Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:36]([F:39])([F:38])[F:37])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[N:13](CC3C=CC(OC)=CC=3)[C:12](=[O:35])[O:11]2)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].O>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:36]([F:37])([F:38])[F:39])[C:15]3[CH:16]=[C:17]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:35])[O:11]2)=[O:7])=[CH:40][CH:41]=1
Reactant: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(N4CCCC4=O)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(N3CCCC3=O)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C

Procedure:
4-Fluoro-N-{[1-(4-methoxybenzyl)-2-oxo-6-(2-oxopyrrolidin-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide (30 mg, 0.0525 mmol), aluminum trichloride (70 mg, 0.525 mmol) were mixed in anisole (0.5 mL), and the mixture was stirred at room temperature. After all the ingredients were dissolved, the temperature of the solution was raised to 100° C. and the solution was stirred for 4 hours. The temperature of the solution was brought to room temperature and the solution was diluted with ethyl acetate and then water was added thereto. Then, the organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/0), and a crude product was crystallized from ethyl acetate-diisopropyl ether, whereby the objective compound (10.1 mg, 43%) was obtained as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=CC(N2C3=NC=CC=C3C(C3C=CC=CC=3)=N2)=C[CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][OH:27]>>[C:26]([O:1][CH2:2][CH3:7])(=[O:27])[CH3:25].[CH:25]([O:1][CH:2]([CH3:3])[CH3:7])([CH3:26])[CH3:24]
Reactant: Oc1ccc(-n2nc(-c3ccccc3)c3cccnc32)cc1
Reactant: OCCCCl
Product: CC(C)OC(C)C
Product: CCOC(C)=O

Procedure:
By reacting in the same manner as in Example 1, using 4 g of 1-(4-hydroxyphenyl)-3-phenyl-1H-pyrazolo[3,4-b]pyridine and 3.6 g of 3-chloropropanol and recrystallizing the obtained crude crystals from ethyl acetate-isopropyl ether, there was obtained 1-[4-(3-hydroxypropoxy)phenyl]-3-phenyl-1H-pyrazolo[3,4-b]pyridine, m.p. 135°-138° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[N:16](S(C3C=CC=CC=3)(=O)=O)[C:13]2=[N:14][CH:15]=1)([O-:9])=[O:8].C(OCC)(=O)C>CO.O>[N+:7]([C:10]1[CH:11]=[C:12]2[CH:18]=[C:17]([C:19](=[O:21])[CH3:20])[NH:16][C:13]2=[N:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(=O)c1cc2cc([N+](=O)[O-])cnc2n1S(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 40 °C
Yield: 100.8 %

Procedure:
Potassium carbonate (1.20 g, 8.69 mmol) was added to a solution of 1-(5-nitro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (0.50 g, 1.45 mmol) in methanol (13 mL) and water (4.3 mL). The reaction mixture was heated at 40° C. for 30 minutes. The reaction mixture was then cooled down and treated with water and ethyl acetate. The layers were then separated. The organic layers were washed twice with water, dried over sodium sulfate, filtered, and evaporated to afford 1-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)ethanone (0.30 g, quantitative yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[F:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: CCCCCc1ccc(Br)cc1
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 84.7 %

Procedure:
1-Bromo-4-pentylbenzene (T-1; 50.0 g), 3-fluorophenylboronic acid (31.4 g), potassium carbonate (91.2 g), Pd(Ph3P)2Cl2 (4.63 g), toluene (150 ml), Solmix A-11 (150 ml), and water (150 ml) were added to a reaction vessel under a nitrogen atmosphere, and heated under reflux for 3 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from Solmix A-11 and dried, whereby 45.2 g of 3-fluoro-4′-pentylbiphenyl (T-2) was obtained. The yield based on the compound (T-1) was 85%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl.[Cl:10][CH2:11][CH2:12][CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:8][C:5]1[N:4]=[N:3][C:2]([N:15]2[CH2:16][CH2:17][CH:13]([CH2:12][CH2:11][Cl:10])[CH2:14]2)=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: ClCCC1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCCC1CCN(c2ccc(Cl)nn2)C1
Temperature: 65 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A mixture of 8.9 parts of 3,6-dichloropyridazine, 8.6 parts of 3-(2-chloroethyl)pyrrolidine hydrochloride, 21,2 parts of sodium carbonate and 235 parts of N,N-dimethylformamide was stirred overnight at about 65° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 12.2 parts (99.1%) of 3-chloro-6-[3-(2-chloroethyl)-1-pyrrolidinyl]pyridazine as a residue (int. 94).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]>C1COCC1.C1(C)C=CC=CC=1>[Br:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH:16]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1cc(Br)ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(Br)ccc1C(=O)O
Temperature: 70 °C
Reaction time: 24 h

