Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=1[CH2:24]Br>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:23]=1[CH2:24][O:13][C:10]1[CH:11]=[CH:12][C:4]([NH:3][CH:1]=[O:2])=[C:5]([CH:9]=1)[C:6]([NH2:8])=[O:7]
Reactant: COc1ccc(OC)c(CBr)c1
Reactant: NC(=O)c1cc(O)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC)c(COc2ccc(NC=O)c(C(N)=O)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 140 mg of 2-formylamino-5-hydroxybenzamide in 15 ml of dry dimethylformamide is treated subsequently with 160 mg of potassium carbonate and 180 mg of 2,5-dimethoxybenzylbromide. The mixture is stirred at room temperature for 4 hours, and then the solvent is distilled off in vacuo. The residue is partitioned between water and ethyl acetate, and the separated organic layer is dried over magnesium sulfate and evaporated in vacuo. Purification of the crude product thus obtained by silica gel chromatography (ethyl acetate) gives the title compound as colourless crystals. mp: 135-138°.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][C:3](=O)[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2
Reactant: O=C1CN2CCC(CC2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C1CN2CCC(CC2)N1

Procedure:
1,4-Diazabicyclo[3.2.2]nonan-3-one (5.12 g; 36 mmol) was dissolved in tetrahydrofuran (50 ml), litium aluminium hydride 2.28 g (60 mmol) was added to the solution and the reaction mixture was refluxed for 36 hours. After cooling the reaction mixture to mom temperature, water (2.3 ml) was added dropwise and the mixture was filtered. The solvent was removed from the filtrate by rotavapor at reduced pressure. The formed substance was distilled with Kugelrohr (0.5 mBar, 70° C.). Yield of the title compound 3.11 g (68%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[O:8][C:7]([CH3:14])([CH3:13])[CH2:6][CH2:5]2.[Li]CCCC.CN([CH:23]=[O:24])C>>[CH3:13][C:7]1([CH3:14])[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=2)[O:8]1
Reactant: Cc1cc(Br)cc2c1OC(C)(C)CC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: Cc1cc(C=O)cc2c1OC(C)(C)CC2

Procedure:
Using essentially the same procedure as Example 5-20, Step 3, 6-bromo-2,2,8-trimethyl-3,4-dihydro-2H-chromene (684 mg, 2.68 mmol), n-BuLi (1.30 mL, 3.22 mmol) and DMF (830 μL, 10.7 mmol) afforded the desired product as a pale-yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=2[CH3:16])=[C:4]([CH3:17])[CH:3]=1.[C:18]([C:22]1[CH:27]=[C:26]([CH:28]=[CH2:29])[CH:25]=[C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]=1[OH:34])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([C:22]1[CH:27]=[C:26]([CH:28]=[CH:29][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[C:14]([CH3:15])=[CH:13][N:12]=[CH:11][C:10]=3[CH3:16])=[C:4]([CH3:17])[CH:3]=2)[CH:25]=[C:24]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]=1[OH:34])([CH3:21])([CH3:20])[CH3:19]
Reactant: C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cncc(C)c1-c1c(C)cc(C=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1C
Temperature: 100 °C
Reaction time: 36 h
Yield: 91 %

Procedure:
A flame-dried sealable Schlenk tube was charged with 11 (1.69 g, 5.0 mmol), 12 (2.32 g, 10.0 mmol), Pd(OAc)2 (112 mg, 0.50 mmol), and PPh3 (131 mg, 0.50 mmol), evacuated, and then backfilled with N2. Next, dry Et3N (10 mL) was added under an N2 flow. The Schlenk tube was next sealed, the mixture was degassed by 3 freeze-thaw cycles, and backfilled with N2. The Schlenk tube was then wrapped with aluminum foil and stirred at 100° C. for 36 h. The reaction mixture was then cooled to room temperature, diluted with methylene chloride (50 mL), filtered through a thin pad of silica gel, and concentrated in vacuo to afford a red solid. The crude product was purified by flash chromatography on silica gel, eluting with 3:1 hexane: ethyl acetate to give the title compound 2.01 g (91.2%) as a colorless solid: mp 234-235° C.; 1H NMR (400 MHz, CDCl3): δ 8.402 (s, 2H), 7.371 (s, 2H), 7.307 (s, 2H), 7.133 (d, 1H, J=16.4 Hz), 6.936 (d, 1H, J=16.0 Hz), 5.331 (s, 1H), 1.951 (s, 6H), 1.911 (s, 6H), 1.499 (s, 18H); 13C NMR (100 MHz, CDCl3): δ 153.971, 148.630, 148.502, 137.347, 136.301, 135.928, 134.817, 131.251, 129.595, 128.876, 125.837, 125.709, 123.598, 34.638, 30.534, 19.997, 16.822; HRMS (EI): m/z 441.3023 [M+]; calcd, 441.3032; Anal. Calcd. for C31H39NO·H2O: C, 81.00; H, 8.99; N, 3.05. Found; C, 81.01; H, 8.64; N, 3.02.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH2:23].C(O)(C)C>CN(C=O)C>[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[CH3:27])[NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1O
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COCCOc1cc2nncc(Nc3ccc(C)c(O)c3)c2cc1OC

