Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([C:19]#[N:20])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1.O1CCCC1.[OH-].[NH4+:34]>>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH2:34])=[O:13])=[CH:14][C:15]([C:19]#[N:20])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(Cl)nn3-c3ncccc3Cl)nc12
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(N)=O)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-8-methyl-4H-3,1-benzoxazin-4-one (i.e. the cyano-benzoxazinone product of Example 3, Step F) (100 mg, 0.25 mmol) tetrahydrofuran (5 mL) was added dropwise ammonium hydroxide (0.5 mL, 12.8 mmol) at room temperature. The reaction mixture was then stirred for five minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 55 mg of the title compound, a compound of the present invention, as a white solid that decomposes in the melting apparatus above 255° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH3:11])([O-:3])=[O:2].[H-].[Na+].[CH3:24]I>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([O:12][C:13]([N:15]([CH3:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])[CH3:11])([O-:3])=[O:2]
Reactant: CI
Reactant: CC(OC(=O)Nc1ccccc1)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(OC(=O)N(C)c1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
N-[1-(2-Nitrophenyl)-1-ethoxycarbonyl]-N-phenylamine Ia (1.0 g; 3.4 mmol) in dry dimethylformamide (10 ml) was added to a slurry of sodium hydride (80% w/w; 0.19 g; 3.5 mmol) in dry dimethylformamide (20 ml) under an inert atmosphere. The mixture was stirred at room temperature for 15 min and then methyl iodide (2.1 ml; 34.9 mmol) was added over a period of 10 min. The reaction mixture was warmed to 50° C. and at this temperature for a further 30 min. The precipitate of sodium iodide was filtered off and the solvent was removed by evaporation under vacuum to give a viscous oil, which was purified by flash chromatography on silica, eluting with dichloromethane, to afford the required compound as a colourless solid. Recrystallization from toluene gave colourless crystals (0.9 g; 86% yield), mp 62-63° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:15]2[C:10]([C:11]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:12]=3[CH2:13][CH2:14]2)=[N:9]1)=[O:7])(=O)C.[OH-].[Na+]>CO.C(OCC)(=O)C>[OH:4][CH2:5][C:6]([N:8]1[C@@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C@@H:15]2[C:10]([C:11]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:12]=3[CH2:13][CH2:14]2)=[N:9]1)=[O:7]
Reactant: COc1ccc([C@H]2[C@H]3CCc4ccc(OC)cc4C3=NN2C(=O)COC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc([C@H]2[C@H]3CCc4ccc(OC)cc4C3=NN2C(=O)CO)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
To a solution 150 (0.150 g, 0.36 mmol) in methanol (10 mL) was added NaOH (50%, 2 mL) at room temperature. The reaction mixture was stirred at room temperature for 24 h before being diluted with ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2SO4, filtered and concentrated. The residue obtained was purified by column chromatography on silica gel column using ethyl acetate-hexane (2:3) as eluent to furnish (151) (0.105 g, 78%): mp 163-64° C., 1H NMR (400 MHz, CDCl3): δ 1.06-1.17 (m, 1H), 1.72-1.78 (m, 1H), 2.76-2.89 (m, 2H), 3.76 (s, 3H), 3.87 (s, 3H), 4.55-7.70 (m, 2H), 5.66 (d, J=10.0 Hz, 1H), 6.82 (d, J=9.2 Hz, 2H), 6.92-6.95 (dd, J=2.4 and 8.8 Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 7.07 (d, J=8.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H). 13C NMR (400 MHz, CDCl3): δ 24.38, 28.90, 48.57, 55.46, 55.76, 61.40, 69.61, 108.02, 114.34, 119.12, 127.53, 127.84, 128.47, 130.32, 132.61, 157.67, 158.36, 159.42, 168.66. Anal. (C21H22N2O4) C, H, N.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2([NH2:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1.Cl[C:18]1[C:19]2[CH:26]=[CH:25][NH:24][C:20]=2[N:21]=[CH:22][N:23]=1.C(N(CC)CC)C>C(O)CCC>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2([NH2:14])[CH2:9][CH2:10][N:11]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:12][CH2:13]2)=[CH:15][CH:16]=1
Reactant: NC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(Cc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Yield: 49.3 %

Procedure:
A solution of 4-(4-chlorobenzyl)piperidin-4-yl amine hydrochloride (0.060 g, 0.2016 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.031 g, 0.2016 mmol) and triethylamine (0.140 ml, 1.0079 mmol) in n-butanol (2.0 ml) was heated to 100° C. for 24 hours. Concentration and purification by preparative silica TLC gave a white solid (0.034 g, 49%). LC-MS (LCT) m/z 342 [M+H+], Rt 3.25 min.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=[O:10].[Na+]>>[CH3:1][C:2]1[C:7](=[N:9][OH:10])[CH:6]=[CH:5][C:4](=[O:8])[CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1cccc(O)c1
