Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]2[C@@H:37]([O:38][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][OH:41])[NH:36][C:35]2=[O:48])=[O:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[C:12]1([CH2:18][CH2:19][C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]2[C@@H:37]([O:38][CH:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:40][O:41][S:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=3)(=[O:9])=[O:8])[NH:36][C:35]2=[O:48])=[O:32])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:21])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OC(CO)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O[C@H]2NC(=O)[C@H]2NC(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
p-Toluenesulfonyl chloride (119 mg, 0.62 mmol) was added to an ice-cooled solution of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(2-hydroxy-1-phenylethoxy)-azetidin-2-one (260 mg, 0.52 mmol) and pyridine (493 mg, 6.2 mmol) in dichloromethane (7 ml). The mixture was stirred at 0° C. for 2 hrs and then at room temperature overnight. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (8:3) as eluent and 160 mg of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(p-toluenesulfonyl)oxy-1-phenylethoxy}-azetidin-2-one was obtained (47% yield).
Reaction SMILES: Br[C:2]1[S:11][C:5]2[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.COCCOC>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[S:11][C:5]3[C:6](=[O:10])[NH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=c1[nH]ccc2cc(Br)sc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: O=c1[nH]ccc2cc(-c3ccc(Cl)cc3)sc12
Temperature: 85 °C
Yield: 89.3 %

Procedure:
Combine 2-bromo-6H-thieno[2,3-c]pyridin-7-one (25.0 g, 108.7 mmol), 4-chlorophenylboronic acid (18.7 g, 119.5 mmol), sodium carbonate (23.5 g, 217.3 mmol), ethanol (121 mL), 1,2-dimethoxyethane (604 mL), and water (121 mL). Purge the mixture with nitrogen for 20 min. Add tetrakis(triphenylphosphine)palladium (3.77 g, 3.26 mmol). Heat the reaction mixture at 85° C. overnight. Allow the reaction to cool to RT. Reduce the reaction solvent volume to half on a rotory evaporator. Filter the mixture with water (2×400 mL), ether (400 mL), and ethylacetate (20 mL) and dry the solids in vacuo at 40° C. to give 25.4 g (89%) of the title compound. LC-MS/ES m/z (35Cl) 262.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=O)[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].C(=O)(O)[O-].[Na+].O>C(O)C>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:33])[C:14]1[CH:19]=[C:18]([CH:20]=[N:35][OH:36])[C:17]([F:22])=[C:16]([F:23])[C:15]=1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=1[F:32])([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NO)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-formyl-benzamide (10.5 mg, 17.7 μmol) prepared in Process B was dissolved in ethanol (1.5 ml). Hydroxylamine hydrochloride (40 mg, 0.57 mmol) and saturated aqueous solution of sodium bicarbonate (0.3 ml) were added thereto, and the mixture was stirred at room temperature for two hours. Water (5 ml) was added to the reaction solution, which was extracted with ethyl acetate (6 ml×3). The organic layers were combined, washed with saturated brine (8 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel-column chromatography (Presep (r) silica gel, 10 g, Wako Pure Chemical Industries, Ltd., n-hexane/ethyl acetate (4:1)) to give N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodophenylamino)-5-(hydroxyiminomethyl)-benzamide (5.0 mg, 46%).
Reaction SMILES: CCN(CC)CC.[N:8]([C@H:11]1[CH2:15][C@@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@@H:12]1[OH:24])=[N+:9]=[N-:10].[CH3:25][S:26](Cl)(=[O:28])=[O:27].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:25][S:26]([O:24][C@@H:12]1[CH2:13][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][C@H:11]1[N:8]=[N+:9]=[N-:10])(=[O:28])=[O:27]
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](OCc2ccccc2)C[C@@H]1O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@H](OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a cooled mixture of Et3N (9.49 g, 94.0 mmol) and (1S,2S,4R)-2-azido-4-(benzyloxy)cyclopentanol (18.25 g, 78.3 mmol) in DCM (500 mL) was added dropwise methanesulfonyl chloride (9.87 g, 86.2 mmol) in DCM (50 mL) at 0° C. The mixture was stirred overnight at a temperature of 0° C. to RT. After complete conversion, aq NaHCO3 (5%, 300 mL) was added. The mixture was extracted with DCM, washed with brine, and dried over Na2SO4 to give the title compound as an oil (23.58 g, 75.8 mmol). 1H NMR (400 MHz, CDCl3) δ ppm 1.83-1.89 (m, 1H), 2.06-2.13 (m, 1H), 2.34-2.49 (m, 2H), 3.04 (s, 3H), 3.94-3.99 (m, 1H), 4.08-4.13 (m, 1H), 4.64 (s, 2H), 4.93-4.98 (q, J=5.6/7.0 Hz, 1H), 7.25-7.36 (m, 5H).
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:42](Cl)([O:44]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[O:60]1[CH2:65][CH2:64][CH:63]([NH:66][OH:67])[CH2:62][CH2:61]1>ClCCl>[NH:20]1[CH:24]=[C:23]([C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][CH2:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([NH:34][C:42](=[O:44])[N:66]([OH:67])[CH:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[CH:35][CH:36]=2)[N:22]=[CH:21]1
Reactant: ONC1CCOCC1
Reactant: Nc1ccc(CCOc2ccccc2-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCOc2ccccc2-c2c[nH]cn2)cc1)N(O)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.4 %

