Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21](O)=[O:22])[N:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:21]([NH:33][CH2:32][C:30]3[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=3)=[O:22])[N:11]=[N:12][C:13]=2[O:14][C@@H:15]([CH3:20])[C:16]([F:17])([F:19])[F:18])=[CH:4][CH:3]=1
Reactant: COc1cc(CN)on1
Reactant: C[C@H](Oc1nnc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Product: COc1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(O[C@@H](C)C(F)(F)F)nn2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridazine-3-carboxylic acid (example AG) and 3-methoxy-5-isoxazole-methanamine hydrochloride as starting materials, 457.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:9][OH:10])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[N:17]2)([CH2:11][C:12]([F:14])([F:15])[F:13])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(CO)(CC(F)(F)F)c1ccc(Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc2c1cnn2C(C=O)(CC(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the product of Step B (200 mg, 0.42 mmol) in DCM (5 mL) was added Dess-Martin periodinane (350 mg, 0.84 mmol) in portion at room temperature. The mixture was stirred at for 0.5 h, and then diluted with water (5 mL), extracted with ethyl acetate. The organic layers were washed with brine (5 mL), dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/PE=1:8) to afford the title compound. LC/MS m/z=468.2[M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:18](=[C:19]([CH:27]([CH:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[CH2:7][CH3:8].C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:18](=[C:19]([CH:27]([CH:29]([O:35][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH3:28])[CH:20]=[CH:21][CH:22]=2)[N:17]=1)[CH2:7][CH3:8]
Reactant: CCCCCC(O)C(C)c1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(OS(C)(=O)=O)C(C)c1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reaction time: 0.5 h

Procedure:
0.17 ml (2.17 mmoles) of methanesulfonyl chloride is added at 0° C. to 740 mg (1.81 mmoles) of the compound from Example 17 and 0.3 ml (2.17 mmoles) of triethylamine in 18 ml of absolute CH2Cl2. The mixture is allowed to come to room temperature and is stirred 30 minutes longer. The mixture is first extracted twice with 30 ml portions of 1 N NaOH and twice with 30-ml portions of 1 N HCl, the organic phase is dried over MgSO4, and the solvent is evaporated under vacuum in a rotary evaporator. The solid residue is stirred with a mixture of 30 ml ethyl acetate and 30 ml petroleum ether, and the product is filtered off. Yield: 650 mg (73.8%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([CH2:12][C:13]([OH:15])=O)[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][NH2:11])[NH:5]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O.O>C(OCC)(=O)C>[NH2:11][CH2:10][CH:6]1[CH2:7][CH2:8][CH2:9][C:4]2([CH2:3][NH:2][C:13](=[O:15])[CH2:12]2)[NH:5]1
Reactant: NCC1CCCC(CN)(CC(=O)O)N1
Agent: CCCP(=O)=O
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NCC1CCCC2(CNC(=O)C2)N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A suspension of 5.590 mmol of (2,6-bis-aminomethylpiperidin-2-yl)acetic acid hydrochloride and 22.340 mmol of N-ethyldiisopropylamine in 20 ml of ethyl acetate is admixed dropwise at 0° C. with a solution of 11.170 mmol of propylphosphonic anhydride (T3P®) (50% w/w in ethyl acetate). The reaction mixture is subsequently stirred at room temperature for 20 h. It is admixed with water (20 ml) the organic phase is separated off and the aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are dried over sodium sulphate and evaporated. From the residue the title compound is obtained by means of flash chromatography (SiO2 60 F) and identified on the basis of the Rf value.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13]O)[N:10]=[CH:9]1.[NH:26]1[CH:31]=[CH:30][CH:29]=[N:28][C:27]1=[S:32].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:15]2[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH2:13][S:32][C:27]2[N:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[N:10]=[CH:9]1
Reactant: S=c1nccc[nH]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CO)c3)c(F)c2)C(=O)O1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CC#N
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(CSc4ncccn4)c3)c(F)c2)C(=O)O1
Yield: 92.3 %