Agent: [Na+]
Product: CC1=CC(=O)C=CC1=NO

Procedure:
3-Methyl-1,4-benzoquinone-4-oxime was prepared by reaction of 3-methylphenol with sodium nitrite under basic conditions by the method of T. Ishikawa et al. described in Tetrahedron 31, 1995, page 8454.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1Br
Reactant: C=CC(=O)OC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=Cc1ccccc1CNC(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
To compound of Step A (161.0 g, 561.8 mmol) in DMF (800 mL) was added methyl acrylate (58.0 g, 674.2 mmol), TEA (170.5 g, 1685.4 mmol) and dichlorobis(triphenylphosphine) palladium(II) (7.9 g, 11.2 mmol). The mixture was heated at 80° C. for about 32 hours. The mixture was cooled, diluted with 1000 mL of EtOAc and washed with 10% aqueous sodium bisulfate. The aqueous portion was extracted three times with EtOAc and the combined organics were dried (Na2SO4) and concentrated to dryness. The residue was dissolved in a small amount of DCM and filtered through 7 inches of silica gel in a 2 L sintered glass funnel eluting with 25% EtOAc/hexanes. The eluent was concentrated to dryness and recrystallized from EtOAc/hexanes to afford about 116.9 g (71%) of Step B compound.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]([C:13]1[CH:14]=[C:15]([CH:36]=[C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]=1[OH:39])[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([NH:26][C:27](=[O:35])[CH2:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[CH:20]=1)=[O:17])([CH3:12])([CH3:11])[CH3:10].CCCCCC>C(Cl)(Cl)Cl>[C:40]([C:37]1[CH:36]=[C:15]([CH:14]=[C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])[C:38]=1[OH:39])[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([NH:26][C:27](=[O:35])[CH:28]([Cl:1])[C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH:20]=1)=[O:17])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)C(=O)CC(=O)Nc1cc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: CC(C)(C)C(=O)C(Cl)C(=O)Nc1cc(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)ccc1Cl
Reaction time: 18 h

Procedure:
N-chlorosuccinimide (16.3 g; 0.122 mole) was added with stirring to a solution of the compound (55.7 g; 0.1 mole) from (c) in chloroform (480 ml) and stirring continued for 18 hr. The volume of the mixture was reduced to approximately 100 ml and hexane (250 ml) added. The mixture was washed with water (2×100 ml) and the organic solution dried and evaporated to give a solid. This material was crystallized from dichloromethane (100 ml) and hexane (500 ml), to give the product (44.5 g; 83%) as a white solid, m.p. 185°-187° C.
Reaction SMILES: C(OC([NH:8][NH:9][C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]3)=[O:25])[CH2:20][CH2:19]2)=[CH:13][CH:12]=1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[CH:32]([N:29]1[CH2:30][CH2:31][N:26]([C:24]([C@H:21]2[CH2:22][CH2:23][C@H:18]([O:17][C:14]3[CH:13]=[CH:12][C:11]([C:10]([NH:9][NH2:8])=[O:35])=[CH:16][CH:15]=3)[CH2:19][CH2:20]2)=[O:25])[CH2:27][CH2:28]1)([CH3:34])[CH3:33]
Reactant: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NNC(=O)OC(C)(C)C)cc3)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(C(=O)NN)cc3)CC2)CC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 440 mg (0.90 mmol) of trans-N′-{4-[4-(4-Isopropyl-piperazine-1-carbonyl)-cyclohexyloxy]-benzoyl}-hydrazinecarboxylic acid tert-butyl ester, 1.53 ml (6.12 mmol) of 4M hydrochloric acid in 1,4-dioxane solution and 4 ml of methanol was stirred for 4 h at 40° C. The mixture was evaporated to dryness to yield 0.44 g of the title compound. MS (m/e): 389.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:16](Cl)[O:17][CH3:18]>C1COCC1.O>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1cccc(OCOC)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of Ethyl 2-(3-hydroxyphenyl)acetate (11 g, 61 mmol) in THF (100 mL) was added NaH (2.93 g, 73.3 mmol) and MOM-Cl) 5.94 g, 73.3 mmol) at 0° C. The reaction mixture was stirred for 16 hrs at 0° C. then warmed to room temperature. The reaction mixture was diluted with H2O (200 mL) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[C:28]([N:29]([CH2:31][CH2:32][CH2:33][S:34][CH2:35][CH3:36])[CH3:30])=[C:27]([S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[C:26]([C:44]#[N:45])=[N:25]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCCl>[Cl:23][C:15]1[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]([Cl:12])[C:14]=1[N:24]1[C:28]([N:29]([CH2:31][CH2:32][CH2:33][S:34]([CH2:35][CH3:36])=[O:9])[CH3:30])=[C:27]([S:37]([C:40]([F:43])([F:42])[F:41])(=[O:38])=[O:39])[C:26]([C:44]#[N:45])=[N:25]1
