Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=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.[NH2:65][C:66]1[CH:67]=[C:68]([CH:72]=[CH:73][CH:74]=1)[C:69]([NH2:71])=[O:70]>C(Cl)Cl.CO>[C:69]([C:68]1[CH:67]=[C:66]([NH:65][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])[CH:74]=[CH:73][CH:72]=1)(=[O:70])[NH2:71]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2cccc(C(N)=O)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.172 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.258 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 3-amino benzamide (Oakwood, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (24 g column, eluent, 30% EtOAc/methylene chloride) to give a white solid. 58 mg. The solid was resolved on a Berger SFC system on a Whelk column under 100 bar, 30° C., and 35% of methanol to give two peaks: Peak 1, undesired enantiomer, 19 mg; Peak 2, 21 mg as white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([C:23]3[CH:24]=[CH:25][C:26]([C:29]#[N:30])=[CH:27][CH:28]=3)=[O:31])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)c2ccc(C#N)cc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)c2ccc(C#N)cc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-(4-cyano-benzoyl)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (414 mg, 0.87 mmol) in CH2Cl2 (8 ml) was added TFA (2 ml). The reaction mixture was stirred at RT for 2 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. Concentration under vacuo gave 302 mg (92%) of the title product as a colorless oil. ES-MS m/e: 374.1 (M+H+).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1>>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(F)cc3)oc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cccc2nc(-c3ccc(F)cc3)oc12

Procedure:
2-(4-Fluorophenyl)benzoxazole-7-carboxylic acid was prepared via the lithium hydroxide mediated hydrolysis of methyl 2-(4-fluorophenyl)benzoxazole-7-carboxylate as described in Step B of Example 14. This material was obtained in quantitative yield as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.25 (dd, J=14.8, 8.9 Hz, 2H), 8.07 (dd, J=13.1, 1.6 Hz, 1H), 7.92 (dd, J=13.1, 1.6 Hz, 1H), 7.51 (m, 3H); MS (ESI) m/z 258 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([NH:5][CH2:6][CH2:7][OH:8])=[O:4].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](Cl)=[O:22])=[CH:16][CH:15]=1)([O-:13])=[O:12]>N1C=CC=CC=1>[C:21](=[O:22])([O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:10])([F:9])[F:1])[O:20][C:17]1[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NCCO)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(OCCNC(=O)C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
17 g (0.108 mol) of 2-(trifluoroacetylamino)ethanol are dissolved in 210 ml of pyridine, 21 g of chloroformic acid 4-nitrophenyl ester are added and the mixture is left to stand overnight at room temperature. It is then concentrated, the residue is taken up in methylene chloride and the methylene chloride mixture is washed with ice-water and dried with Na2SO4. After evaporating off the solvent, 33 g of a light-colored oil are obtained.
Reaction SMILES: [CH2:1]([O:6][CH2:7][CH2:8][CH2:9][CH:10]([C:15]([CH3:17])=O)[C:11](OC)=[O:12])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1>C(O)(=O)CC>[OH:12][C:11]1[N:20]2[N:21]=[CH:22][N:23]=[C:19]2[N:18]=[C:15]([CH3:17])[C:10]=1[CH2:9][CH2:8][CH2:7][O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)C(CCCOCC(C)(C)C)C(C)=O
Reactant: Nc1nc[nH]n1
Solvent: CCC(=O)O
Product: Cc1nc2ncnn2c(O)c1CCCOCC(C)(C)C
Yield: 57.1 %

Procedure:
22.0 g (90 millimoles) of methyl 2-[3-(neopentyloxy)propyl]-acetoacetate and 7.14 g (84.9 millimoles) of 3-amino -1,2,4-triazole in 300 ml of boiling propionic acid are allowed to react for 21 hours. The mixture is cooled and then evaporated down, the residue is stirred into ice water, the solution is neutralized with 2N NaOH, and the product is filtered off under suction to give 13.5 g (57%) of colorless crystals of melting point 155°-159° C., which are reacted without further purification.
Reaction SMILES: [ClH:1].N[N:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[ClH:1].[CH3:13][C:11]1[CH:10]=[C:9]2[C:8]3[N:3]([C:18]4[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][C:17]=42)[CH2:4][CH2:5][O:6][C:7]=3[CH:12]=1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc2c(c1)OCCN2N
Agent: Cl
Product: Cc1cc2c3c(c1)c1c(n3CCO2)CCN(C)C1

