Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C1C[O:32][CH2:31][CH2:30]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>O>[C:31]([N:21]1[CH2:22][C:19]([CH2:23][C:24]#[N:25])([N:17]2[CH:18]=[C:14]([C:12]3[N:11]4[CH:26]=[CH:27][N:28]=[C:10]4[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=4)[N:13]=3)[CH:15]=[N:16]2)[CH2:20]1)(=[O:32])[CH3:30]
Reactant: C1CCOC1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CC(CC#N)(n2cc(-c3nc(-c4cnn(C)c4)cc4nccn34)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 20 mg, 0.046 mmol) in THF (460 μL, 0.046 mmol) was added triethylamine (19 μL, 0.14 mmol) and acetic anhydride (5.7 mg, 0.056 mmol). After stirring at ambient temperature for 30 minutes, the reaction mixture was diluted in water. The reaction mixture was directly purified by reverse phase HPLC using a 0-100% acetonitrile/water gradient to afford 2-(1-acetyl-3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (15 mg, 0.038 mmol, 82% yield) as a fluffy white solid. MS (apci) m/z=402.2 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])/[CH:23]=[N:16]/[S:15]([C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:18])=[O:17]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)C(=O)Nc1cccc(O)c1S(N)(=O)=O
Solvent: CN(C)C=O
Product: CN(C)/C=N/S(=O)(=O)c1c(O)cccc1NC(=O)C(C)(C)C

Procedure:
A solution of N-(3-hydroxy-2-sulfamoyl-phenyl)-2,2-dimethyl-propionamide (15.2 g, 55.9 mmol) and N,N-dimethylformamide dimethylacetal (9.7 ml, 72.6 mmol) in DMF (65 ml) is stirred at 60° C. for 1 h. Volatiles are evaporated at reduced pressure. Chromatography of the residue (21.8 g) dissolved in dichloromethane (silica gel, hexanes/EtOAc=1:1) gives N-(2-{[1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}-3-hydroxy-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:4].O.Cl>C(O)C>[OH:5][CH:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:17]([S:18]([NH:21][C:22]3[C:27]([O:28][CH3:29])=[N:26][C:25]([CH3:30])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C(C)=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.8 %

Procedure:
Sodium tetrahydridoborate (0.051 g) was added portionwise over 5 minutes to a solution of 2-(4-acetylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.135 g) in ethanol (5 ml). The mixture was stirred for 45 minutes at ambient temperature and was then poured into water (20 ml) and acidified to pH 3 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (3×20 ml). The extracts were combined, washed with water and saturated sodium chloride solution and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with 10-70% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(1-hydroxyethyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.096 g) as a foam; 1H NMR (CDCl3+CD3COOD): 1.55 (d, 3H), 2.3 (s, 3H), 3.85 (s, 3H), 4.95 (q, 1H), 7.25 (s, 1H), 7.3 (d, 2H), 7.35 (d, 2H), 7.55 (dd, 1H), 8.7 (d, 1H), 8.85 (d, 1H); mass spectrum (+ve ESP): 401 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C@@H:13]([C:14]([NH:16][C@H:17]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH3:18])=[O:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1.O[Li].O>>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[C@@H:13]([C:14]([NH:16][C@H:17]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH3:18])=[O:15])[CH2:12][CH:11]3[CH:9]2[CH2:10]3)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]O
Solvent: O
Product: C[C@H](NC(=O)[C@H]1CC2CC2N1Cc1ccc(C(F)(F)F)cc1)c1ccc(C(=O)O)cc1
Yield: 90.7 %