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-hydroxymethylimidazol-1-yl)phenyl)-2-oxooxazolidin-5-yl-methyl]acetamide (174 mg, 0.5 mM) and pyrimidine-2-thione (112 mg, 1 mM) were suspended in dry acetonitrile (20 ml), and N,N-dimethylformamide dineopentyl acetal (462 mg, 2 mM) added. The mixture was heated to reflux for 6 hours giving a solution. Solvent was evaporated, the residue dissolved in dichloromethane, and subjected to mplc on silica, eluting with a gradient increasing in polarity from 0 to 20% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (204 mg) as a gum.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:22])([F:21])[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]#[N:20])[CH:14]=1)[CH3:12]>C(O)C>[F:22][C:10]([F:9])([F:21])[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([NH2:20])=[O:2])[CH:14]=1)[CH3:12]
Reactant: O=C([O-])O
Reactant: CC(c1ccnc(C#N)c1)C(F)(F)F
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: CC(c1ccnc(C(N)=O)c1)C(F)(F)F
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To 7 ml of ethanol were added 0.44 g of sodium bicarbonate and 0.37 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.7 g of 4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 4 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.78 g of 4-(2,2,2-trifluoro-1-methyl-ethyl)pyridine-2-carboxamide=oxime.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:18][CH:17]([C:19](=[O:21])[CH3:20])[CH2:16]1)=O)(C)(C)C>ClCCl>[OH:5][C:3]([C:2]([F:7])([F:6])[F:1])=[O:4].[NH:15]1[CH2:18][CH:17]([C:19](=[O:21])[CH3:20])[CH2:16]1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1CNC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (8 mL) was added to a suspension of 3-acetyl-azetidine-1-carboxylic acid tert-butyl ester (800 mg, 4.0 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 4 hours and concentrated to dryness to afford the title product as a colorless gum (800 mg, 100%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=1[S:11][CH2:12][CH:13]([CH3:15])[CH3:14].OO.C(O)(=[O:20])C>CCCCCC>[OH:10][C:4]1[CH2:5][C:6]([CH3:8])([CH3:9])[CH2:7][C:2](=[O:1])[C:3]=1[S:11]([CH2:12][CH:13]([CH3:15])[CH3:14])=[O:20]
Reactant: CC(C)CSC1=C(O)CC(C)(C)CC1=O
Reactant: CC(=O)O
Agent: OO
Solvent: CCCCCC
Product: CC(C)CS(=O)C1=C(O)CC(C)(C)CC1=O
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A mixture of 3-hydroxy-2-isobutylthio-5,5-dimethyl-2-cyclohexen-1-one (10 g., 0.044 mole), 30 percent hydrogen peroxide (5.0 g., 0.044 mole), and 100 ml. of glacial acetic acid was allowed to stand at room temperature for 19 hours. The solution was poured into ice-water and the solid filtered to give 4.7 g. of crude product. After two from hexane the pure product was obtained as pink crystals 3.3 g., m.p. b 48.5°-50°C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:25][C:26](OC(C)=O)=[O:27]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:26](=[O:27])[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (46.6 mg, 0.20 mmol), Et3N (26.0 mg, 0.26 mmol) and DMAP (2.5 mg, 0.02 mmol) in CH2Cl2 (4 mL) was added dropwise Ac2O (24.5 mg, 0.24 mmol), and the reaction mixture was then heated to reflux under argon for 1 hr. Cooled to r.t., the reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as an oil (54.0 mg, 98.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:5]([CH2:13][OH:14])=[CH:4][N:3]=1>N1C=CC=CC=1.[O-2].[O-2].[O-2].[Cr+6]>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10](=[O:12])[CH3:11])[C:5]([CH:13]=[O:14])=[CH:4][N:3]=1
Reactant: CC(=O)OCc1cc(C)ncc1CO
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Product: CC(=O)OCc1cc(C)ncc1C=O

Procedure:
This product is prepared by oxidation of 2-methyl-4-acetoxymethyl-5-hydroxymethylpyridine (from Step A) with chromium trioxide in pyridine by the procedure substantially as described in Example 11, Step A.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[N:7][OH:8])[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[N+](=[CH2:28])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.O.C(COC)OC>[OH:1][CH:2]1[CH2:6][C:5](=[N:7][OH:8])[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:28])=[O:16])=[C:3]1[CH:18]=[CH:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=NO
Reactant: C=[N+]=[N-]
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: COCCOC
Product: COC(=O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=NO