Procedure:
4-Amino-3,4-dihydro-7-methyl-2H-1,4-benzoxazine hydrochloride is reacted with 1-methyl-4-piperidone according to the procedure of Example 110 to yield the title compound, m.p. 248°-249° .
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][C:11]([C:13]1[C:14](OS(C(F)(F)F)(=O)=O)=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:6]([O:10][C:11]([C:13]1[C:14]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[CH:24]=1)=[CH:20][C:19]([Cl:32])=[CH:18][CH:17]=2)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CCNCC
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of diethyl amine (0.078 ml, 0.75 mmol) in THF (5 ml) was added 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (200 mg, 0.38 mmol) and potassium carbonate (208 mg, 1.51 mmol) at 25° C. The resulting reaction mixture was stirred at 70° C. for 3 h. Volatiles were removed in vacuo and the resulting crude mixture was diluted with water (15 ml), and extracted with EtOAc (2×30 ml). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (3% EtOAc in hexane) to afford 6-chloro-2-diethylamino-4-(3-isopropyl-phenyl)-quinoline-3-carboxylic acid tert-butyl ester (110 mg, 64%) as a pale yellow solid. LC-MS (ESI): 453 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:11]1[CH:16]=[C:15]([O:17]COC)[CH:14]=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22].Cl>CN(C)C=O.O1CCCC1.CCCCCC.C(OCC)(=O)C.O>[N+:21]([C:12]1[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=1[O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:23])=[O:22]
Reactant: COCOc1ccc([N+](=O)[O-])c(F)c1
Reactant: OC1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccc(O)cc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-ol (54.7 g) in N,N-dimethylformamide (500 mL) was added under ice-cooling sodium hydride (oily, 60%) (14 g), and the mixture was stirred for 30 min. To the reaction solution was added 2-fluoro-4-(methoxymethoxy)-1-nitrobenzene (98 g) and the mixture was stirred at 120° C. for 4 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was dissolved in tetrahydrofuran (300 mL), 1N hydrochloric acid (500 mL) was added and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to column chromatography (ethyl acetate:hexane=0:100 to 50:50, volume ratio) to give the title compound (27 g, yield 23%) as pale-yellow crystals.
Reaction SMILES: [CH:1]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[C:12]([F:15])([F:14])[F:13].[OH-].[Na+].Br[CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].Cl>O>[F:15][C:12]([F:13])([F:14])[C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:7]([F:9])([F:8])[F:10])[CH:1]=1)[O:11][CH2:19][C:20]([OH:22])=[O:21]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred solution containing 115 g (0.50 mole) of 3,5-ditrifluoromethylphenol, 44 g (0.55 mole) of 50% aqueous sodium hydroxide and 500 ml of water, 76.4 g (0.55 mole) of bromoacetic acid in 250 ml of water neutralized with 38.7 g of potassium carbonate to pH=9 was added in one portion. The stirred reaction mixture was heated at 80°-90° C. for 24 hours. After cooling to 0° C., 60 g (0.60 mole) of concentrated hydrochloric acid in 500 ml of water was added dropwise to the solution. After stirring at 0°-10° C., the resulting solid was collected by filtration, washed with water until the washings were neutral to litmus and air-dried at 25°-30° C. A product with a melting point of 103°-104° C. was obtained in 80% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH:32]=[CH2:33])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[Pd]>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH2:32][CH3:33])[CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH:18]=1)[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A suspension of 5% Pd on carbon (0.01 g) in a solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic-acid tert-butyl ester (0.07 g) in toluene (10 ml) was stirred under an atmosphere of hydrogen for 2 h. The catalyst was filtered through diatomaceous earth and the filtrate evaporated to give the title compound as a pale yellow gum (0.07 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9](F)(F)F)[CH:5]=[CH:6][C:7]=1[F:8].[Al+3].[Cl-:15].[Cl-:16].[Cl-:17]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:9]([Cl:17])([Cl:16])[Cl:15])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C(F)(F)F)c(F)c1Cl
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClCCl
Product: Fc1ccc(C(Cl)(Cl)Cl)c(F)c1Cl
Temperature: 42 °C
Yield: 86.9 %