Procedure:
The title compound (E32) (12.3 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-((1S)-1-((3R)-2-(4-(trifluoromethyl)benzyl)-2-azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (D149) (14 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:37])([CH3:36])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1>O1CCCC1>[CH3:40][N:4]([CH3:3])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:26]1[CH:35]=[CH:34][C:33]2[C:32]([CH3:36])([CH3:37])[CH2:31][CH2:30][C:29]([CH3:39])([CH3:38])[C:28]=2[CH:27]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCN(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 90.3 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 1.12 g (28 mmol) of sodium hydroxide with 960 mg (1.87 mmol) of ethyl 4′-(3-dimethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 7a) in 30 ml of tetrahydrofuran. 820 mg of 4′-(3-dimethylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=199° C., yield=90%).
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO.O>[CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCN(CCOC(c2ccccc2)c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
To a solution of 4.12 g (11.2 mmol) of the piperazine derivative in methanol (20 ml) and water (10 ml) was added 13.2 g (235 mmol) of of potassium hydroxide, and the mixture was refluxed for 19 hours. Water was added to the reaction mixture and the whole mixture was extracted with n-butanol. The organic layer was washed with water and concentrated by evaporation under reduced pressure. The residue was subjected to Sephadex column chromatography, eluted with methanol, to give 3.15 g (10.6 mmol) of N-(2-benzhydroxyethyl)piperazine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@:11]2([CH2:19][OH:20])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25](O)=[CH:24][C:23]=2[O:22]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([N:8]1[CH2:12][C@:11]2([CH2:19][O:20][C:26]3[CH:25]=[CH:24][C:23]4[O:22][CH2:21][O:29][C:28]=4[CH:27]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@]12CN(Cc3ccccc3)C[C@H]1c1ccccc12
Reactant: Oc1ccc2c(c1)OCO2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CN2C[C@H]3c4ccccc4[C@@]3(COc3ccc4c(c3)OCO4)C2)cc1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
In a three-necked flask, 3.5 g of the compound obtained in Step D, 2 g of 3,4-methylenedioxyphenol and 3.8 g of triphenylphosphine are mixed in 40 ml of tetrahydrofuran. The mixture is cooled to 0° C. and 2.4 ml of diethyl azodicarboxylate are added dropwise over a period of 20 minutes. After reacting for 4 days at ambient temperature, the reaction mixture is concentrated under reduced pressure. Chromatography on silica gel (CH2Cl2 /AcOEt: 95/5) allows 4.4 g of expected product to be isolated.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].P([O-])(O)(O)=O.[Na+].[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24]>O1CCCC1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:24][CH2:23][C:22]([O:26][CH3:27])=[O:25])(=[O:13])=[O:12])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
To a stirred solution of 23° C. of 4-acetamidobenzenesulfinic acid (57.8 g., 290 mmol), sodium hydroxide (11.6 g, 290 mmol), and sodium dihydrogen phosphate (40.0 g, 290 mmol) was added a solution of methyl acrylate (31.2 g, 362 mmol) in 50 mL of tetrahydrofuran. The reaction vessel was stirred at 23° C. for 18 hours, and the resulting white precipitate was filtered and washed with water. The product was air dried, then recrystallized from 2-butanone to produce 59.4 g (71%) of a white powder, mp 156°-158° C.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4]O.C[CH:10](OC1C=CC=CC=1)[C:11]([NH:13][C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@H]12)=O>>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH2:10][CH2:11][NH2:13]
Reactant: CC(Oc1ccccc1)C(=O)N[C@@H]1C(=O)N2[C@@H]1SC(C)(C)[C@@H]2C(=O)O
Reactant: N[C@@H](CCO)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Plasmid pAJ 201 was introduced into Brevibacterium lactofermentum AJ 12019 (NRRL B-15346) (auxotrophy for homoserine) by the transformation method described in (4). The results obtained by examination of lysine productivity with the thus-obtained transformant AJ 12073 (FERM-P 7205) are shown in Table 3. The cultivation was carried out by charging in a shoulder-equipped flask 20 ml of medium containing 10 g/dl of glucose, 5.5 g/dl of ammonium sulfate, 0.1 g/dl of KH2PO4, 0.1 g/dl of MgSO4 . 0.001 g/dl of FeSO4 . 4H2O, 0,001 g/dl of MnSo4 . 4H2 0, 200 μg/l of thiamine hydrochloride, 2.5 mg/dl of nicotinamide, 105 mg/dl of soybean protein hydrolysate (as total nitrogen), and 5 g/dl of calcium carbonate, the pH of which had been adjusted to 8.0, while shaking at 31.5° C. for 72 hours. After completion of the cultivation, lysine in the culture liquid was quantitatively determined with high speed liquid chromatography.
Reaction SMILES: C([O:8][C:9]1[C:13]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]CC2C=CC=CC=2)O)=[C:12]([CH:30]([CH3:32])[CH3:31])[N:11]([CH2:33][CH2:34][OH:35])[N:10]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:14][C:13]1[C:9](=[O:8])[NH:10][N:11]([CH2:33][CH2:34][OH:35])[C:12]=1[CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)c1c(C(O)c2ccccc2OCc2ccccc2)c(OCc2ccccc2)nn1CCO
Agent: [Pd]
Solvent: CO
Product: CC(C)c1c(Cc2ccccc2O)c(=O)[nH]n1CCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a solution of 2-benzyloxybromobenzene (1.66 g) in tetrahydrofuran (50 mL) was added tert-butyllithium (1.6 mol/L pentane solution, 4.33 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 5 minutes. To the reaction mixture was added a solution of 1-(2-benzoyloxyethyl)-3-benzyloxy-4-formyl-5-isopropyl-1H-pyrazole (620 mg) in tetrahydrofuran (5 mL), and the mixture was stirred at 0° C. for 30 minutes. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/1–2/1) to give 2-{3-benzyloxy-4-[(2-benzyloxyphenyl)hydroxymethyl]-5-isopropylpyrazol-1-yl}ethanol (448 mg). To a solution of 2-{3-benzyloxy-4-[(2-benzyloxyphenyl)hydroxymethyl]-5-isopropylpyrazol-1-yl}ethanol (448 mg) in methanol (5 mL) was added 10% palladium-carbon powder (448 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (220 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:31]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:31][CH2:10][CH:9]=[CH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cccc(C=CCO)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(C=CCCl)c1
Yield: 57.8 %