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (0.4 g, 1.5 mmol) and 3-hydroxy-4-methylaniline (0.2 g, 1.6 mmol) in DMF (5 ml) was heated at 150° C. for 20 minutes. After cooling, isopropanol (15 ml) was added and the resulting solid filtered off, washed with isopropanol and dried under vacuum to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(2-methoxyethoxy)cinnoline as the hydrochloride salt (yellow solid, 537 mg 91%).
Reaction SMILES: [NH2:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([F:22])[CH:15]=1)#[N:13].C([O-])(O)=O.[Na+].O>CN(C=O)C>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]([CH3:11])([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:16]([F:22])[CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)NCc1ccc(C#N)cc1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 2-amino-2-methylpropanoate (Bachem, 7.9 g, 0.05 mol) in dry DMF (50 mL) under nitrogen, was added 4-cyano-2-fluoro benzyl bromide (10.6 g, 0.05 mol) and NaHCO3 (8.3 g, 0.099 mol) as a solid. The reaction mixture was stirred for 16 h at 70° C. Water (70 mL) was added and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×100 mL) and the solvent was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography using silica gel (60-120 mesh) and petroleum ether/ethyl acetate as eluent, affording the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, J=10.0 Hz, 1H), 7.71-7.65 (m, 2H), 3.69 (d, J=6.9 Hz, 2H), 2.55 (s, 1H), 1.44 (s, 9H), 1.19 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][N:4]=1.[O-:16]Cl=O.[Na+]>C(#N)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=[O:15])=[CH:5][N:4]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ncc(C=O)c2c(C)cccc12
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1ncc(C(=O)O)c2c(C)cccc12

Procedure:
To a stirred solution of 1-methoxy-5-methylisoquinolin-4-carbaldehyde (Intermediate-7) (2 g, 10 mmol) in ACN—H2O (120 mL, 1:1) was added, NaClO2 (5.4 g, 59.7 mmol), NaH2PO4 (5.5 g, 40 mmol) and the mixture was stirred at RT overnight. It was then extracted with EtOAc (3×150 mL), dried over Na2SO4, filtered and concentrated to give the desired acid derivative (1.2 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: NCc1ccccc1
Product: Nc1cc(C(=O)NCc2ccccc2)ccn1

Procedure:
The title compound was prepared from 2-aminoisonicotinic acid (L. W. Deady, O. L. Korytsky, J. E. Rowe, Aust. J. Chem., 1982, 35, 2025) and benzylamine:
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[C@H:11]([NH2:13])[CH3:12].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@@H:11]([C:4]1[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[F:2])[CH3:12])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1c(F)ccc(F)c1F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3c(F)ccc(F)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2,3,6-trifluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 557 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:5][C:6]=1[C:7](O)=[O:8].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]([CH3:59])[CH2:57][OH:58]>CN(C=O)C>[OH:58][CH2:57][CH:56]([NH:55][C:7]([C:6]1[S:5][C:4]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3][C:2]=1[CH3:1])=[O:8])[CH3:59]
Reactant: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)O
Reactant: CC(N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(CCc2c(-c3ccccc3)noc2C)sc1C(=O)NC(C)CO
Reaction time: 2 h
Yield: 49.4 %