Procedure:
216.5 g of 3-chloro-2,4-difluoro-benzotrifluoride in 440 ml of methylene chloride are initially introduced into a stirred apparatus, and 150 g of AlCl3 are introduced in small portions. The reaction is slightly exothermic. When the addition has ended, the mixture is heated under reflux (42° C.) for 2 hours, cooled and poured onto 1 l of ice-water. After intensive thorough mixing, the mixture is filtered over a suction filter and the organic phase is then separated off. After drying, the methylene chloride phase is distilled. 231 g of 3-chloro-2,4-difluoro-benzotrichloride with a boiling range of 124-126° C./18 mbar are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH3:27])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[NH3:28]>CC(O)C.C(Cl)Cl>[CH3:27][C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:28])[C:3]2=[C:10]([C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:18]3)=[CH:13][CH:12]=2)[N:9]=1
Reactant: N
Reactant: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
7-(8-Chloro-3-methyl-imidazo[1,5-a]pyrazin-1-yl)-2-phenyl-quinoline was dissolved in 10.0 mL of 2.0M NH3 in IPA and 5.0 mL of CH2Cl2. The reaction was heated to 110° C. for 64 h. The salts were filtered off and washed with CH2Cl2. Purified with silica gel column chromatography [Jones Flashmaster, 10 g cartridge, eluting with 1% MeOH: EtOAc] to yield a dark yellow solid; 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 5.61 (brs, 2H), 7.13 (d, 1H, J=5.1 Hz), 7.2 (d, 1H, J=5.1 Hz), 7.48-7.56 (m, 3H), 7.89-7.97 (m, 3H), 8.18-8.21 (m, 2H), 8.27 (d, 1H, J=8.6 Hz), 8.39 (s, 1H); MS (ES+): 352.06 (M+1), 353.07 (M+2), 354.09 (M+3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Br:27])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=2)=[O:10])[CH:5]=[CH:6][C:7]=1[CH2:8][Br:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C(=O)c2ccc(C)c(Br)c2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc(C(=O)c2ccc(CBr)c(Br)c2)cc1
Temperature: 100 °C
Yield: 50.1 %

Procedure:
To a stirred solution of (3-bromo-4-methylphenyl)(4-ethoxyphenyl)methanone (0.864 g, 2.71 mmol) in CCl4 (3.5 mL) were added N-bromosuccimide (0.506 g, 2.84 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg, 0.14 mmol). After being vigorously stirred under reflux at an external temperature of 100° C. for 110 min, additional N-bromosuccimide (0.1 g, 0.56 mmol) and 2,2′-azobis(isobutyronitrile) (20 mg, 0.14 mmol) were added. The mixture was stirred for another 30 min, then cooled with ice-water. The resulting precipitates were collected by filtration and washed with ethyl acetate. The filtrate was washed 3× with 5% citric acid, and dried over Na2SO4. Concentration under reduced pressure gave the crude product which was recrystallized from ethyl acetate to yield 0.54 g of the title compound. 1H NMR (CDCl3, 300 MHz: δ 7.96 (s, 1H), 7.80 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 6.96 (d, J=8.4 Hz, 2H), 4.64 (s, 2H), 4.13 (q, J=6.8 Hz, 2H), 1.46 (t, J=6.8 Hz, 3H); MS ESI (m/z) 397 (M+1)+, calc. 396.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC3C=CC=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCCc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CCc3ccccc3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CCc3ccccc3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.048 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using (2-chloroethyl)benzene (0.045 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-phenethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.52-7.47 (m, 4H), 7.28-7.21 (m, 3H), 7.03-7.01 (m, 2H), 4.39 (t, J=6.4 Hz, 2H), 3.20-3.18 (m, 2H), 3.13-3.10 (m, 2H), 2.95-2.93 (m, 2H), 2.91-2.89 (m, 2H), 2.69-2.67 (m, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1)[N:8]([CH3:18])[C:7]2=[O:19].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1>>[CH3:18][N:8]1[C:7](=[O:19])[C:6]2[C:11](=[C:2]([C:27]3[NH:26][C:25]4[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=4[CH:28]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C:13]1([CH3:17])[CH2:16][CH2:15][CH2:14]1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: Cn1c(NC2(C)CCC2)nc2c(I)cccc2c1=O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC5(C)CCC5)nc34)[nH]c21
Yield: 54.6 %

Procedure:
This compound (169 mg, 54% yield) as a brown solid was prepared according to the procedure described for Example 448, using 8-iodo-3-methyl-2-((1-methylcyclobutyl)amino)quinazolin-4(3H)-one (711) (303 mg, 0.82 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (215 mg, 0.82 mmol) as the starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.27 (1H, br.), 8.00 (1H, dd, J=7.6, 1.4 Hz), 7.85 (1H, dd, J=7.8, 1.4 Hz), 7.66 (1H, s), 7.15 (1H, t, J=7.7 Hz), 6.98 (1H, s), 6.81 (1H, s), 4.60 (1H, q, J=6.5 Hz), 3.41 (3H, s), 2.38 (2H, m), 2.14 (2H, m), 1.88 (2H, m), 1.67 (3H, s), 1.40 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 378.2 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=1.[I-].[Li+]>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:11](=[O:12])[NH:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:24])=[O:2])=[CH:19][CH:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(NC(=O)Nc2cccc(C(=O)O)c2)cc1
Yield: 67.2 %