Procedure:
Compound 103-1 (2.00 g) was dissolved in methylene chloride (45 ml), triphenylphosphine (3.89 g) and N-chlorosuccinimide (1.98 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=100:0-95:5) to give the object product (1.30 g) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C)=[O:8])[CH2:3][CH2:2]1.[Li+].[OH-]>C(O)C>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)C1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCOCC1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (270 g, 1.87 mol) was diluted in ethanol (2 L). A 1M aqueous LiOH solution (1870 ml, 1.87 mol) was added (slight exotherm) at RT and the reaction was stirred for 3 hrs. The reaction mixture was concentrated to ca. 1 L and acidified to pH 2 with 5M HCl solution. The aqueous solution was extracted with ethyl acetate (3×600 ml) and the organic layer was dried (MgSO4) and evaporated to dryness to give a white solid (230.3 g, 94%).
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:33])(=O)C.[NH:34]1[CH2:38][CH2:37][CH2:36][C:35]1=[O:39]>>[O:39]=[C:35]1[CH2:36][CH2:37][CH2:38][N:34]1[C:13]1[CH:12]=[CH:11][C:10]([C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:22][CH2:23]2)=[O:17])=[C:9]([N:6]2[CH2:7][CH2:8][NH:4][C:5]2=[O:33])[CH:14]=1
Reactant: O=C1CCCN1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)C1=O
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCNC3=O)CC2)nc1C
Yield: 48.8 %

Procedure:
Using 1-acetyl-3-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (188 mg) described in Preparation Example 258 and pyrrolidin-2-one (51 mg) and by the reaction and treatment in the same manner as in Example 649, the title compound (93 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:37]1C=CC(O)=C(C)C=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:28]([O:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)=[O:29])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:24])[O:23]2)=[CH:15][C:14]=1[CH3:37])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)OC1CCCC1
Reactant: Cc1cc(Br)ccc1O
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1

Procedure:
Synthesised by analogous methods to Intermediate 2b, using 4-bromo-2-methyl-phenol at Stage 6 of Scheme 2. m/z 504 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=[C:7]([C:18]2[S:22][N:21]=[N:20][C:19]=2[CH:23]([CH3:25])[CH3:24])[CH:6]=1)C.[Li+].[OH-]>C1COCC1>[CH:23]([C:19]1[N:20]=[N:21][S:22][C:18]=1[C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:8]=1)[C:4]([OH:26])=[O:3])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cc(-c2ccc(C)cn2)cc(-c2snnc2C(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(C(=O)O)cc(-c3snnc3C(C)C)c2)nc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
A mixture of 3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid ethyl ester (250 mg, 0.68 mmol) in 10 mL THF was cooled to 0° C., and LiOH (0.5 mL of 2N aqueous solution) was added. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was acidified with 3N aqueous HCl to a pH of 6. The mixture was extracted with ethyl actetate, and the combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give 200 mg of 3-(4-isopropyl-[1,2,3]thiadiazol-5-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid, MS (M+H)=340.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.CN(C=O)C.[CH3:26][C:27]1([CH3:42])[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].[Na+].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>[CH3:26][C:27]1([CH3:42])[C:28]([C:11]2[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=2[C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reactant: CC1(C)CCCC=C1B1OC(C)(C)C(C)(C)O1
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: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CCCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 48.6 %

