Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]([OH:11])[CH2:10][C:4]=2[CH:3]=1.[Br:18][CH2:19][CH2:20]O.B(F)(F)F.CCOCC.O>C1C=CC=CC=1>[Br:18][CH2:19][CH2:20][O:11][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][C:2]([CH3:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: Cc1ccc2c(c1)CC(O)c1ccccc1S2
Reactant: OCCBr
Agent: FB(F)F
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)CC(OCCBr)c1ccccc1S2
Temperature: 12.5 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To a solution of 2-methyl-10,11-dihydrodibenzo[b,f]thiepin-10-ol (3.63 g, 15 mmol, prepared as described in Ger. Offen. 2,336,130, 1974) and 2-bromoethanol (2.5 g, 20 mmol) in absolute benzene (25 ml), a solution of boron trifluoride etherate (2.25 g. 15.8 mmol) in absolute benzene (10 ml) was dropwise added at 10-15° C. over 15 minutes. The reaction mixture was stirred at 10-15° C. for 2 h and water (18 ml) was added. The organic layer was separated, washed with water (2×25 ml), dried (Na2SO4) and evaporated in vacuo to give 3.83 g (73%) crude 10-(2-bromoethoxy)-2-methyl-10,11-dihydrodibenzo[b,f]thiepine, which was used without further purification in the next step.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].[O:24]1C[CH2:27][CH2:26][CH2:25]1>C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:19]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][O:1][C:25](=[O:24])[CH:26]=[CH2:27])(=[O:22])[CH:20]=[CH2:21]
Reactant: OCCOc1ccccc1O
Reactant: C=CC(=O)Cl
Reactant: C1CCOC1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOc1ccccc1OC(=O)C=C
Yield: 62 %

Procedure:
A 500-ml, two necked flask was equipped with magnetic stirring bar, nitrogen atmosphere and an addition funnel. The flask was charged with 25 g of 2-(2-hydroxyethoxy)phenol (0.16 mol.), 33 g of triethylamine (0.32 mol.), 250 ml of tetrahydrofuran and 1 g of phenothiazine. Next, 30 g of acryloyl chloride (0.18 mol.) was slowly added to the reaction over 1 hour via the addition funnel. The triethylamine hydrochloride salt was removed by filtration and the mother liquor was evaporated with a rotoevaporator. The remaining liquid was dissolved in chloroform and washed with NaCl(aq.), NH4OH(10%), NaCl(aq.) and dried over MgSO4. The chloroform was removed with a rotoevaporator to yield 26 g (62%) of a reddish brown liquid. The product was confirmed by IR and 13C NMR.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].[Cl:5][CH:6]([Cl:11])[P:7](Cl)(Cl)=[O:8].[CH2:12]([OH:14])[CH3:13]>C1(C)C=CC=CC=1>[CH2:2]([O:3][P:7]([CH:6]([Cl:11])[Cl:5])(=[O:8])[O:14][CH2:12][CH3:13])[CH3:1]
Reactant: CC[O-]
Reactant: O=P(Cl)(Cl)C(Cl)Cl
Reactant: CCO
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(Cl)Cl
Temperature: 20 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
153.5 g (2.26 mol) of sodium ethylate in 800 ml of ethanol were added dropwise, at 5°-10° C., to a solution of 227.5 g (1.13 mol) of dichloromethane-phosphonic acid dichloride in 800 ml of toluene. The mixture was subsequently stirred at 20° C. for 5 hours. It was then filtered, the filtrate was concentrated and the residue was subjected to fractional distillation. 195 g (78% of theory) of dichloromethane-phosphonic acid diethyl ester were obtained in the form of a colorless oil of boiling point 84° C./1 mbar.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:3]=1[CH2:20][CH2:21][OH:22].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>ClCCl.O>[CH3:30][S:31]([O:22][CH2:21][CH2:20][C:3]1[N:4]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)(=[O:33])=[O:32]
Reactant: Cc1c(CCO)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(CCOS(C)(=O)=O)n(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a solution of 2-[3-methyl-1-[benzenesulfonyl)indol-2-yl]ethanol (7.1 g) and triethylamine (2.96 g) in dichloromethane (71 ml) was added dropwise methanesulfonyl chloride (2.84 g) in dichloromethane (57 ml) at -40° C. After being stirred at the same temperature for 30 minutes, the reaction mixture was diluted with chilled water, and neutralized with 1N-hydrochloric acid. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 2-[2-(methanesulfonyloxy)ethyl]-3-methyl-1-(benzenesulfonyl)indole (8.8 g) as amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][N:19]([CH3:23])[C:20](Cl)=[O:21]>C(Cl)Cl>[CH3:18][N:19]([CH3:23])[C:20]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1)=[O:21]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 32 %

Procedure:
4.2 g of Compound [II] and 3.2 g of triethylamine were dissolved in 50 ml of methylene chloride, and 3.2 g of N,N-dimethylcarbamoyl chloride was added to the solution. The mixture was heated under refluxing and cooled, followed by washing with water. The organic layer was collected, and the solvent was distilled off. The residue was solidified by the addition of a mixed solvent of hexane and benzene. The solid obtained was collected by filtration and dried to obtain 2.0 g of N,N-dimethyl N'-(5-t-butyl-3-pyrazolyl)urea. This compound was recrystallized from hydrous methanol and found to have a melting point of 220° C. to 222° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1B(O)O.C(=O)([O-])O.[Na+].COCCOC>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.O>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:27]=2[F:26])[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(F)c(-c2cc(CN(C)C(=O)OC(C)(C)C)cn2S(=O)(=O)c2cccnc2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