Procedure:
A cold solution of 1 part of 3-hydroxy-5-hydroxyimino-2-styrylcyclopent-1-eneheptanoic acid in 42.3 parts of dimethoxyethane is treated with a cold ethereal solution of diazomethane, prepared from 1.2 parts of N-nitrosomethylurea, 1.4 parts of potassium hydroxide and 2.5 parts of water. That mixture is allowed to react for 2 minutes, after which time, the cold excess diazomethane is decomposed by the careful addition of glacial acetic acid. The ethereal solution is washed with dilute aqueous sodium bicarbonate, then with water and dried over anhydrous sodium sulfate. The ether is removed and the crystalline residue is recrystallized from ethyl acetate-hexane to yield colorless crystals of methyl 3-hydroxy-5-hydroxyimino-2-styrylcyclopent-1-eneheptanoate. That compound melts at about 109°-110° and displays, in chloroform, absorption peaks in the infrared spectrum at about 3590 and 1735 reciprocal centimeters. It is further characterized by the following structural formula ##SPC19##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>ClCCl.CN(C)C1C=CN=CC=1>[CH:27]([NH:30][C:31](=[O:32])[O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])([CH3:29])[CH3:28]
Reactant: CC(C)N=C=O
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
To a solution of Example 179A (50 mg, 0.2 mmol) in dichloromethane (1 mL) was added triethylamine (0.13 mL, 1 mmol), 4-dimethylaminopyridine (9 mg, 0.08 mmol), and isopropyl isocyanate (0.1 mL, 1 mmol). The solution was stirred at room temperature for 18 h. After which, additional 5.0 equivalents (0.1 mL) of isopropyl isocyanate were added, and the solution was stirred for another 18 h. The solution was diluted with dichloromethane (2 mL), washed with water (2× 1 mL), dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (0-5% ethyl acetate/hexane) afforded product (39 mg, 59%). 1H NMR (300 MHz, CDCl3) δ ppm 0.70 (m, 7H), 0.91 (m, 8H), 1.37 (m, 1H), 1.60 (m, 1H), 1.93 (m, 1H), 3.49 (d, J=3.68 Hz, 2H), 3.58 (s, 3H), 4.21 (d, J=10.30 Hz, 1H), 4.45 (d, J=10.30 Hz, 1H), 5.00 (t, J=3.68 Hz, 1H), 7.17 (m, 3H), 7.30 (m, 1H).
Reaction SMILES: [ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][C@H:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1.C[O-].[Na+].CO.[F:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:38])[N:32]2[CH2:35][CH:36]=O)=[N:27][CH:26]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(OCC)(=O)C.C(O)(=O)C>[ClH:1].[O:2]1[C:11]2[CH:10]=[C:9]([CH2:12][NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([CH2:36][CH2:35][N:32]4[C:33]5[C:28](=[N:27][CH:26]=[C:25]([F:24])[CH:34]=5)[CH:29]=[CH:30][C:31]4=[O:38])[CH2:15]3)[N:8]=[CH:7][C:6]=2[O:5][CH2:4][CH2:3]1
Reactant: c1nc(CN[C@H]2CCNC2)cc2c1OCCO2
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(F)cc2n1CCN1CC[C@H](NCc2cc3c(cn2)OCCO3)C1
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
To a solution of 62 mg of (3S)—N-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)pyrrolidin-3-amine hydrochloride in 3 mL of methanol, 0.10 g of a 28% sodium methoxide/methanol solution, 37 mg of (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, 60 μL of acetic acid, 0.12 g of molecular sieves 3A and 11 mg of sodium cyanoborohydride were added at room temperature, and the mixture was stirred at the same temperature for 1 hour 10 minutes. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=30:1, thereto were added ethyl acetate and a 4 mol/L hydrogen chloride/ethyl acetate solution, and the solid was filtered off to obtain 33 mg of 1-(2-((3S)-3-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pyrrolidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[CH3:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Cc1ccc(S)cc1C
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1C

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethylthiophenol.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([OH:14])=O)=[O:9])=[CH:4][CH:3]=1.[NH2:17][CH:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]3[S:31][C:30]([CH3:32])=[N:29][N:28]=3)[CH2:23][S:24][C@H:19]12>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH:17][CH:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][S:26][C:27]4[S:31][C:30]([CH3:32])=[N:29][N:28]=4)[CH2:23][S:24][C@H:19]23)=[O:14])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Reactant: CCC(CC(=O)O)S(=O)c1ccc(O)cc1
Product: CCC(CC(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)S(=O)c1ccc(O)cc1

