Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.Br[CH2:22][CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([CH:24]=[CH:23][CH2:22][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCC=Cc1ccccc1
Reactant: CCOC(=O)COc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1Cc1sc(SCC=Cc3ccccc3)nc1-2
Yield: 50 %

Procedure:
Using ethyl [(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl)oxy]acetate and 3-bromo-1-phenyl-1-propene, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 50%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][N:8]([CH3:15])[CH2:7][CH2:6][C:5]2=1.[Cl:16][C:17]1[N:18]=[C:19]2[N:23]([C:24]=1[S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:21][S:20]2.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:15][N:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([NH:1][S:25]([C:24]4[N:23]5[C:19]([S:20][CH:21]=[CH:22]5)=[N:18][C:17]=4[Cl:16])(=[O:26])=[O:27])[CH:3]=3)[NH:11][C:10]=2[CH2:9]1
Reactant: CN1CCc2c([nH]c3ccc(N)cc23)C1
Reactant: O=S(=O)(Cl)c1c(Cl)nc2sccn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN1CCc2c([nH]c3ccc(NS(=O)(=O)c4c(Cl)nc5sccn45)cc23)C1
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 6-amino-2-methyl-2,3,4,9-tetrahydro-1H-β-carboline (description 2) (150 mg, 0.68 mmol) in pyridine (5 mL) cooled in an ice bath, were added 200 mg of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (0.68 mmol). Under N2, the reaction mixture was left to reach room temperature and stirred for 1 h at this temperature. The reaction mixture was basified with aqueous saturated solution of NaHCO3 and the pyridine evaporated. The mixture was treated with EtOAc and H2O, the organic phase washed with aqueous saturated solution of NaHCO3, separated and dried with Na2SO4. The crude was further purified using SiO2 column chromatography with EtOAc/MeOH/NH3 mixtures to yield 130 mg of 6-chloro-imidazo[2,1-b]thiazole-5-sulfonic acid (2-methyl-2,3,4,9-tetrahydro-1H-β-carbolin-6-yl)-amide. Cream colored amorphous solid, mp 232-233° C. 1H-NMR (300 MHz, DMSO-d6): (ppm) 2.36 (s, 3H); 2.54 (bb, 2H); 2.61 (bb, 2H); 3.45 (bb, 2H); 6.65 (dd, 1H, J=8.7, 2.1 Hz); 6.99 (d, 1H, J=1.8 Hz); 7.09 (d, 1H, J=8.7 Hz); 7.53 (d, 1H, J=4.5 Hz); 7.81 (d, 1H, J=4.5 Hz); 10.37 (bb, 1H); 10.74 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][C@@H:14]([C:18]([OH:20])=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+]>O1CCOCC1>[C:18]([C@@H:14]1[CH2:15][CH2:16][CH2:17][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13]1)(=[O:20])[NH2:21]
Reactant: O=C(N[C@H]1CCC[C@@H](C(=O)O)C1)OCc1ccccc1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: C1COCCO1
Product: NC(=O)[C@@H]1CCC[C@H](NC(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of (1R,3S)-3-Benzyloxycarbonylaminocyclohexanecarboxylic acid, 18c, (10.0 g, 36.1 mmol) in 1,4-dioxane (300 mL) was added pyridine (2.9 mL, 36.1 mmol), followed by di-tert-butyl dicarbonate (10.7 mL, 46.9 mmol) and ammonium bicarbonate (10.1 g, 126.2 mmol). After 3 hours, another portion of di-tert-butyl dicarbonate (1.5 g, 6.8 mmol) and ammonium bicarbonate (1.5 g, 6.8 mmol) was added and stirring was continued overnight. The reaction was quenched by addition of 2N HCl (400 mL) and stirred for 1 hour. The resulting suspension was filtered under reduced pressure, washed with 2N HCl (50 mL), water (8×50 mL) and hexanes (3×50 mL) and vacuum dried to provide benzyl N-[(1S,3R)-3-carbamoylcyclohexyl]carbamate, 18d, (9.1 g, 91%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24]O)[CH3:16]>>[CH2:15]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCc1cc(C)ccc1CO
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CCc1cc(C)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-ethyl-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.20 (3H, t, J=7.6 Hz), 2.35 (3H, s), 2.68 (2H, q, J=7.6 Hz), 5.21 (2H, s), 5.79 (1H, d, J=1.6 Hz), 7.03 (1H, d, J=7.6 Hz), 7.07 (1H, s), 7.27 (1H, d, J=8.4 Hz), 7.36 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.58 (1H, d, J=1.6 Hz), 7.96-7.97 (1H, s), 8.66 (1H, dd, J=0.8 Hz, 5.2 Hz). [M+H] Calc'd for C19H18N4O, 319. Found, 319.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:14]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.9 %