tert-Butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (431 mg), (2-fluoro-5-methoxyphenyl)boronic acid (256 mg), sodium hydrogencarbonate (253 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were added to a degassed mixture of 1,2-dimethoxyethane (8 mL) and water (2 mL), and the mixture was stirred under a nitrogen atmosphere at 90° C. for 1 hr. The reaction mixture was allowed to cool, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1) to give the title compound as a colorless oil (yield 475 mg, about 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH:6]=[O:7].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[S:16][CH:17]=1
Reactant: COc1cc(C=O)ccc1OCc1csc(N2CCOCC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCc1csc(N2CCOCC2)n1
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To a solution of 3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde (1.20 g) in tetrahydrofuran (10 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.14 g) at room temperature. After stirring the reaction mixture for 2 hrs, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-methoxy-4-[(2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol as colorless crystals (1.03 g, yield 85%). melting point: 94-95° C.
Reaction SMILES: [F:1][C:2]1([F:23])[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[C:24]([OH:30])=[O:25].[F:23][C:2]1([F:1])[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1
Reactant: COc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)CC2(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2CCNCC2(F)F)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of (R)-t-butyl 3,3-difluoro-4-(4-methoxyphenyl)piperidine-1-carboxylate (65 mg, 0.2 mmol) in DCM (0.8 mL) was added TFA (0.4 mL, 5.2 mmol) at rt. The mixture was stirred for 2 h, then concentrated to dryness in vacuo to afford crude 3,3-difluoro-4-(4-methoxyphenyl)piperidine trifluoroacetate (67.8 mg, 0.2 mmol, 100% yield), which was used in step G without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].CN(C)C=O.[C:31](O[C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)(=O)[C:32]1C=CC=C[CH:33]=1.C(Cl)(Cl)Cl>O>[CH:32]([O:22][CH:13]([CH3:12])[CH3:14])([CH3:33])[CH3:31].[C:40]([NH:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8])(=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)OC(C)C
Product: O=C(Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1F)c1ccccc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
1-(3-amino-4,6-difluorophenyl)-7-chloro-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (310 mg) was added to 920 mg of N,N-dimethylformamide together with 220 mg of benzoic anhydride, which was stirred at 70° C. for 2 hours and at 100° C. for 2.5 hours. The reaction solution was combined with 50 ml of chloroform and 150 ml of distilled water. The solution was separated, the chloroform layer was dried over anhydrous magnesium sulfate and concentrated in vacua. Ethanol (6 ml) was added to the residue, which was allowed to stand. The precipitate was collected by filtration and washed with ethanol and then with diisopropyl ether to give 184 mg of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:32][CH2:33][CH3:34])[C:13]2[C:22]3[CH:21]=[CH:20][C:19]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[CH:18][C:17]=3[N:16]=[C:15]([NH2:30])[C:14]=2[N:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(Cl)(Cl)Cl>[C:1]([N:27]1[CH2:26][CH2:25][CH:24]([O:23][C:19]2[CH:20]=[CH:21][C:22]3[C:13]4[N:12]([CH2:32][CH2:33][CH3:34])[C:11]([CH2:10][CH2:9][O:8][CH3:7])=[N:31][C:14]=4[C:15]([NH2:30])=[N:16][C:17]=3[CH:18]=2)[CH2:29][CH2:28]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCNCC4)ccc3c21
Reactant: CC(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCn1c(CCOC)nc2c(N)nc3cc(OC4CCN(C(=O)C(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyryl chloride (0.273 mL, 2.61 mmol) was added dropwise to a stirred solution of 2-(2-methoxyethyl)-7-(piperidin-4-yloxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-ylamine (prepared as described in Part A of Example 388, 1.00 g, 2.61 mmol) in chloroform at 0° C. After 2 hours, the solution was allowed to warm to ambient temperature for 1 hour. Saturated aqueous sodium carbonate (15 mL) and water (10 mL) were added and the mixture was allowed to stir for 16 hours. The mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with dichloromethane (2×30 mL). The organic layers were combined, washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Recrystallization from acetonitrile afforded 1.00 g of 7-[(1-isobutyrylpiperidin-4-yl)oxy]-2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a flocculent white solid, mp 165-166° C.
