8][N:7]=[C:5]([C:4]2[CH:9]=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:6]=1
Reactant: N=C(NO)c1cccc(F)c1
Reactant: O=C(O)CCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2noc(CCl)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
3-Fluoro-N-hydroxy-benzamidine (1.4 g, 9.08 mmol), chloroacetic acid (0.94 g, 9.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.91 g, 9.99 mmol) and 1-hydroxybenzotriazole hydrate (1.35 g, 9.99 mmol) were mixed in N,N-dimethylformamide (15 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL), washed with aqueous saturated sodium bicarbonate (75 mL), washed with water again (50 mL) and washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated to give a solid. The solid was dissolved in N,N-dimethylformamide (10 mL) and the reaction mixture stirred at 120° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (3×50 mL) and washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified on silica gel eluting with 10 to 30% ethyl acetate in hexanes to give the product as a yellow oil (1.15 g, 60%). 1H NMR (300 MHz, CDCl3): δ 7.91 (dd, 1H), 7.82 (m, 1H), 7.5 (m, 1H), 7.25 (m, 1H), 4.78 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:39])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:39])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
110 mg (0.28 mmol) of the compound from Example 100 were introduced into 20 ml of dichloromethane at 0° C., 68 mg (0.28 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 93 mg (81% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:15]O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:26][C:25]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:28][CH:27]=3)=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(Cl)cc1

Procedure:
Ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate and 4-nitrobenzylamine are reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-chlorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate, which is dissolved in ethyl alcohol. 1 M Sodium hydroxide solution is added and the mixture is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-chlorophenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:23])=[C:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.Cl[S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=1)(=[O:34])=[O:33]>>[Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[O:8][C:9]([CH3:28])=[C:10]([CH3:27])[C:11]=2[C:12]([C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:23][S:32]([C:35]3[CH:43]=[CH:42][C:38]([C:39]([OH:41])=[O:40])=[C:37]([OH:44])[CH:36]=3)(=[O:34])=[O:33])=[C:16]([CH:24]([CH3:25])[CH3:26])[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2cc(C(C)C)c(O)c(C(C)C)c2)c1C
Product: Cc1oc(Cc2ccc(Br)cc2)c(C(=O)c2cc(C(C)C)c(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)c(C(C)C)c2)c1C
Yield: 52.8 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using [2-(4-bromo-benzyl)-4,5-dimethyl-furan-3-yl]-(3,5-diisopropyl-4-hydroxy-phenyl)-methanone (1.30 g, 2.77 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.00 g, 4.22 mmol). Purification on Dynamnax C18 (90% CH3CN/H2O) gave 0.98 g (53%) of the title compound as an off white solid, mp 165-168° C. 1H NMR (DMSO-d6) δ1.05 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.06 (septet, 2H), 3.81 (s, 2H), 6.92 (d, 2H), 7.39 (dd, 2H), 7.44 (s, 1H), 7.45 (s, 2H), 7.48 (d, 1H), 8.05 (d, 1H). IR (KBr) 3400, 2950, 1680, 1375 and 1190 cm−1. mass spectrum (−ESI) m/z 667 (M−H). Anal. Calcd. for C33H33BrO8S: C, 59.20; H, 4.97; N, 0.00. Found: C, 59.18; H, 5.21; N, 0.08.