Procedure:
Imidazole (10.0 g, 146.9 mmol) was added to sodium hydride (60% dispersion in mineral oil, pre-washed in hexane, 6.5 g, 161.6 mmol) in DMF (200 ml), triphenylmethylchloride (41.0 g, 146.9 mmol) was then added and the reaction mixture stirred at room temperature for 18 h. The mixture was poured onto ice and the solid precipitate formed filtered off and partitioned between water and dichloromethane. The organic phase was washed with brine and dried over sodium sulphate and concentrated in vacuo to give the title compound (37.8 g, 83%). 1H NMR (CDCl3) δ 7.42-7.03 (1H, m). MS (ES) m/e 311 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.II.[Cl:13]Cl>>[Cl:13][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: ClCl
Agent: II
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 99 %

Procedure:
141 G of 4-fluoronitrobenzene, 3.8 g of ferric chloride and 0.2 g of iodine were charged and then heated. At a temperature of 60° to 70° C., chlorine gas was blown into the liquid until the starting material could not be detected (over 12 hours) to complete the reaction. Subsequently, the reaction mixture was washed three times with 100 g each of warm water followed by liquid separation to obtain 174 g (yield: 99%) of 3-chloro-4-fluoronitrobenzene. Analytical value thereof by gas chromatography was as follows:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=3)[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][O:29][C:27](=[O:28])[C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:11]3[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=3[CH:15]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-(4-Methoxycarbonyl-benzyloxy)-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (D3) (6.35 g) was dissolved in dichloromethane (30 ml) and treated with trifluoroacetic acid (30 ml). The solution was stirred at room temperature for 2 hours, concentrated in vacuo and then twice co-evaporated with dichloromethane. The residue was dissolved in dichloromethane and washed with 10% aqueous sodium hydroxide, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound (D4).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:6]=1)=[O:4].CO.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]1)=[O:17]
Reactant: COC(=O)c1ccc(=O)n(CCCNC(=O)c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(=O)n(CCCNC(=O)c2ccccn2)c1

Procedure:
1,6-dihydro-1-[3-(2-pyridinylcarbonylamino)propyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.260 g, 0.83 retool) was hydrolysed in a mixture consisting of methanol (1.0 ml), water (1.0 ml), and 15% aqueous sodium carbonate (2.0 ml) at 60° for 1.5 hours. The solution was filtered and acidified (to pH 5.5 with acetic acid). The precipitated product was recovered by filtration, washed with water, and dried, MP: 180°-182° C.
Reaction SMILES: CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OC([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:38][O:39][CH3:40])[C:34]([NH:36][CH3:37])=[O:35])C)C>[Cl-].[Na+].O>[OH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:38][O:39][CH3:40])[C:34]([NH:36][CH3:37])=[O:35]
Reactant: CCOC(C)OCc1ccccc1C(=NOC)C(=O)NC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)C(=NOC)c1ccccc1CO
Yield: 90 %