Reaction SMILES: C([Cl:4])(=O)C.[N:5]1[CH:6]=[N:7][N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:31][CH2:30][C:17]4([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[CH2:16][CH2:15]3)[CH2:10][C:9]=12>C(O)C>[ClH:4].[ClH:4].[CH2:18]1[C:17]2([CH2:30][CH2:31][CH:14]([N:11]3[CH2:12][CH2:13][N:8]4[N:7]=[CH:6][N:5]=[C:9]4[CH2:10]3)[CH2:15][CH2:16]2)[CH2:22][CH2:21][NH:20][CH2:19]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCn4ncnc4C3)CC2)CC1
Solvent: CCO
Product: Cl
Product: c1nc2n(n1)CCN(C1CCC3(CCNCC3)CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Acetyl chloride (5 eq.) was added to an ice-cold solution of tert-butyl 9-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-3-azaspiro[5.5]undecane-3-carboxylate (0.666 mmol, 1 eq.) in ethanol (5 ml). The reaction mixture was stirred at room temperature for overnight. The white solid was filtered out, washed with diethyl ether and dried in vacuo. Yield: 91%
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)=O.[NH2:11][C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1>C(O)C>[BrH:1].[N:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]1[N:11]=[C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]2[CH:2]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: Nc1ncccn1
Solvent: CCO
Product: Br
Product: c1ccc(-c2cn3cccnc3n2)nc1
Temperature: 70 °C
Reaction time: 17 h
Yield: 77.3 %

Procedure:
2-Bromo-1-pyridin-2-ylethanone (66.1 g; 330 mmol) was dissolved in ethanol (330 mL), 2-aminopyrimidine (31.5 g; 330 mmol) was added thereto, and the mixture was stirred for 17 hours at 70° C. The precipitated crystals were collected by filtration, washed with acetone, and then dried to give 70.7 g of the title compound (yield 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]3[CH:39]4[CH2:40][CH:41]([OH:43])[CH2:42][CH:35]3[CH2:36][O:37][CH2:38]4)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:45]1[N:50]=[CH:49][C:48]([S:51]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[N:65]=[CH:64][C:63]([C:66]([OH:75])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])=[CH:62][N:61]=3)[C@@H:56]([CH2:76][N:77]3[CH:82]4[CH2:83][C:84](=[O:86])[CH2:85][CH:78]3[CH2:79][O:80][CH2:81]4)[CH2:55]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1.[OH-].[NH4+].CCO>O.CCOC(C)=O>[NH2:50][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=3)[C@@H:13]([CH2:33][N:34]3[CH:39]4[CH2:40][CH:41]([OH:43])[CH2:42][CH:35]3[CH2:36][O:37][CH2:38]4)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:7][C:45]1[N:50]=[CH:49][C:48]([S:51]([N:54]2[CH2:59][CH2:58][N:57]([C:60]3[N:65]=[CH:64][C:63]([C:66]([OH:75])([C:71]([F:74])([F:73])[F:72])[C:67]([F:70])([F:69])[F:68])=[CH:62][N:61]=3)[C@@H:56]([CH2:76][N:77]3[CH:82]4[CH2:83][C:84](=[O:86])[CH2:85][CH:78]3[CH2:79][O:80][CH2:81]4)[CH2:55]2)(=[O:53])=[O:52])=[CH:47][CH:46]=1
Reactant: O=S(=O)(c1ccc(Cl)nc1)N1CCN(c2ncc(C(O)(C(F)(F)F)C(F)(F)F)cn2)[C@@H](CN2C3COCC2CC(O)C3)C1
Reactant: O=C1CC2COCC(C1)N2C[C@H]1CN(S(=O)(=O)c2ccc(Cl)nc2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CN3C4COCC3CC(=O)C4)C2)cn1
Product: Nc1ccc(S(=O)(=O)N2CCN(c3ncc(C(O)(C(F)(F)F)C(F)(F)F)cn3)[C@@H](CN3C4COCC3CC(O)C4)C2)cn1
Temperature: 150 °C

Procedure:
A 30-mL sealed tube was charged with 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) and 9-(((2S)-4-((6-chloro-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (50 mg, 0.076 mmol), ammonium hydroxide (266 mg, 7.59 mmol) and EtOH (5 mL) and was heated to 150° C. o/n. The reaction was diluted with water (50 mL) and EtOAc (100 mL) and the organic layer was separated, dried (Na2SO4), filtered and concentrated. The resulting residue was purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in CH3CN/H2O (10% to 100% over 15 min) to give 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (endo) (12 mg) and 9-(((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one (10 mg).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([NH:6][C:7]1[C:12]2[N:13]([CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=3)[C:14](=[O:17])[CH2:15][O:16][C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[OH-].[Na+].C1COCC1>CO>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][N:13]1[C:12]2[C:7]([NH:6][C:4](=[O:5])[C:3]([OH:29])=[O:2])=[CH:8][CH:9]=[CH:10][C:11]=2[O:16][CH2:15][C:14]1=[O:17]