Procedure:
To a solution of 4-methyl-2-[2-(5-methyl-3-phenyl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (100 mg, 0.31 mmol) in DMF (3 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (108 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (197 μL, 1.67 mmol) and rac-2-amino-1-propanol (30 mg, 0.40 mmol). The resulting reaction mixture was stirred for 2 h. The reaction mixture was extracted with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered and evaporated. Concentration and purification by chromatography (silica, 0 to 2.5% methanol in dichlormethane) afforded the title compound (59 mg, 50%) as a colourless oil. MS: m/e=386.2 [M+H]+.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[CH2:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14][NH:13][CH2:12]1>C(OCC)(=O)C>[CH:5]([N:13]1[CH2:12][CH2:11][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15][CH2:14]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCNCC2
Solvent: O=CO
Solvent: CCOC(C)=O
Product: O=CN1CCc2ccccc2CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Acetic anhydride (40 ml) was added dropwise to formic acid (80 ml) at room temperature and after the mixture was stirred for 30 minutes, a solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (30 g),in ethyl acetate (80 ml) was added dropwise at room temperature. The mixture was then stirred for 30 minutes, after which it was diluted with ice-water and extracted with ethyl acetate. The extract was washed successively with water, aqueous solution of sodium hydroxide (NaOH/H2O), and saturated NaCl/H2O and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) and recrystallized from-n-hexane to provide the title compound (29 g) as colorless crystals melting at 65-66° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:13][C:9]2([CH2:12][CH2:11][CH2:10]2)[O:8][N:7]=1)=[O:5])[CH3:2].CSC.B>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][C:9]2([CH2:10][CH2:11][CH2:12]2)[O:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NOC2(CCC2)C1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(CCC2)ON1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of crude 5-oxa-6-aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester (7.5 g, <40.9 mmol) in tetrahydrofuran (270 mL) at 0° C. was slowly added a solution of borane-dimethyl sulfide complex (10 M in THF, 16.4 mL, 164 mmol). The reaction was allowed to warm to room temperature overnight then recooled to 0° C., and quenched by the careful addition of water. The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to yield a large amount of white solids. These solids were thoroughly triturated three times with dichloromethane (150 mL). The combined dichloromethane washings were concentrated and the resulting oil was purified by flash chromatography to yield 5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (1.08 g, 29% over 2 steps). 1H-NMR: 400 MHz, (CDCl3) δ: 8.01-7.95 (br, 1H), 4.39-4.28 (m, 2H), 4.18-4.10 (m, 1H), 2.80-2.75 (m, 1H), 2.62-2.49 (m, 2H), 2.37-2.29 (m, 1H), 2.25-2.17 (m, 1H), 2.13-1.95 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.56 (m, 1H), 1.34 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][CH:22]=1.ClC(OCC)=O>C(Cl)Cl>[CH3:16][C:17]1[N:18]=[N:19][CH:20]=[CH:21][C:22]=1[C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12
Reactant: Cc1cccnn1
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: Cc1nnccc1-c1c(-c2ccccc2)nn2ccccc12
Reaction time: 6 h
Yield: 32 %

Procedure:
To a mixture of 2-phenylpyrazolo[1,5-a]pyridine (5.00 g), 3-methylpyridazine (2.90 g) and methylene chloride (20 ml), was added a solution of ethyl chloroformate (5.57 g) in methylene chloride for 17 minutes under ice-cooling and stirred for an hour at the same temperature and then for 6 hours and 40 minutes at room temperature. To the reaction mixture was added methylene chloride (20 ml), and washed with a solution of potassium carbonate (10 ml) and a saturated aqueous solution of sodium chloride (10 ml) and dried over magnesium sulfate. The solvent was removed and chromatographed on silica gel (70 g) with a mixture of n-hexane and ethyl acetate (2:1). The fractions containing the object compound were combined and evaporated in vacuo and recrystallized from a mixture of ethyl acetate and n-hexane to give 3-(3-methylpyridazin-4-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.36 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:15][C:10]1[N:9]=[C:8]([NH2:7])[CH:13]=[CH:12][C:11]=1[F:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Br)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(F)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a solution of (6-bromo-5-fluoro-pyridin-2-yl)-carbamic acid tert-butyl ester (1.43 g, 4.91 mmol) in DCM (25 mL) was added TFA (3.78 mL, 49.1 mmol, Eq: 10.0). The mixture was stirred at room temperature for 2 h, after which it was concentrated in vacuo, and redissolved in EtOAc. The organic layer was washed with sat. aq. NaHCO3 followed by water and brine. The resulting organic layer was concentrated on to silica gel and chromatographed (10% to 40% EtOAc/hexanes) to give 6-bromo-5-fluoro-pyridin-2-ylamine (850 mg, 91%). 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 7.23 (dd, J=8.6, 7.5 Hz, 1H), 6.41 (dd, J=8.6, 2.6 Hz, 1H), 4.40 (br. s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([O:30]CC)=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+].C(O)(=O)C>O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][CH:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 51.3 %

