Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][N:12]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13]1.C1(C2C3C(=CC=CC=3)C(C3C4C(=CC=CC=4)C=CC=3)=C(P)C=2C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][N:12]([CH3:11])[N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1ccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: Pc1c(-c2ccccc2)c(-c2ccccc2)c2ccccc2c1-c1cccc2ccccc12
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 130 °C
Yield: 54.4 %

Procedure:
3,5-Dibromo-1-methyl-1H-pyridin-2-one (469 mg, 1.76 mmol), 1-Methyl-1H-pyrazol-3-ylamine (205 mg, 2.11 mmol), tris(dibenzylidineacetone)dipalladium(0) (80 mg, 0.087 mmol), 2,2′-bis(diphenyl phosphino-1,1′-binaphthalene (82 mg, 0.13 mmol), and cesium carbonate (801 mg, 2.46 mmol) were deposited in a sealed vial with 10 mL toluene. This was heated at 130° C. for 18 hours. The resulting mixture was poured into 50 mL water. This was extracted with ethylacetate. The ethylacetate layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (eluted with ethylacete/hexanes) to yield 5-Bromo-1-methyl-3-(1-methyl-1H-pyrazol-3-ylamino)-1H-pyridin-2-one (271 mg, 0.957 mmol). MS (EST) 284.9 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](O)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH:18]=[O:19])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CO
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Yield: 65.6 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (7.36 g: 30 mmole) in tetrahydrofuran (30 ml), formic acid (1.36 ml: 36 mmole), triphenylphosphine (9.44 g: 36 mmole) and diethyl azodicarboxylate (5.67 ml: 36 mmole) are successively added in a nitrogen atmosphere under ice cooling. The mixture is stirred to react for 40 minutes at the same temperature to give (2S,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (5.38 g). Yield: 66%. Colorless crystals. NMR δ(CDCl3) ppm: 1.45(d, J=8.6 Hz, 9H), 2.2 to 2.4(m, 1H), 2.4 to 2.7(m, 1H), 3.5 to 3.9(m, 2H), 3.75(s, 3H), 4.3 to 4.6(m, 1H), 5.3 to 5.5(m, 1H), 7.98 (s, 1H). IR ν (KBr) cm-1 : 3420, 1748, 1712, 1681.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[C:28]([CH:30]([OH:33])[C:31]#[N:32])[CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:33][CH:30]([C:31]#[N:32])[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([O:23][C:20]3[CH:19]=[CH:18][CH:17]=[CH:22][CH:21]=3)[CH:29]=2)=[O:12])=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: N#CC(O)c1cccc(Oc2ccccc2)c1
Reactant: CC(C)C(C(=O)Cl)c1ccc(N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(N=[N+]=[N-])cc1

Procedure:
2-(4-Azidophenyl)-3-methylbutanoyl chloride, prepared in Example 7, was dissolved in 10 ml of methylene chloride. A solution of 3.79 g of m-phenoxybenzaldehyde cyanohydrin in 10 ml of methylene chloride was added, with cooling by an ice bath, followed by 2.4 ml of triethylamine, causing an exothermic reaction and precipitating white solid. After an hour without cooling, the mixture was evaporated to a residue, which was extracted with diethyl ether, the extract filtered, and the filtrate washed with water and saturated sodium bicarbonate solution, dried (MgSO4), and evaporated to 7.4 g of residual oil, 2-(4-azidophenyl)-3-methylbutanoic acid, α-cyano-3-phenoxybenzyl ester. The infrared spectrum shows absorption peaks at 2130 cm-1 (azide) and 1760 cm-1 (ester carbonyl). Mass spectral analysis showed a molecular ion, m/e 426, corresponding to the product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:12])[CH:5]=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](F)=O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[FH:13].[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]2[NH:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]4[C:11]=3[C:10]([N:12]=2)=[CH:9][CH:8]=[CH:7]4)=[CH:23][CH:24]=1
Reactant: Nc1cccc2cccc(N)c12
Reactant: O=C(F)c1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: F
Product: FC(F)(F)Oc1ccc(C2=Nc3cccc4cccc(c34)N2)cc1
Reaction time: 4 h

Procedure:
1,8-Diaminonaphthalene (1.52 grams; 0.0096 mole) was dissolved in 25 ml. of toluene, then decanted. p-Trifluoromethoxybenzoyl fluoride (2.0 grams; 0.0096 mole) was dissolved in 25 ml. of toluene. Both solutions were added simultaneously to 25 ml. of toluene. After the reaction mixture had been stirred for approximately 4 hours, TLC indicated that the reaction was complete.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(#N)C.C(O)(C)C.[Pt]>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: [Pt]
Solvent: CC(C)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2cc(Br)ccc12
Yield: 91.1 %