Procedure:
Methanol (4 ml) and pyridinium p-toluenesulfonate (0.04 g, 0.00017 mol) were added to an E/Z mixture of 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-methoxyimino-N-methylacetamide (0.50 g, 0.0017 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, half-saturated brine (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.34 g, Yield: 90.0%, E/Z=96/4) as a colorless oil.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:14][C:13]1[O:12][C:11]([C:15]2[CH:28]=[CH:27][C:18]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)=[N:10][C:9]=1[CH2:8][CH2:7][OH:6]
Reactant: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(OCc3ccccn3)cc2)nc1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a mixture of 2-(4-{4-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-5-methyl-oxazol-2-yl}-phenoxymethyl)-pyridine (0.97 g, 1.76 mmol) in THF (20 mL) at 0° C. is added a solution of TBAF in THF (1.0 M, 1.76 mL). The mixture is warmed to room temperature and stirred for 2 h. The mixture is partitioned between EtOAc and water. The aqueous phase is extracted with EtOAc (3×). The combined organic phase is washed with brine (2×), dried (Na2SO4), and concentrated. The residue is purified by flash chromatography (SiO2, elute 0% to 10% MeOH/CH2Cl2) to yield 0.53 g of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.6 (dd, 1H), 7.8 (m, 3H), 7.6 (d, 1H), 7.4 (dd, 1H), 7.2 (d, 2H), 5.2 (s, 2H), 3.6 (t, 2H), 2.6 (t, 2H), 2.2 (s, 3H). MS (m/e) 311.1 (M+1)
Reaction SMILES: CC1N=C(N2C(=O)NN=C2)SC=1C(OCC)=O.[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][NH:28][C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19].[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br>>[C:18]([C:21]1[S:25][C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH2:38][C:37]3[CH:40]=[CH:41][CH:42]=[C:35]([C:34]([F:33])([F:43])[F:44])[CH:36]=3)[C:27]2=[O:31])=[N:23][C:22]=1[CH3:32])(=[O:20])[CH3:19]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Agent: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Product: CC(=O)c1sc(N2CCN(Cc3cccc(C(F)(F)F)c3)C2=O)nc1C
Yield: 50 %

Procedure:
Following the procedure as describe in Preparation 16, making variations as required to replace ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one to react with 3-(trifluoromethyl)benzyl bromide, the title compound was obtained as a yellow solid in 50% yield: mp 149-151° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.70-7.58 (m, 4H), 4.55 (s, 2H), 4.04 (t, J=6.0 Hz, 2H), 3.51 (t, J=6.0 Hz, 2H), 2.51 (s, 3H), 2.45 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ190.9, 160.4, 155.6, 155.1, 138.5, 132.5, 130.4, 129.9 (q, 3JC-F=38 Hz), 126.6, 125.9, 125.1-124.8 (m), 122.9, 47.1, 42.6, 42.4, 30.5, 18.8; MS (ES+) m/z 384.2 (M+1).
Reaction SMILES: COC(=O)C1C=C[CH:7]=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH2:25])=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH:15]=2)[CH:5]=1.C(O)(=O)C1C=CC=CC=1.S1C2C=CC=CC=2N=C1C1C(N)=NC=C(Br)C=1.C[O:54][C:55]([C:57]1[CH:62]=CC(B2OC(C)(C)C(C)(C)O2)=C[N:58]=1)=[O:56].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.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>[NH2:25][C:13]1[N:12]=[CH:11][C:10]([C:6]2[CH:5]=[N:58][C:57]([C:55]([OH:56])=[O:54])=[CH:62][CH:7]=2)=[CH:15][C:14]=1[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COC(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Nc1ncc(Br)cc1-c1nc2ccccc2s1
Agent: O=C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)nc2)cc1-c1nc2ccccc2s1