Procedure:
A mixture of 4-(2-(2-(1-trityl-1H-imidazol-4-yl)phenoxy)ethyl)aniline (113 mg, 0.217 mmol), triphosgene (21 mg, 0.07 mmol) and triethylamine (0.04 mL, 0.260 mmol) in dry dichloromethane (6 mL) was heated at reflux for 2 h and then cooled with an ice bath. To this mixture was added N-(tetrahydro-2H-pyran-4-yl)hydroxylamine (76 mg, 0.650 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the crude was dissolved in methanol (4 mL) and acetic acid (1 mL). The reaction mixture was heated at 80° C. for 2 h. The reaction mixture was basified with aqueous 10% NaOH and the aqueous layer extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography using 5% MeOH/dichloromethane as an eluent at afford the desired product as a yellowish solid (30 mg, 33%). 1H NMR: 1.63 (d, 2H, J=10.4 Hz), 1.98-2.07 (m, 2H), 3.15 (t, 3H, J=5.6 Hz), 3.46 (t, 2H, J=11.6 Hz), 3.78 (s, 1H), 4.02 (dd, 2H, J=11.2 Hz, 4 Hz), 4.36-4.45 (m, 4H), 6.98-7.03 (m, 3H), 7.19-7.27 (m, 3H), 7.30-7.42 (m, 3H), 7.66 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([OH:16])=O)=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]2([OH:38])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH2:20][CH2:19]1.C(P(=O)(OCC)OCC)#N.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([NH:17][C@H:18]3[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@@H:21]([CH2:31][C:32]4([OH:38])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:20][CH2:19]3)=[O:16])=[N:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N)CC[C@@H]1CC1(O)CCOCC1
Reactant: O=C(O)c1nn(C2CCC2)c2ccccc12
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2nn(C3CCC3)c3ccccc23)CC[C@@H]1CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.7 %

Procedure:
The mixture of 1-cyclobutyl-1H-indazole-3-carboxylic acid (135 mg, 0.63 mmol, step 2 of Example 4), tert-butyl cis-5-amino-2-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]piperidine-1-carboxylate (197 mg, 6.27 mmol, step 5 of Example 2), diethyl cyanophosphonate (0.13 mL, 0.75 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 12 h. Then the mixture was poured onto aqueous saturated sodium hydrogencarbonate (100 mL), and the aqueous layer was extracted with ethyl acetate/toluene (3:1, 100 mL×3). The combined organic layer was concentrated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:2) to give 112 mg (35%) of the title compound as a pale yellow amorphous.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C1(O)CCC1.[CH2:13]([Sn:17]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]I)[CH2:14][CH2:15][CH3:16]>O.CCCCCCC.CN(C)C=O>[CH2:24]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][O:3][CH:7]1[CH2:6][CH2:5][CH2:4]1)[CH2:25][CH2:26][CH3:27]
Reactant: C1CCOC1
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Agent: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)COC1CCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
To a mixture of sodium hydride (250 mg, 7.0 mmol, 66% in oil) and tetrahydrofuran (20 mL) were added cyclobutanol (0.55 mL, 7.0 mmol) and N,N-dimethylformamide (20 mL) at 0° C., and then the reaction mixture was stirred for 40 minutes at room temperature. The tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) described in Manufacturing Example 197-2-2 was added dropwise to the reaction mixture at 0° C., and then the reaction mixture was stirred overnight at room temperature. Heptane and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed and saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the title compound (1.6 g, 92%).
Reaction SMILES: CO[CH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:4]1.[Cl-:17].[NH4+:18]>CO>[ClH:17].[C:11]1([CH2:10][CH:5]2[NH:4][C:3](=[NH:18])[CH2:9][CH2:8][CH2:7][CH2:6]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC1CCCCC(Cc2ccccc2)N1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: Cl
Product: N=C1CCCCC(Cc2ccccc2)N1
Yield: 91.4 %