Procedure:
A mixture of 7-[2-(2-aminothiazol-4-yl)-2ethoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.45 g) and sodium bicarbonate (0.63 g) in water (15 ml) was stirred at ambient temperature for 7 days. The reaction mixture was adjusted to pH 6.0 with acetic acid. The solution was subjected to column chromatography on macroporous nonionic adsorption resin "Diaion HP-20 " (30 ml) and eluted with water. The eluate was acidified to pH 2.2 with 10% hydrochloric acid under ice-cooling. The precipitates were collected by filtration and dried to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (0.7 g), which was identified by comparing the physico-chemical data with those of the object compound in Example 90.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH:20]([CH:25](Br)[CH3:26])[CH2:21][C:22]([OH:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:25]([CH3:26])[CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Br)C(Br)CC(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C=CC(=O)O)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 74.9 %

Procedure:
In a reactor, 30 g of tetrahydrofuran was charged and 12.7 g (0.05 mole) of 4-(4-trifluoromethylphenoxy)phenol, 14.3 g (0.055 mole) of 3,4-dibromopentanoic acid and 16.6 g of potassium carbonate were charged. They were refluxed for 6 hours to react them. After the reaction, tetrahydrofurane was distilled off from the reaction mixture and then 50 ml of chlorobenzene was added to the resulting mixture and then conc. hydrochloric acid was added to the resulting mixture with stirring to be acidic and then, the water phase was separated and the organic phase washed with water and then, chlorobenzene and low boiling by-products were distilled off at 100° C. under a reduced pressure (0.02-0.05 mmHg) to obtain 13.2 g of 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoic acid. (nD20 1.5284). The yield was 75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:15][C@@H:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:13][C@H:12]1[CH2:11][O:10][NH:9]2.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C.[Zn]>[NH2:9][C@@:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:15][C@@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:13][C@H:12]1[CH2:11][OH:10]
Reactant: Fc1ccc(CO[C@H]2C[C@H]3CON[C@@]3(c3ccccc3F)C2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N[C@@]1(c2ccccc2F)C[C@@H](OCc2ccc(F)c(F)c2)C[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 101 %

Procedure:
Zinc (3.0 g) was added to a solution of (3aR*,5S*,6aS*)-6a-(2-fluorophenyl)-5-(3,4-difluorobenzyloxy)-hexahydrocyclopenta[c]isoxazole (620 mg) in acetic acid (25 mL), and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and zinc was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain the title compound (630 mg).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:29][CH:30]([OH:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCC(O)Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a mixture of 15 ml of methylene chloride and 1.2 ml of pyridine was gradually added 2 g of chromic anhydride under cooling to 0° C. to -5° C. and after stirring the mixture for 10 minutes at 0° to -3° C., a solution of 0.9 g of 3,4-dibenzyloxyphenyl-2-undecanol in 3 ml of methylene chloride was added to the mixture. After further stirring the mixture for 20 minutes at 0° to 10° C., the supernatent methylene chloride solution was concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with toluene to provide 0.8 g of 1-(3,4-dibenzyloxyphenyl)-2-undecanone.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2=[CH:9][S:10][CH:11]=[C:4]2[S:3]1(=[O:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[N:24]=[C:25]=[O:26].C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[C:5](=[CH:9][S:10][CH:11]=2)[C:6]=1[C:25](=[O:26])[NH:24][C:16]1[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=1[CH3:14]
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=O
Reactant: CN1C(=O)Cc2cscc2S1(=O)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1=C(O)N(C)S(=O)(=O)c2cscc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1 g (4.6 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide are stirred at room temperature under nitrogen for 3 hours with 0.82 g (4.6 mmol) of 2-methyl-4-nitrophenylisocyanate and 0.47 g (4.6 mmol) of triethylamine in 10 ml of absolute dimethylsulfoxide. Thereafter, the mixture is poured into 40 ml of 2-N hydrochloric acid and 25 g of ice and stirred for 20 minutes. The separated precipitate is filtered off under suction and washed neutral with water. The precipitate is dissolved in 200 ml of methylene chloride, the turbid solution is dried over sodium sulfate, stirred with 0.3 g of active carbon and filtered. The filtrate is extracted with five 100 ml portions of saturated sodium carbonate solution, each of the aqueous phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with two 150 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate. The solvent is distilled off, whereby the product crystallizes out. For purification, the product is recrystallized from ca 50 ml of methanol. There is obtained 3-hydroxy-2-methyl-4-(2-methyl-4-nitrophenylcarbamoyl)-2H-thieno[3,4-e]-1,2-thiazine 1,1-dioxide of melting point 186°-188° C.