Procedure:
Following the procedures for 3-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-benzoic acid methyl ester and the benzoic acid, the title compound was prepared from 3-benzothiazol-2-yl-5-bromopyridin-2-ylamine (BB7) (1.1 g, 3.6 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid methyl ester (1.0 g, 3.8 mmol), Pd(PPh3)4 (2 mol %), and Cs2CO3 (2.83 g, 8.7 mmol) in DMF/H2O (24 mL, 5:1). 1H NMR (400 MHz, DMSO-d6): δ=8.90 (s, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 8.20-8.07 (m, 5H), 7.96 (brd, J=8.4 Hz, 1H), 7.57 (dt, J=1.0, 8.0 Hz, 1H), 7.49 (dt, J=1.0, 8.0 Hz, 1H); COOH proton not visible. MS(ES+): m/z=349.08 (100) [MH+], 305.09 (8) [MH+—CO2]. HPLC: tR=2.89 min (polar—5 min, ZQ3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-benzyloxyacetophenone (1.14 g, 5.06 mmol), lithium bis(trimethylsilyl)amide (0.930 g, 5.56 mmol), chlorotrimethylsilane (0.705 mL, 5.56 mmol), THF (57 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 139-142° C.; 1H NMR (400 MHz, DMSO-d6) δ2.77 (t, 2 H), 2.98 (t, 2 H), 5.19 (s, 2 H), 6.68 (s, 1 H), 7.26 (m, 7 H), 7.43 (m, 5 H), 7.76 (d, 2 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@@H:23]2[C@@H:28]([OH:29])[CH2:27]O[CH2:25][CH2:24]2)[C:12]3=[O:30])=[CH:4][CH:3]=1.N[C@H:32]1CCOC[C@@H]1O>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:24][CH2:25][CH2:32][CH2:27][C@@H:28]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCOC[C@@H]1O
Reactant: N[C@H]1CCOC[C@@H]1O
Product: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCCC[C@@H]1O

Procedure:
6-[(6-Chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 1,5-anhydro-3-{6-[(6-chloropyridin-3-yl)methyl]-4-oxobenzo[h]quinazolin-3(4H)-yl}-2,3-dideoxy-L-threo-pentitol in Example 2, substituting (1S,2S)-2-aminocyclohexanol for (3R,4S)-4-aminotetrahydro-2H-pyran-3-ol.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[NH2:16][C:17]1[S:18][C:19]([C:29]([NH2:31])=[O:30])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[Cl:28][C:24]1[CH:23]=[C:22]([C:20]2[N:21]=[C:17]([NH:16][C:6]3[CH:5]=[C:4]([CH:3]([O:14][CH3:15])[O:2][CH3:1])[CH:9]=[CH:8][C:7]=3[N+:10]([O-:12])=[O:11])[S:18][C:19]=2[C:29]([NH2:31])=[O:30])[CH:27]=[CH:26][CH:25]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)c1
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A mixture of 2.56 g (11.9 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene (IV.2a), 3.00 g (11.85 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 11.6 g (35.7 mmole) of cesium carbonate and 40 mL of dimethylformamide was stirred at 60 degrees for 3 hours. The mixture was cooled, poured into dilute ammonium chloride solution, and the precipitated yellow solid was collected by filtration, washed with water, and air-dried to give 4.43 g of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2a).
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]>CO.CCOC(C)=O.[Pd].[OH-].[OH-].[Pd+2]>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]
Reactant: COc1ccccc1C(O)C1CCCCC1=O
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccccc1CC1CCCCC1=O
Temperature: 25 °C
Reaction time: 28 h
Yield: 76.7 %