Reactant: COC(=O)C(=O)Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)Nc1cccc2c1N(Cc1ccc3ccccc3c1)C(=O)CO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-5-yl)-oxalamic acid methyl ester, K-67 (95 mg,) in methanol (2.0 mL), 1.0 M NaOH (0.5 mL) was added followed by THF (2.0 mL) resulting in a clear solution. Reaction was stirred at room temperature for 30 minutes and then concentrated to remove the solvents. The residue was taken in water (2.0 mL), acidified with 1.0 M HCl and extracted with ethyl acetate (5.0 mL×4). Combined extracts were washed with water (5.0 mL), dried (brine, Na2SO4) and concentrated to afford N-(4-Naphthalen-2-ylmethyl-3-oxo-3,4-dihydro-2H-benzo [1,4]oxazin-5-yl)-oxalamic acid, A51 (69 mg). 1H NMR (CDCl3) 4.66 (s, 2H), 5.21 (s, 2H), 7.02 (m, 2H), 7.07 (d, J=8.5 Hz, 1H), 7.14 (br s, 1H), 7.33 (br s, 2H), 7.50 (s, 1H), 7.65 (m, 3H), 8.69 (s, 1H). MS (ESI−) Calcd. for: 376.4; Found: 375.5 (M−H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:16])([CH3:15])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)C.O>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([CH3:15])([CH3:16])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc(C(C)(C)C(=O)O)cc1
Yield: 92 %

Procedure:
A mixture of ethyl (4-dimethylaminophenyl)-2,2-dimethylacetate (1.00 g, 4.25 mmol) and sodium hydroxide (0.85 g) in ethanol (20 ml ) and water (9 mL) was heated under reflux for 18 hours. The mixture was cooled, acidified with 10% HCl, and washed with ethyl acetate. The aqueous phase was evaporated. The residue was dissolved in aqueous saturated sodium bicarbonate, and extracted with ethyl acetate. The organic phase was dried, filtered and evaporated to give (4-dimethylaminophenyl)-2,2-dimethylacetic acid as a faint red solid (0.81 g, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].COC1C=C2C(C(=O)C=[CH:25][NH:26]2)=CC=1C(O)=O.CN.O>O1CCCC1>[CH3:25][NH:26][C:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[Cl:13])=[O:15]
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Reactant: COc1cc2[nH]ccc(=O)c2cc1C(=O)O
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(Cl)ccnc2cc1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloride synthesized by the method of Production Example 152-2 from 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (947 mg) in tetrahydrofuran (70 ml), the solution was cooled to 0° C. A 40% aqueous methylamine solution (0.4 ml) was added, and the mixture was stirred at room temperature for 30 minutes. Water was added, extraction was performed 3 times with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and then dried under reduced pressure to obtain the title compound (710 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([OH:12])=O.C[Si](CC(N)=O)(C)C.[NH2:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12>C(OCC)(=O)C.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[N:15][S:16][CH:17]=1)[C:10]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH2:32][S:33][C@H:28]12)=[O:12]
Reactant: CON=C(C(=O)O)c1csnn1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1csnn1
Temperature: -5 °C
Yield: 42.3 %

Procedure:
Dimethylformamide (0.34 g.) was added to dry ethyl acetate (1 ml.), and then phosphorus oxychloride (0.72 g.) was added thereto under 10° C. The mixture was stirred at -5° C. to solidify. Dry ethyl acetate (10 ml.) was added thereto and 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.8 g.) was added to the mixture at 0° C., after which the resulting mixture was stirred for 30 minutes at the same temperature. On the other hand, trimethylsilylacetamide (4.9 g.) was added to a suspension of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.54 g.) in dry ethyl acetate (30 ml.), and the mixture was stirred for 1 hour at 40° C. to give a clear solution. To this solution was added dropwise at -20° C. the above-obtained ethyl acetate solution, and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was post-treated according to a similar manner to that of Example 12 to give pale yellow powder of 7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g.).