Procedure:
The title product of Example 3 (0.30 g, 1.4 mmol) and 0.06 g (1.1 mmol) of ammonium chloride (NH4Cl) were refluxed in 13 mL of methanol (MeOH) under a nitrogen atmosphere for 19 h. After cooling the reaction to room temperature, it was filtered, stripped of all solvent under reduced pressure, and partitioned between 15 mL of water and 7 mL of CH2Cl2. The organic and aqueous phases were separated and the aqueous phase was washed with a 25 mL portion of EtOAc before it was lyophilized to provide 0.24 g (92%) of the white solid title material.
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])O)[OH:4].[O:12]=[C:13]([O-:22])[C@@H:14]([C@H:16]([C@H:18]([CH2:20][OH:21])[OH:19])O)[OH:15]>>[C:2]([O-:11])(=[O:1])[C:3]([CH2:5][C@@H:7]([CH2:9][OH:10])[OH:8])=[O:4].[C:13]([O-:22])(=[O:12])[C:14]([CH2:16][C@H:18]([CH2:20][OH:21])[OH:19])=[O:15]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)CO
Product: O=C([O-])C(=O)C[C@@H](O)CO
Product: O=C([O-])C(=O)C[C@H](O)CO

Procedure:
D-Xylonate and L-arabinonate dehydratase can be assayed according to procedures described by Dahms. (Dahms, A. S.; Donald, A. Meth. Enzymol. 1982, 90, 302.; Anderson, R. L.; Dahms, A. S. Meth. Enzymol. 1975, 42C, 305.) The 2-keto acids 3-deoxy-D-glycero-pentulosonate and 3-deoxy-L-glycero-pentulosonate formed during enzyme-catalyzed dehydration are measured as semicarbazone derivatives. Two solutions are prepared and incubated separately at 30° C. for 3 min. The first solution (150 μL) contained Tris-HCl (50 mM), MgCl2 (10 mM) and an appropriate amount of cell lysate at pH 8.0. The second solution (25 μL) contained potassium D-xylonate or L-arabinonate (0.1 M). After the two solutions are mixed (time=0), aliquots (30 μL) are removed at timed intervals and mixed with semicarbazide reagent (200 μL), which contained 1% (w/v) of semicarbazide and 0.9% (w/v) of sodium acetate in water. Following incubation at 30° C. for 15 min, each sample is diluted to 1 mL with H2O. After removing the precipitated protein by centrifugation, the absorbance of semicarbazone is measured at 250 nm. One unit of D-xylonate or L-arabinonate dehydratase activity is defined as the formation of 1 μmol of 3-deoxy-D-glycero- or 3-deoxy-L-glycero-pentulosonate per min at 30° C. A molar extinction coefficient of 10,200 M−1cm−1 (250 nm) is used for 2-keto acid semicarbazone derivatives.
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]=O.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1.Cl>C(O)(C)C>[ClH:1].[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH2:32][CH2:22][N:13]2[CH2:14][CH2:15][CH:10]([C:8]([OH:9])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11][CH2:12]2)=[CH:27][CH:26]=1
Reactant: C=O
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CCN1CCC(C(O)(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1

Procedure:
A mixture of 30.4 g (0.1 mole) of α,α -diphenyl-4-piperidinemethanol hydrochloride, 9 g (0.3 mole) of paraformaldehyde and 13.8 g (0.1 mole) of 4' -fluoroacetophenone in 100 ml of isopropyl alcohol containing 2 drops of concentrated HCl was refluxed for 24 hours. The mixture was filtered and the filtrate concentrated to about 100 ml and cooled. The resulting precipitate was filtered off and recrystallized from ethanol and isopropyl alcohol to give the desired product, M.P. 250° C.
Reaction SMILES: P(OCC)(OCC)(OCC)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH:26]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][C:29]=1[S:36][CH3:37])=O.[F:38][C:39]([F:51])([F:50])[C:40]1[CH:41]=[C:42]([NH:46][C:47]([NH2:49])=[O:48])[CH:43]=[CH:44][CH:45]=1.[C:52]([O:58][CH2:59][CH:60]=[CH2:61])(=[O:57])[CH2:53][C:54]([CH3:56])=O>CC(OC)(C)C>[C:32]([C:31]1[CH:34]=[CH:35][C:28]([CH:26]2[C:53]([C:52]([O:58][CH2:59][CH:60]=[CH2:61])=[O:57])=[C:54]([CH3:56])[N:46]([C:42]3[CH:43]=[CH:44][CH:45]=[C:40]([C:39]([F:50])([F:51])[F:38])[CH:41]=3)[C:47](=[O:48])[NH:49]2)=[C:29]([S:36][CH3:37])[CH:30]=1)#[N:33]
Reactant: CSc1cc(C#N)ccc1C=O
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: C=CCOC(=O)CC(C)=O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: COC(C)(C)C
Solvent: CCOP(=O)(OCC)OCC
Product: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1SC