Procedure:
A solution of tert-butyl [2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]carbamate (165.0 g, 401.2 mmol) in acetonitrile (3.3 L) and isopropanol (990 mL) and 5% platinum on carbon (13.2 g) were added to a Parr vessel, which was placed under hydrogen pressure (50 psi, 3.4×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure to provide 139.29 g of tert-butyl [2-(3-amino-7-bromoquinolin-4-ylamino)ethyl]carbamate as a yellow solid. The product was suspended in a mixture of dichloromethane (4 mL/g) and chloroform (8 mL/g), and the suspension was divided into two equal portions.
Reaction SMILES: [I:1][CH3:2].[N+:3]([C:6]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-:5])=[O:4]>CC(C)=O>[I-:1].[C:11]([O:10][C:8]([C:7]1[CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][N+:22]([CH3:2])=[CH:21][CH:20]=2)=[CH:18][C:6]=1[N+:3]([O-:5])=[O:4])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1ccc(-c2ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1
Product: [I-]
Temperature: 60 °C

Procedure:
7.55 mL of iodomethane (121 mmol) is added to a solution of 16.2 g of tert-butyl 2-nitro-4-(pyridin-4-yl)benzoate (60.6 mmol) in 20 mL of acetone. The reaction medium is heated at 60° C. for 4 hours and then at room temperature overnight. After dry concentration, 27 g of orange crystals are isolated (100%).
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[O:13]1C=CC=[C:14]1[C:18]#[N:19].P([O-])(O)(O)=[O:21].[K+]>CCCCCC.O1CCCC1>[CH:8]([C:9]1[O:13][C:14]([C:18]#[N:19])=[CH:11][CH:10]=1)=[O:21]
Reactant: N#Cc1ccco1
Reactant: O=P([O-])(O)O
Reactant: [Li]CCCC
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: N#Cc1ccc(C=O)o1
Reaction time: 1 h

Procedure:
75 ml of tetrahydrofuran and 22.6 ml of diisopropylamine were cooled to -60° C. and 100 ml of 1.6M n-butyllithium in hexane were added over 25 minutes. The mixture was stirred for 1 hour and 13.02 g of 2-furancarbonitrile in 50 ml of tetrahydrofuran were added. The mixture was stirred for 40 minutes at -70° C. and 13 ml of N-dimethylformamide in 25 ml of tetrahydrofuran were added. The mixture was stirred for 2 hours at -70° C. and then poured into an aqueous potassium dihydrogen phosphate solution and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain after chromatography on silica (eluent: 7/3 hexane/ethyl acetate) 3.51 g of the expected product.
Reaction SMILES: CN([C:4]([O:8][N:9]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]2[N:47]=[C:46]([S:48][CH3:49])[N:45]=[C:44]([C:50]([OH:52])=O)[CH:43]=2)[CH2:38][CH2:37]1)=[O:34].Cl.O(N)C>CN(C=O)C.CCOC(C)=O.O>[Cl:25][C:26]1[C:30]([Cl:31])=[C:29]([CH3:32])[NH:28][C:27]=1[C:33]([NH:35][CH:36]1[CH2:37][CH2:38][N:39]([C:42]2[N:47]=[C:46]([S:48][CH3:49])[N:45]=[C:44]([C:50]([NH:9][O:8][CH3:4])=[O:52])[CH:43]=2)[CH2:40][CH2:41]1)=[O:34]
Reactant: CSc1nc(C(=O)O)cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(SC)n1
Yield: 81.2 %

Procedure:
HATU (197 mg, 0.52 mmol) was added to a solution of TEA (0.14 ml, 1.0 mmol), 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(methylthio)pyrimidine-4-carboxylic acid (Example 7, 230 mg, 0.52 mmol) and methoxylamine hydrochloride (43 mg, 0.52 mmol) in DMF (3 ml) under nitrogen. The resultant mixture was stirred overnight at room temperature, then diluted with EtOAc (50 ml) and water (10 ml) and the organic phase was separated. The organic phase was washed with 1 N HCl (5 ml), saturated NaHCO3 solution (5 ml) and brine (5 ml). The aqueous layers were back extracted with EtOAc (25 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum to give 400 mg of crude product. which was purified by preparative reversed-phase HPLC (water/acetonitrile gradient, 20-95%) to give 200 mg of the title compound.
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](/[CH:14]=[CH:15]/[C:16]3[CH:17]=[C:18]([C@H:22]([S:35][CH2:36][C:37]4(CC#N)[CH2:39][CH2:38]4)[CH2:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([OH:34])([CH3:33])[CH3:32])[CH:19]=[CH:20][CH:21]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH2:43]([OH:45])[CH3:44]>>[CH3:32][C:31]([OH:34])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][C@@H:22]([S:35][CH2:36][C:37]1([CH2:44][C:43]([OH:1])=[O:45])[CH2:39][CH2:38]1)[C:18]1[CH:19]=[CH:20][CH:21]=[C:16](/[CH:15]=[CH:14]/[C:10]2[CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([Cl:3])=[CH:13][C:12]=3[N:11]=2)[CH:17]=1)[CH3:33]
Reactant: CCO
Reactant: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC#N)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 60 °C