Reactant: CCSCCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCS(=O)CCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (0.091 g, 77%, 0.4 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(3-ethylthiopropyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole (0.23 g, 0.4 mmol) in 1,2-dichloroethane at 0-5° C. The mixture was stirred at 0-5° C. for 0.5 hour, then poured into saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), evaporated and chromatographed on silica gel eluting with heptane-ethyl acetate (1/1 to 3/7) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(ethylsulfinylpropyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole as a light brown oil (Compound number 2-15, 0.186 g, 71%),19F: −63.8, −78.7.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH2:31][CH2:32][O:33][CH3:34])[N:21]=[CH:20][N:19]=[C:18]2[CH:7]1[C:6]2[C:10](=[CH:11][C:3]([C:2]([F:1])([F:13])[F:14])=[CH:4][CH:5]=2)[NH:9][C:8]1=[O:12]
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2ncnc(C3C(=O)Nc4cc(C(F)(F)F)ccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
6-Trifluoromethyloxindole (270 mg, 1.3 mmol) was dissolved in dry, degassed DMF (5 ml) under argon. Sodium hydride (63 mg, 1.6 mmol) was added and the suspension stirred for 30 minutes at ambient temperature. A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (111 mg, 0.332 mmol), (prepared as described for the starting material in Example 2), in dry, degassed DMF (5 ml) was added dropwise and the mixture heated at 100° C. for 2 hours. The mixture was allowed to cool and the DMF was removed by evaporation. The residue was purified by flash column chromatography eluting with methylene chloride/methanol (100/0 and then 15/1). The purified orange solid was triturated with ether, collected by filtration and dried under vacuum at 40° C. to give 6-methoxy-7-(2-methoxyethoxy)-4-(6-trifluoromethyloxindol-3-yl)quinazoline (100 mg, 52%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>Cl.O1CCCC1>[CH2:26]([NH:33][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NCc1ccccc1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
2-Chloronicotinic acid (25 grams, 158.67 mmol) is placed into a 2L 4-neck round bottom flask equipped with mechanical stirring, thermometer, nitrogen inlet and a rubber septum and is charged with 800 ml of tetrahydrofuran (THF). The reaction is chilled to 0° C. N-methylmorpholine (16.05 grams, 158.67 mmol) is added via syringe. The reaction is chilled to -10° C. and isobutyl chloroformate (21.67 grams, 158.67 mmol) is added to the reaction via syringe while maintaining the temperature at less than 0° C. The reaction is allowed to stir at -10° C. for 30 minutes. Benzylamine (18.70 grams, 174.54 mmol) is then added via syringe while maintaining the temperature below 0° C. The reaction is allowed to slowly warm to room temperature. After stirring for 18 hours IN HCl (300 ml) is added to the reaction. This is then extracted with ethyl acetate (2×350 ml). The organics are combined and washed with 1N HCl (1×300 ml) and 12% sodium hydroxide (2×300 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to a white paste. The paste is triturated with diethyl ether to yield a solid. This is filtered and washed with diethyl ether (2×65 ml). The filtrates are concentrated and triturated with fresh diethyl ether to yield a second crop of compound which is combined with the first to yield 28.11 grams (71.8%) of N-benzyl-2-chloronicotinamide as a white crystalline solid.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:21][N:20]=[N:19][N:18]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12.CN(C)C=O.[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38](O)=[O:39])=[O:36]>C(N(CC)CC)C>[F:32][C:33]([F:42])([F:41])[CH2:34][S:35]([CH2:37][C:38]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH:9]([S:16][C:17]3[NH:18][N:19]=[N:20][N:21]=3)[CH2:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:7][S:8][C@H:3]12)=[O:39])=[O:36]
Reactant: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)CS(=O)CC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)NCCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