Procedure:
Ethyl chloroformate (5.00 ml, 52.1 mmol) was added to a solution of 2-amino-4-bromobenzoic acid (3.75 g, 17.36 mmol) in THF (70 ml) at room temperature. The mixture was heated to 70° C. and let stir for 24 hrs. The reaction was concentrated to give an oily solid. The resulting solid was diluted with toluene (50 mL), concentrated and then triturated with 5% ether/hexanes (100 mL) to give upon filtration and subsequent washing of the solid with hexane the title compound (4.6 gm, 92%) as a solid. LCMS (ES+) m/z 287.88 (M+H)+.
Reaction SMILES: N[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:35])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:5][CH:4]=1.NC1C=CC(C[OH:42])=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CS(C)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:35])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:16][CH2:15]2)=[O:11])=[CH:5][CH:4]=1)=[O:42]
Reactant: NCc1ccc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reactant: Nc1ccc(CO)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=Cc1ccc(NC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl ester (1 g, 2.7 mmol; prepared as described in Preparation 14), 4-aminobenzyl alcohol (498 mg, 4.05 mmol), HATU (1.54 g, 4.05 mmol) and DIPEA (1.41 mL, 8.1 mmol) in DCM (14 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with 100 mL of DCM and washed first with a 1:3 mixture of 1N HCl/water (100 mL), then brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM (100 mL) and the solution was cooled to −5° C. DIPEA (1.1 mL, 6.33 mmol) and DMSO (1.5 mL, 21.1 mmol) were added to the solution, followed by sulfur trioxide pyridine complex (1 g, 6.33 mmol). The reaction mixture was stirred at 0° C. for 1 hour then washed with a saturated solution of sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated to give 0.84 g of the title intermediate (66% yield) as an oil.
Reaction SMILES: [Si:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](B(O)O)=[CH:14][CH:15]=2)[C:10]([CH:20]([CH3:22])[CH3:21])=[CH:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:23][C:24]1[C:38]([CH3:39])=[CH:37][C:27]([O:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=1[CH3:40].N1C=CC=CC=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:33]([O:32][C:30](=[O:31])[CH2:29][O:28][C:27]1[CH:26]=[C:25]([CH3:40])[C:24]([O:23][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:9]=[C:10]3[CH:20]([CH3:22])[CH3:21])=[C:38]([CH3:39])[CH:37]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)c1cn([Si](C)(C)C(C)(C)C)c2ccc(B(O)O)cc12
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)cc(C)c1O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(OCC(=O)OC(C)(C)C)cc(C)c1Oc1ccc2c(c1)c(C(C)C)cn2[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
0.50 g (1.58 mmol) of 1-[tert-butyl(dimethyl)silyl]-3-isopropyl-1H-indol-5-yl-boronic acid (Example XII), 0.437 g (173 mmol) of tert-butyl-(4-hydroxy-3,5-dimethylphenoxy)acetate (Example IX), 0.286 g (1.58 mmol) of copper(II) acetate and 0.50 g of molecular sieve (4 Å, powdered) are suspended in 10 ml of dried dichloromethane. 0.64 ml (7.88 mmol) of pyridine and 1.10 ml (7.88 mmol) of triethylamine are added dropwise at room temperature. The batch is stirred overnight at room temperature. The batch is subsequently filtered through silica gel and washed with dichloromethane. The filtrate is concentrated and the residue is filtered through silica gel (dichloromethane). 0.525 g (62%) of tert-butyl-[4-({1-[tert-butyl-(dimethyl)silyl]-3-isopropyl-1H-indol-5-yl}oxy)-3,5-dimethylphenoxy]acetate is obtained.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:13])(=O)=O.CN(C=O)C.[N-:34]=[N+:35]=[N-:36].[Na+]>C(OCC)(=O)C>[N:34]([CH2:6][CH2:7][O:8][CH:9]([C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[CH3:28])[CH2:10][CH2:11][N:12]([CH3:13])[C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N+:35]=[N-:36]
Reactant: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCOS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1C(CCN(C)C(=O)OC(C)(C)C)OCCN=[N+]=[N-]
Temperature: 80 °C