Procedure:
484 mg. of 3-(p-hydroxyphenylsulfinyl)pentanoic acid and 7-amino-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were reacted in the same manner as described in Example 28 and 555 mg. of 7-[3-(p-hydroxyphenylsulfinyl)pentanamido]-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:38][CH2:39][CH2:40][NH:41][C:18]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:23]=[CH:24][C:2]=2[Cl:1])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and tert-butyl(2-aminoethyl)carbamate. The residue was dissolved in DCM (10 mL) and treated with 4M HCl in dioxane (5 mL) with stirring at room temperature for 4 hours. The reaction was concentrated in vacuo and eluted through an SCX-2 column using MeOH followed by 7N NH3 in MeOH; followed by reverse phase chromatography eluting with 5-95% MeCN (with 0.1% NH3) in water (with 0.1% NH3); followed by silica gel column chromatography eluting with 1-5% 7N NH3/MeOH in DCM and finally trituration with TBME.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[Cl:23].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1>O>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[S:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)c(Cl)c1
Temperature: 37.5 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
Potassium carbonate (10.4 g) was added to a mixture composed of 50 mL of N,N-dimethylacetamide, 19.2 g of 1,2-dichloro-4-nitrobenzene, and 14.5 g of 4-chlorobenzenethiol. This mixed solution was stirred at 35 to 40° C. for 2.5 hr. This reaction solution was poured into 500 mL of iced water, and the precipitated crystals were collected by filtration to give 27.8 g of 2-chloro-1-(4-chlorophenylthio)-4-nitrobenzene (yield 92.5%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCCN1CCN(c2ccncc2)CC1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(4-pyridyl)piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.6 g compound (I-44) with a yield of 65.3%. ESI-MS [M+H]+: m/z 336.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2([NH:19][C:20]([C:22]3[N:26]4[C@@:27]([CH2:40][C:41]5[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=5)([CH3:39])[C:28](=[O:38])[N:29]([C:30]5[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=5)[C:25]4=[N:24][CH:23]=3)=[O:21])[CH2:18][CH2:17]2)=[O:15])[CH:10]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:9]1)=O)(C)(C)C.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>C(Cl)Cl>[F:59][C:58]([F:61])([F:60])[C:56]([OH:62])=[O:57].[C:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C@@:27]2([CH3:39])[N:26]3[C:22]([C:20]([NH:19][C:16]4([C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[C:49]([OH:51])=[O:50])=[O:15])[CH2:17][CH2:18]4)=[O:21])=[CH:23][N:24]=[C:25]3[N:29]([C:30]3[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=3)[C:28]2=[O:38])=[CH:42][CH:43]=1)#[N:48]
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N4CCNCC4C(=O)O)CC3)n21
Reaction time: 16 h

Procedure:
4-(1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-piperazine-1,3-dicarboxylic acid di-tert-butyl ester (256 mg, 0.32 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added dropwise. After 16 h, the reaction was concentrated in vacuo. The crude orange oil was dissolved in DMSO (1.5 mL), purified via reverse phase HPLC to afford 64 mg of 1-(1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclo-propanecarbonyl)-piperazine-2-carboxylic acid trifluoroacetic acid salt as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([C:12](OCC)=[O:13])=[C:10]([O:19][CH2:20][CH3:21])[CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:18]=[CH:17][C:11]([CH2:12][OH:13])=[C:10]([O:19][CH2:20][CH3:21])[CH:9]=1
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(Cl)ccc1CO
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of lithium aluminum hydride (4.12 g, 0.108 mol) in dry tetrahydrofuran under an atmosphere of nitrogen cooled to 5° C. is added a solution of ethyl 4-chloro-2-ethoxybenzoate (12.4 g, 54.24 mmol) in dry tetrahydrofuran (20 ml) dropwise over 15 min. The suspension is stirred at room temperature overnight then cooled to 0° C. and water (4.12 ml), aq. 15% sodium hydroxide (4.12 ml) and water (12.4 ml) added dropwise. The resulting suspension is filtered through celite and washed with ethyl acetate. Evaporate to give a colourless oil that crystallises on standing, triturate with iso-hexane and filter to give 4-chloro-2-ethoxybenzyl alcohol as a colourless solid.