A suspension of 4.0 g. (0.01 mol.) of 7-amino-3-[1-(2-ureidoethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 50 ml. of dry dimethylformamide is treated with 2 ml. of triethylamine and the mixture is stirred for 15 minutes at 25°. A slight excess of 0.01 mol. of the activated ester of 2,2,2-trifluoroethylsulfinylacetic acid is added to the mixture and it is stirred an additional hour. The reaction mixture is evaporated to dryness and water and ethyl acetate are added to the residue. The layers are separated, the ethyl acetate layer is discarded, fresh ethyl acetate is added to the aqueous phase and it is acidified to pH 2.5 by addition of 6N hydrochloric acid. The mixture is filtered, the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined extracts are washed with water, dried (MgSO4) and evaporated to dryness to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C1CCC(N=C=NC2CCCCC2)CC1>C1C=CC=CC=1.Cl[Cu]>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)CC1=CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of (+/−) ethyl 4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate (Compound D1, 108 mg, 0.25 mmol), DCC (55.9 mg, 0.271 mmol) and CuCl (36.6 mg, 0.37 mmol) in 8 ml of dry benzene was heated under reflux for 7 days. After cooling to room temperature, the solids were filtered out and the solution was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, the crude material was purified by flash chromatography (silicagel, 10 % ethyl acetate in hexane) to afford the pure title compounds as red oils.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].C(O)(=O)C>C(O)C>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)NC1CCC(O)c2sccc21
Reaction time: 8 h
Yield: 6 %

Procedure:
7-Keto-4,5,6,7-tetrahydrobenzo[b]-thien-4-ylurea (0.5 grams, 2.38 mm) is suspended in ethanol (50 ml.) and to the stirred solution is added solid sodium borohydride (0.5 grams, 13.2 mm). After stirring overnight the mixture is treated cautiously with 5% aqueous acetic acid (20 ml.). After stirring 15 minutes the solvent is removed, the residue dissolved in a small volume of methanol and percolated through a 11/2'×13/4" silica gel dry column eluting with 20% methanolic methylene chloride. The resulting gum is crystallized from ethyl acetate/methanol to afford 66 mg. (13% Y) of the more polar (L.L.C) alcohol (B), melting point 194° C. to 197° C. The mother liquor material is separated into its two major components 7-hydroxy-4,5,6,7-tetrahydrobenzo[b]thien-4-ylurea by high pressure liquid chromatography on "Spherosil XOA 400" using the solvent system: hexane (1800 ml.)/methanol (425)/chloroform (1000) (flow rate~13 ml./min.). This procedure affords the less polar alcohol A (29 mgs. 6% yield) melting point, 162° C. to 169° C. (methanol/ethyl acetate), and the more polar alcohol B (50 mg., 10% yield), melting point 197° C. to 198° C.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.Cl.[CH3:48][N:49]([CH3:54])[CH2:50][C:51](O)=[O:52].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:51](=[O:52])[CH2:50][N:49]([CH3:54])[CH3:48])=[CH:42][CH:41]=2)=[N:17]1
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 16 %

Procedure:
The title compound was prepared as described in Example 379, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.304 g, 0.50 mmol) in methylene chloride (3 mL) was added N,N-dimethylglycine hydrochloride (0.137 g, 0.98 mmol), 1-hydroxybenzotriazole (0.081 g, 0.60 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.115 g, 0.60 mmol). The final crude product was purified by preparative HPLC (10–70% acetonitrile in H2O, 20 min.) (0.029 g, 16% yield): 1H NMR (DMSO-d6) δ 14.3 (br s, 1H), 13.38 (br s, 1H), 9.91 (s, 1H), 8.69 (s, 1H), 8.08 (d, 1H), 7.95 (d, 2H), 7.87 (d, 2H), 7.68 (d, 1H), 3.12 (s, 2H), 2.30 (s, 6H); ES-MS (m/z) 362 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C1C[O:12][CH2:11][CH2:10]1.[Li+].CC([N-]C(C)C)C.C(=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:11]([OH:12])[CH3:10])[C:5]([F:8])=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CC(O)c1cc(Br)ncc1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
To a 1000 mL 3-neck flask was added 2-bromo-5-fluoropyridine (8.80 g, 50 mmol) and THF (200 mL) at −78° C. followed by dropwise addition of LDA (20.0 mL, 50 mmol, 2.5 M). After stirring at −78° C. for 4 h, acetaldehyde (3.1 mL, 55 mmol) was added dropwise via syringe. The contents were removed from the cold bath and stirred at room temperature overnight. The mixture was diluted with H2O (150 mL), and vigorously stirred for 5 min. The contents were extracted with ethyl ether (3×150 mL), the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford a yellow oil. The crude product was passed through a short silica column (eluent: 3:1 PE/EtOAc) to afford 1-(2-bromo-5-fluoropyridin-4-yl)ethanol as a white solid (9.5 g, 86%). ESI MS m/z=220 (M+1)