Procedure:
2-(3-(tert-Butoxycarbonyl(methyl)amino)-1-(5-chloro-2-methylphenyl)propoxy)ethyl methanesulfonate (414 mg, 0.95 mmol) was dissolved into anhydrous DMF (15 mL), solid NaN3 (186 mg, 2.86 mmol) was added and the reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, the organic phase was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to the crude product (270 mg, 74%), which was used for next step without purification.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC([O:17][CH2:18][CH:19]1[O:24][CH:23](Br)[CH:22]([O:26]C(C)=O)[CH:21]([O:30]C(C)=O)[CH:20]1[O:34]C(C)=O)=O>CC(C)=O.[OH-].[K+]>[C@@H:23]1([O:13][C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][CH:11]=2)[O:24][C@H:19]([CH2:18][OH:17])[C@H:20]([OH:34])[C@H:21]([OH:30])[C@H:22]1[OH:26]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC[C@H]1O[C@@H](Oc2ccc(-c3ccccc3)cc2)[C@H](O)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of p-phenylphenol (250 mg, 1.46 mmol) in acetone, 1 mL of 10N KOH was added followed by acetobromogalactose (1.8 g, 4.37 mmol). The reaction mixture was stirred overnight at room temperature. TLC analysis showed no starting material left. 10N KOH (1 mL) was added to complete deacetylation and the solution was again stirred overnight. After evaporation of acetone, the crude material was taken up in ethyl acetate and washed with 5×150 mL of water. Ethyl acetate was dried with MgSO4 and concentrated under reduced pressure to obtain a white solid which was further purified by column chromatography using 30% methanol/ethyl acetate; 1H NMR (CD3OD) δ3.56-3.91 (m, 6H), 4.89 (m, 1H), 7.15-7.57 (m,9H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](=O)(OCC)[O:20]CC.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH:15]([CH2:16][OH:17])[O:18][C:19]3=[O:20])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCC(O)CNc1ccc(C2CCCCC2)cc1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1OC(CO)CN1c1ccc(C2CCCCC2)cc1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
2.4 g (9.62 mmol) of (RS)-3-(4-cyclohexyl-phenylamino)-propane-1,2-diol were dissolved in 50 ml of toluene, treated with 1.25 g (10.6 mmol) of diethyl carbonate and 0.4 ml of a 1 molar sodium methylate solution in methanol and stirred overnight at an oil bath temperature of 110°. The solvent was distilled off in a water-jet vacuum and the residue was treated with water and 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and the solvent was distilled off. 1.4 g of product in the form of yellowish crystals were obtained from ethyl acetate/hexane. A further 0.9 g of pure product was obtained from the mother liquor. M.p.: 167°-167.5°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(O)C>ClCCl>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)c2ccc(O)cc2)cc1

Procedure:
4-Hydroxybenzoic acid (1.38 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (2.06 g) was obtained after silica gel column chromatography (0, 1, 2, 3% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.40.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14](=[O:20])[O:15][CH:16]([CH3:19])[CH2:17]Cl>O.CO>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:17][CH:16]([CH3:19])[O:15][C:14]1=[O:20]
Reactant: CC(CCl)OC(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1CN(c2ccc([N+](=O)[O-])cc2Cl)C(=O)O1