Procedure:
143.6 g of sodium hydroxide were added to a solution of 102 g of (R,E)-2-(1-((1-(3-(2-(7-chloroquinolin-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2-yl)phenyl)propylthio)methyl)cyclopropyl)acetonitrile in 407 ml of ethanol 96% (v/v). The mixture was stirred at reflux temperature for 30 hours. After this period of time, the solvent was distilled off under vacuum (Purity by HPLC: 61.5 area %; impurity i2: 1.84 area %; impurity i5: 3.70 area %; impurity i6: 1.42 area %). The mixture was partitioned with 1000 ml of toluene and 1500 ml of water at room temperature. The aqueous phase with the inorganic salts dissolved, was discarded. The organic phase was mixed with 1500 ml of water and the mixture was heated to 60° C. and stirred for 15 minutes. At this point the product was dissolved in the aqueous layer. The pH of the aqueous layer was 12.5. Some impurities from the process were dissolved in the organic layer. Therefore, the organic layer was discarded. The toluene wash at 60° C. was repeated. The outcome aqueous layer was cooled down to room temperature and 1000 ml of toluene were added. Then, the pH of the mixture was adjusted to 5.6 with a 2M solution of acetic acid. The mixture was stirred for 30 minutes and the aqueous layer was discarded. Finally, the organic layer was washed with 1000 ml of water and kept as a solution of purified Montelukast acid (Purity by HPLC: 84.4 area %; impurity i2: 0.81 area %; impurity i5: 0.70 area %; impurity i6: 0.007 area %). Yield corrected by HPLC of the title compound from the outcome solution: 86%.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1)#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:7]1([CH3:15])[CH2:8][CH2:9][C:10](=[O:13])[C:11]2[CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=[CH:5][C:6]1=2
Reactant: C#Cc1ccc2c(c1)C(=O)CCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4 g (21.7 mmol) of 7-ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound E ) flushed for 15 minutes with a stream of argon, and 6 g (21.7 mmol) of ethyl 4-iodobenzoate in 100 ml of triethylamine was added 5 g (7.2 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.4 g (7.2 mmol) of cuprous iodide. The mixture was flushed with argon for 5 minutes and then stirred at ambient temperature for 18 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. Purification by flash chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid. PMR (CDCl3) : δ1.41 (3H, t, J=7.2 Hz), 1.41 (6H, s), 2.04 (2H, t, J=6.5 Hz), 2.76 (2H, t, J=6.5 Hz), 4.40 (2H, q, J=7.2 Hz), 7.44 (1H, d, J=8.2 Hz), 7.59 (2H, d, J=8.4 Hz), 7.68 (1H, dd, J=1.8, 8.2 Hz), 8.04 (2H, d, J=8.4 Hz), 8.15 (1H, d, J=1.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20](O)[CH:19]=2)=[CH:8][N:7]=1.P(Cl)(Cl)([Cl:32])=O.Cl.N>C(#N)C.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[CH2:28][CH3:29])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:32])[CH:19]=2)=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(Nc2ncc(CCc3ccnc(O)c3)c3ccccc23)cc1Br
Agent: Cl
Agent: N
Solvent: CC#N
Solvent: C1COCCO1
Product: CCc1ccc(Nc2ncc(CCc3ccnc(Cl)c3)c3ccccc23)cc1Br
Temperature: 65 °C
Reaction time: 48 h

Procedure:
Under a N2 atmosphere, 150 mg (0.334 mmol) of 1-(3-bromo-4-ethyl-anilino)-4-[2-(2-hydroxy-pyridin-4-yl)-ethyl]-isoquinoline (Ex. 32a) in 5 ml of acetonitrile are mixed with 76 μl (0.83 mmol) of phosphorus oxychloride and 0.17 ml (0.68 mmol) of 4 N HCl in dioxane, and stirred at 65° C. A further 76 μl of phosphorus oxychloride is added after 12 h, and stirring continues for 48 h at 65° C. The mixture is cooled to RT, 4 ml of 10% NH3 solution added, and it is partitioned between 3 portions of EtOAc, 2 portions of water and brine. Drying (Na2SO4), concentrating by evaporation and chromatography on silica gel (acetone/methylene chloride 3:2) yield 1-(3-bromo-4-ethyl-anilino)-4-[2-(2-chloro-pyridin-4-yl)ethyl]-isoquinoline; FAB-MS: (M+H)+=466/468; HPLC(gradient20-100) tRef=13.4.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[NH2:16][C:17]1[S:18][C:19]([Cl:48])=[C:20]([C:22](=[N:38][O:39][CH2:40][C:41]([O:43]C(C)(C)C)=[O:42])[C:23]([NH:25][CH:26]2[C:36](=[O:37])[N:28]3[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1>CCOCC>[NH2:16][C:17]1[S:18][C:19]([Cl:48])=[C:20]([C:22](=[N:38][O:39][CH2:40][C:41]([OH:43])=[O:42])[C:23]([NH:25][CH:26]2[C:36](=[O:37])[N:28]3[C:29]([C:33]([OH:35])=[O:34])=[CH:30][CH2:31][S:32][C@H:27]23)=[O:24])[N:21]=1
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nc(N)sc1Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Nc1nc(C(=NOCC(=O)O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c(Cl)s1
Yield: 79.2 %