Procedure:
The reaction was carried out under argon. Triethyl phosphate (1.46 g, 8.04 mmol) and diphosphorus pentoxide (761 mg, 5.36 mmol) were stirred at 50° C. overnight. The mixture was then diluted with MTBE (27 ml), and 4-formyl-3-(methylsulfanyl)benzonitrile (1.18 g, 6.70 mmol; Example 9A), 1-[3-(trifluoromethyl)phenyl]urea (1.37 g, 6.70 mmol) and allyl acetoacetate (1.43 g, 10.1 mmol) were added. The mixture was stirred under reflux overnight. For work-up, the solvent was removed under reduced pressure and the residue was suspended in diethyl ether and then filtered of with suction. This gave 978 mg (19% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][CH:6]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([C:6]2[NH:5][C:4](=[O:7])[NH:3][C:2]=2[CH3:1])=[O:19])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1c[nH]c(=O)[nH]1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2[nH]c(=O)[nH]c2C)cc1

Procedure:
To 19.6g of 1,3-dihydro-4-methyl-2H-imidazol-2-one and 53.2 g of anhydrous aluminum chloride in 150 ml of nitrobenzene is added dropwise 34.2 g of p-methoxybenzoyl chloride and the mixture is poured on 500 ml of 2N-HCl and ice, washed 3 times with ethyl ether, the resulting solid is recrystallized from isopropanol-water to give the title compound. M.P. 257°-258° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17]Br.C(N(C(C)C)CC)(C)C>C1C=CC=CC=1.O>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1ccc(N2CCCC2)cc1

Procedure:
1.69 g (10.2 mmol) of ethyl 4-aminobenzoate was dissolved in 10 ml of benzene. 2.18 g (10.1 mmol) of 1,4-dibromobutane and 3.53 ml (20.2 mmol) of diisopropylethylamine were added to the solution, and they were heated under reflux for 48 hours. The reaction solution was diluted with water. After the extraction with ethyl acetate, the organic layer was washed with water and then with saturated Aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[S:13][C:14]([CH2:18][N:19]([CH3:21])[CH3:20])=[C:15]([CH3:17])[CH:16]=2)=[N:5]S(=O)[N:3]=1.[ClH:23]>CO>[ClH:23].[ClH:23].[ClH:23].[CH3:21][N:19]([CH2:18][C:14]1[S:13][C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])=[CH:16][C:15]=1[CH3:17])[CH3:20]
Reactant: Cc1cc(CSCCNC2=NS(=O)N=C2N)sc1CN(C)C
Agent: Cl
Solvent: CO
Product: Cc1cc(CSCCNC(=N)C(=N)N)sc1CN(C)C
Reaction time: 3 h
Yield: 80 %

Procedure:
A stirred solution of 3-amino-4-{2-[(5-dimethylaminomethyl-4-methyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (17.9 g, 50.0 mmoles) [prepared according to the general procedure described in published U.K. patent application No. 2,067,987] in 500 mL of methanol was treated with 33.3 mL of concentrated HCl. After stirring for 3 hours, the reaction mixture was concentrated and excess water was removed by azeotropic concentration with absolute ethanol to give an almost colorless crystalline residue. The residue was triturated with 200 mL of absolute ethanol at 0° C., filtered and dried to give 16.9 g (80%) of the title compound, m.p. 206°-220° C. (dec.). Recrystallization from 50% methanol-ethyl acetate gave a product having m.p. 210°-221° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (16.06 g, 37.3 mmol) in 75 mL of CH2Cl2 was treated with 75 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (7.82 g, 41.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature. After 30 min, the reaction was treated with 75 mL of CH2Cl2 and 75 mL of water and the layers were separated. The organic portion was then washed with 1% Na2CO3 solution (2×), water, brine, dried over Na2SO4, concentrated give 14.95 g of tert-butyl 2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=C(NC12CCC(C(=O)O)(CC1)CC2)OCc1ccccc1
Solvent: ClCCl
Product: O=C(NC12CCC(C(=O)OC3CCCCO3)(CC1)CC2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (1.00 g) was dissolved in dichloromethane (10 mL). To this solution, 3,4-dihydro-2H-pyran (1.20 mL) and p-toluenesulfonic monohydrate (6.3 mg) were sequentially added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was sequentially washed with a saturated aqueous solution of sodium bicarbonate and saturated brine. The mixture was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant:hexane:ethyl acetate=4:1) to give 2-tetrahydropyranyl 4-benzyloxycarbonylaminobicyclo[2.2.2]octane-1-carboxylate (1.18 g).