Procedure:
To a stirred solution of 66.15D (0.750 g, 1.9 mmol) in DMF (4.00 mL, 52 mmol) at 23° C. was added 66.21B (0.92 g, 3.9 mmol), potassium carbonate (0.81 g, 5.8 mmol), and then tetrakis(triphenylphosphine)palladium (0.22 g, 0.19 mmol). The mixture was heated to 90° C. and stirred for 24 hours. The reaction was then cooled to room temperature, diluted with brine, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.21C as a colorless oil (0.34 g, 48% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][C@H:4]1[O:9][C@@H:8]([CH3:10])[CH2:7][N:6]([CH2:11][C:12]2[O:16][C:15]([C:17]3[CH:25]=[C:24]([C:26]4[CH:27]=[C:28]([NH:34][S:35]([C:38]5[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=5[F:45])(=[O:37])=[O:36])[C:29]([O:32][CH3:33])=[N:30][CH:31]=4)[CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4S(C3C=CC=CC=3)(=O)=O)=[N:14][N:13]=2)[CH2:5]1>O1CCOCC1>[CH3:10][C@H:8]1[O:9][C@@H:4]([CH3:3])[CH2:5][N:6]([CH2:11][C:12]2[O:16][C:15]([C:17]3[CH:25]=[C:24]([C:26]4[CH:27]=[C:28]([NH:34][S:35]([C:38]5[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:39]=5[F:45])(=[O:36])=[O:37])[C:29]([O:32][CH3:33])=[N:30][CH:31]=4)[CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[N:14][N:13]=2)[CH2:7]1
Reactant: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.7 %

Procedure:
Sodium hydroxide (2 ml, 4.00 mmol) was added to a solution of N-[5-[4-(5-{[(2R,6S)-2,6-dimethyl-4-morpholinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (194 mg, 0.212 mmol) in 1,4-dioxane (2 ml). The mixture was stirred at room temperature for 2 h. The solvent was evaporated under a stream of nitrogen and the residue partitioned between ethyl acetate (10 ml) and saturated ammonium chloride (5 ml). The organic layer was separated by hydrophobic frit, washed with water and the solvent removed in vacuo. The residual solid was purified by Mass Directed Automated Preparative HPLC (Method B) and the solvent was evaporated under a stream of nitrogen to give the title compound as a cream coloured solid (10 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:16])=[CH:13][N:12]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(N)cc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COc1ccc(NC(=O)c2ccc(Cl)nc2)cc1

Procedure:
6-Chloro-N-(4-methoxy-phenyl)-nicotinamide was prepared from 4-methoxyaniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C13H11N2OCl [M+H]+: 263.0582. Found: 263.0582.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8]1([O:13][CH2:12][CH2:11][O:10]1)[CH3:9])[C:5]([OH:7])=O.[NH2:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[CH3:1][O:2][N:3]=[C:4]([C:8]1([O:13][CH2:12][CH2:11][O:10]1)[CH3:9])[C:5]([NH:14][CH:15]1[C:32](=[O:33])[N:17]2[C:18]([C:29]([OH:31])=[O:30])=[C:19]([CH2:22][S:23][C:24]3[S:25][CH:26]=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12)=[O:7]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12
Reactant: CON=C(C(=O)O)C1(C)OCCO1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)C1(C)OCCO1
Yield: 81.2 %

Procedure:
2-Methoxyimino-3,3-ethylenedioxybutyric acid (syn isomer, 15.1 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (29.1 g.) were treated in a similar manner to that of Example 10-(2) to give 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 32.5 g.). Mp. 145° to 152° C. (dec.).
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH:14]1[CH2:15][O:16]1
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: ClCC1CO1
Product: c1cc2c(cc1OCC1CO1)CCCC2

Procedure:
The title compound was prepared from 5,6,7,8-tetrahydro-naphthalen-2-ol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.