Procedure:
A mixture of 2-[hydroxy-(2-methoxyphenyl)methyl]-cyclohexanone (3.71 g), 10% Pd/C (wet) (1.0 g), and 20% Pd(OH)2/C (180 mg) in MeOH-EtOAc (2:1, 150 ml) was stirred under hydrogen atmosphere at room temperature for 28 hours. The catalyst was removed by filtration and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane-EtOAc 7:1) to give 2-(2-methoxybenzyl)cyclohexanone (2.65 g) as an oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([O:17][CH3:18])=[C:10]([CH:12]2[O:16][CH2:15][CH2:14][O:13]2)[CH:11]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:21]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:21][N:5]([C:6]1[CH:7]=[CH:8][C:9]([O:17][CH3:18])=[C:10]([CH:12]2[O:13][CH2:14][CH2:15][O:16]2)[CH:11]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CI
Reactant: COc1ccc(NS(C)(=O)=O)cc1C1OCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)S(C)(=O)=O)cc1C1OCCO1
Temperature: 60 °C
Reaction time: 1 h
Yield: 113.3 %

Procedure:
To a solution of 2-(5-methylsulfonylamino-2-methoxyphenyl)-1,3-dioxolane (8.63 g, 31.6 mmol) in DMF (30 ml) was added NaH (1.51 g, 37.9 mmol) and methyl iodide (2.36 ml, 37.9 mmol) and then stirred at 60° C. for 1 hr. After aqueous ammonium chloride was added to the reaction mixture, the mixture was extracted with ether/CH2Cl2. The extract was dried over MgSO4 and evaporated in vacuo to give crude 2-[5-(N-methyl-N-methylsulfonylamino)-2-methoxyphenyl]-1,3-dioxolane (10.29 g) as a brown oil.
Reaction SMILES: NC1SC=C(C(=O)C(N[C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([CH3:34])[N:33]=[C:29]4[N:28]=[C:27]([C:35](=[O:38])[NH:36][OH:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=O)N=1.Cl.NOCS(C1C=C(O)C(=CC=1)O)(=O)=O>CC(N(C)C)=O>[OH:37][NH:36][C:35]([C:27]1[CH:26]=[C:25]([S:24][CH2:23][C:15]2[CH2:14][S:13][CH:12]3[N:17]([C:18](=[O:19])[CH2:11]3)[C:16]=2[C:20]([OH:22])=[O:21])[N:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:29]2[N:28]=1)=[O:38]
Reactant: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)C(=O)c5csc(N)n5)[C@H]4SC3)n2n1
Agent: Cl
Agent: NOCS(=O)(=O)c1ccc(O)c(O)c1
Solvent: CC(=O)N(C)C
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)CC4SC3)n2n1

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (65 mg) (0.11 mmol) and 37 mg (0.14 mmol) of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol hydrochloride are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours a further 4.2 mg (0.016 mmol) of 4-[[(aminooxy)methyl]sulphonyl]pyrocatechol hydrochloride are added. After a further 24 hours the solvent is removed in a high vacuum at room temperature and the residue is treated with water. The precipitated product is filtered off and washed in succession with water and diethyl ether. After drying in a high vacuum there are obtained 55 mg of (6R,7R)-7-[(Z)-2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5 -a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)[CH2:3][CH3:4].I([O-])(=O)(=O)=[O:22].[Na+].CCOCC>CO.O>[CH3:1][CH:2]([S:5]([C:6]1[CH:20]=[CH:19][C:9]([O:10][CH2:11][CH2:12][NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=[CH:8][CH:7]=1)=[O:22])[CH2:3][CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCOC(=O)NCCOc1ccc(SC(C)CC)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: CCOC(=O)NCCOc1ccc(S(=O)C(C)CC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl N-[4-(1-methylpropylthio)phenoxyethyl]carbamate (cpd. 40, from Example 13) (2.13 g, 7.1 mmol) in 7 ml of methanol at 0° is added, dropwise over 5 min., sodium metaperiodate (1.67 g, 7.8 mmol) in 13 ml of water. The mixture is stirred for 3 hours while warming to RT. The reaction is worked up by addition of water and extraction of ether. The combined organic extracts are washed with saturated sodium thiosulfate, with water and with brine, dried and the solvent is removed to give ethyl N-{2-[4-(1-methylpropylsulfinyl)phenoxy]-ethyl}carbamate (compound 80, Table A).