Procedure:
A solution of methyl-3-[3-(4-tert-butylphenyl)-ureido]-benzoate (0.19 g, 0.58 mmol) in pyridine (15 mL) was treated with anhydrous lithium iodide (0.78 g, 6.0 mmol), and the resulting solution was heated to reflux for 20 h. The solution was cooled and partially evaporated, and the residual material was partitioned between 1 N aq. HCl and ethyl acetate. The aqueous layer was extracted with more ethyl acetate, and the organic extracts were washed with brine, combined, dried over magnesium sulfate, filtered, and evaporated. The remaining powdery solid was triturated with ether, collected by filtration and dried under vacuum to afford the title compound (0.12 g, 0.39 mmol, 66%). m.p. 147-148° C. 1H NMR (d6-DMSO, 300 MHz): d 8.58 (1H, s), 8.10 (1H, t, J=2 Hz), 7.72-7.62 (2H, m), 7.40-7.25 (5H,m), 6.53 (1H, s), 1.25 (9H, s).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:14]=[C:13]([CH2:15][C:16]([O-:18])=O)[O:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[C:1]([O:9][C:10]1[CH:14]=[C:13]([CH2:15][C:16]([Cl:23])=[O:18])[O:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C([O-])Cc1cc(OC(=O)c2ccccc2)no1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(OC(=O)c2ccccc2)no1
Reaction time: 0.5 h

Procedure:
0.59 g of sodium (3-benzoyloxyisoxazol-5-yl)acetate was suspended in 5 ml of methylene chloride, and 0.37 ml of oxalyl chloride were then added, with ice-cooling. After adding one drop of N,N-dimethylformamide, the mixture was stirred for 30 minutes. The solvent was then distilled off under reduced pressure to give (3-benzoyloxyisoxazol-5-yl)acetyl chloride, which was then dissolved in 5 ml of methylene chloride. This solution was added dropwise to a solution of 685 mg of benzhydryl 3-acetoxymethyl-7β-amino-7α-methoxy-3-cephem-4-carboxylate and 325 mg of N,N-diethylaniline in 5 ml of methylene chloride, maintaining the internal temperature at about -10° C. After stirring the mixture at a temperature between -10° C. and -5° C. for 45 minutes, the reaction mixture was evaporated to dryness under reduced pressure and the residue was adsorbed on a silica gel preparative thin layer chromatograph and developed by a 2:1 by volume mixture of benzene and ethyl acetate. The portion having an Rf value of 0.54 was extracted to give 660 mg (64.7%) of the benzhydryl ester of the desired Compound No. 4.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([CH2:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:24]=2[N:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]3)[N:3]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)OC>[Cl:29][C:18]1[CH:19]=[C:20]2[C:24](=[C:16]([CH2:15][N:4]3[C:5]4[C:10](=[CH:9][C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=4)[C:2]([NH:1][CH3:30])=[N:3]3)[CH:17]=1)[N:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[N:22]=[CH:21]2
Reactant: COC(=O)c1ccc2c(c1)c(N)nn2Cc1cc(Cl)cc2cnn(CC(C)C)c12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: CNc1nn(Cc2cc(Cl)cc3cnn(CC(C)C)c23)c2ccc(C(=O)OC)cc12
Temperature: 60 °C

Procedure:
A mixture of compound 67 (0.054 g, 0.13 mmol), p-toluenesulphonic acid (0.003 g, 0.013 mmol), in trimethylorthoformate (3 mL) was heated at 100° C. in a closed vessel for 16 h. Then, the reaction was concentrated to dryness under vaccum. The residue was dissolved in tetrahydrofuran (4 mL), sodium borohydride was added (0.015 g, 0.395 mmol) and the resulting mixture was heated at 60° C. for 5 h.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]1=[O:12].Cl.[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>CN(C=O)C>[OH:21][CH2:20][CH:17]1[CH2:18][CH2:19][N:14]([CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][N:6]([CH:9]([CH3:11])[CH3:10])[C:5]2=[O:12])[CH2:15][CH2:16]1
Reactant: CC(C)n1ccn(CCCl)c1=O
Reactant: OCC1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1ccn(CCN2CCC(CO)CC2)c1=O
Temperature: 70 °C
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of 1-(2-chloroethyl)-1,3-dihydro-3-(1-methylethyl)-2H-imidazol-2-one (12 g), 4-piperidinemethanol hydrochloride (9.1 g), N,N-diethylethanamine (21 ml) and KI (catalytic amount) in DMF (200 ml) was stirred for 20 hours at 70° C. The reaction mixture was cooled and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding 6.9 g (43%) 1,3-dihydro-1-[2-[4-(hydroxymethyl)-1-piperidinyl]ethyl]-3-(1-methylethyl)-2H-imidazol-2-one (intermediate 3).