Procedure:
A solution of 5 g of potassium hydroxide in 10 ml of water was added to a stirred solution of 21.5 g of 2A in 300 ml of methanol. The mixture was heated for 0.5 hour by a steam bath and concentrated to dryness under reduced pressure. The residue was diluted with water; the mixture was acidified with hydrochloric acid and extracted with ether. The extract was dried and the solvent was evaporated under reduced pressure. Trituration of the residue with hexane gave 3-(2-chloro-4-nitrophenyl)-5-methyl-2-oxazolidinone (2B), as a solid, mp: 73°-75° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:24]#[N:25])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1.[S-2:26].[Na+].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[S:34][CH:35]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C(#N)C.O>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:33]2[S:34][CH:35]=[C:31]([CH2:30][S:26][C:2]3[C:3]([C:24]#[N:25])=[C:4]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][OH:23])=[CH:18][CH:19]=4)[C:5]4[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=4[N:13]=3)[N:32]=2)=[CH:37][CH:38]=1
Reactant: [S-2]
Reactant: N#Cc1c(Cl)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccc(OCCO)cc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.229 mmol) of the compound from Example 11A were dissolved in 0.46 ml of DMF, 21 mg (0.274 mmol) of sodium sulfide were added and the mixture was stirred at RT overnight. 33 mg (0.137 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 23 mg (0.275 mmol) of sodium bicarbonate were then added, and the reaction solution was stirred at RT for 2 h. Water was added to the reaction mixture for further purification via a preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA) purified.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:12]([CH:14]1[O:16][CH2:15]1)Br>CN(C)C=O>[C:1]1([CH2:7][CH2:8][O:9][CH2:12][CH:14]2[CH2:15][O:16]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCOCC2CO2)cc1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 4.28 g of 2-phenylethanol, 1.68 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.1 ml of epibromohydrin and 100 ml of anhydrous dimethylformamide were used. The resulting crude product was purified by silica gel column chromatography, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.68 g of the title compound as a colorless oil having an Rf value of 0.77 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:25]=[C:18]2[C:19]([O:21]C(=O)[NH:23][C:17]2=[CH:16][CH:15]=1)=O>C(O)C.O>[NH2:23][C:17]1[CH:16]=[CH:15][C:14]([Br:13])=[CH:25][C:18]=1[C:19]([N:3]([O:4][CH3:5])[CH3:2])=[O:21]
Reactant: CNOC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CON(C)C(=O)c1cc(Br)ccc1N
Yield: 67.8 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (9.42 g, 96 mmol) and triethyl amine (13.5 mL, 96 mmol) in ethanol and water (100 mL/10 mL) was added a solution of 5-bromoisatoic anhydride (20 g, 74 mmol) in ethanol and water (100 mL/10 mL) at ambient temperature under nitrogen. The reaction mixture was heated at reflux for 3 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate (100 mL), washed with 1N aqueous sodium hydroxide solution (2×20 mL), brine (30 mL), and dried with MgSO4. After removal of the solvent, the residue was purified by a silica gel flash chromatography (hexane:ethyl acetate/3:2) to give 2-amino-5-bromo-N-methoxy-N-methylbenzamide as an off-white solid (13 g, 68%): mp 80-81° C.; 1H-NMR (CDCl3) δ 7.49 (d, 1H, J=2.1 Hz), 7.26 (dd, 1H, J=8.3, 2.0 Hz), 6.59 (d, 1H, J=8.4 Hz), 4.69 (br, 2H), 3.58 (s, 3H), 3.34 (s, 3H); Anal. Calc. For C9H11BrN2O2: C, 41.72; H, 4.28; N, 10.81. Found: C, 41.99; H, 4.16; N, 10.82.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([O:19][CH3:20])=[N:10][N:11]([CH2:15][C:16](O)=[O:17])[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH3:29]>ClCCl.O1CCOCC1>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([O:19][CH3:20])=[N:10][N:11]([CH2:15][C:16]([NH2:29])=[O:17])[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: N
Reactant: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
The acid of step (b) above (180 mg, 0.6 mmol) was suspended in dichloromethane (5 ml), and oxalyl chloride (150 μl, 1.72 mmol) was added, resulting in gas evolution. The reaction mixture was stirred at room temperature for 1 hour, under nitrogen. The solvent was then evaporated under reduced pressure and the residue was azeotroped with toluene 3 times. The crude intermediate acid chloride was carried straight through to the next step. It was dissolved in tetrahydrofuran (2 ml), and ammonia 0.5M in dioxane (10 ml) was added. After stirring overnight at room temperature, analysis by TLC showed little product had formed. A further portion of fresh 0.5M ammonia in dioxane (10 ml) was added to the reaction mixture and stirring was continued for another overnight period. The reaction mixture was evaporated and the residue was partitioned between dichloromethane (20 ml) and aqueous sodium bicarbonate (10 ml). The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane (10 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate to provide the title compound (20 mg, 17%).