Procedure:
To a mixture of anisole (2 ml) and trifluoroacetic acid (6 ml) was added 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.7 g) at 20° to 25° C. with stirring. The reaction mixture was stirred for an hour at the same temperature. The resultant solution was poured into a mixed solvent of dissopropyl ether (300 ml) and petroleum ether (100 ml). The precipitates were collected by filtration, washed with petroleum ether, and were dissolved in an aqueous solution of sodium bicarbonate at pH 7.5. The aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with a diluted hydrochloric acid, and extracted with a mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After removing the solvent in vacuo, diisopropyl ether was added to the residue. The insoluble precipitates were collected by filtration to give 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer)(1.2 g), mp 165° to 167° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.BrC1C(C2C=CN=CC=2)=C(C2C=CC(F)=CC=2)NN=1.[CH2:46]1[C@@H:54]2[N:49]([CH2:50][CH2:51][C:52](=O)[CH2:53]2)[CH2:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:52]3[CH2:53][C@H:54]4[N:49]([CH2:48][CH2:47][CH2:46]4)[CH2:50][CH:51]=3)[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCN2CCC[C@H]2C1
Reactant: C[Si](C)(C)CCOCn1ncc(-c2ccncc2)c1-c1ccc(Cl)cc1
Agent: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Product: Clc1ccc(-c2[nH]nc(C3=CCN4CCC[C@H]4C3)c2-c2ccncc2)cc1
Yield: 4 %

Procedure:
Following a procedure similar to that described in Example 2-2), but using 5-(4-chlorophenyl)-4-(pyridin-4-yl)-1-(2-trimethylsilylethoxy)methylpyrazole prepared as described in 1) instead of 3-bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole, and using (S)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one instead of (±)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one, the resulting product was subjected to a dehydration reaction as described in Example 3 and then treated by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=10:1:1), to give the title compound (Rf=0.50, 357 mg) as a pale brown powder (yield 4%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=O)=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:19][OH:20]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[N:19][OH:20])=[C:10]([O:16][CH3:17])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2ccc(O)cc2)ccc1C=O
Reactant: NO
Agent: Cl
Product: COc1cc(-c2ccc(O)cc2)ccc1C=NO

Procedure:
The title compound was prepared by reacting 4′-hydroxy-3-methoxy-1,1′-biphenyl-4-carbaldehyde (225 mg, 0.986 mmol) with hydroxylamine hydrochloride (137 mg, 1.97 mmol) according to Method C to yield 210 mg (88%) of yellowish solid: mp 228-230° C.; 1H NMR (DMSO-d6): δ 3.91 (3H, s), 6.85 (2H, d, J=8.29 Hz), 7.18 (1H, d, J=8.08 Hz), 7.21 (1H, s), 7.56 (2H, d, J=8.59 Hz), 7.68 (1H, d, J=7.98 Hz), 8.28 (1H, s), 9.63 (1H, s), 11.19 (1H, s); MS (ESI) m/z 242 (M−H)−, 244 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34]3[NH:38][N:37]=[N:36][N:35]=3)=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(-c3nnn[nH]3)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(-c3nnn[nH]3)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-(1H-tetrazol-5-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:18][C:19]([O-:21])=[O:20])C=CC=CC=1.[CH3:34]O>>[Cl:1][C:2]1[C:3]([CH3:10])=[C:4](/[CH:5]=[CH:18]/[C:19]([O:21][CH3:34])=[O:20])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c(Cl)cccc1C=O
Reactant: CO
Product: COC(=O)/C=C/c1cccc(Cl)c1C
Yield: 24 %

Procedure:
A mixture of (2-methoxy-2-oxoethyl)triphenylphosphonium bromide (10.0 g, 24.08 mmol) in 100 mL DCM, 50 mL water and NaOH (10 N) (4.82 ml, 48.2 mmol) was vigorously shaken in a separatory funnel. The organic layer was separated and the aqueous phase was extracted with DCM. The combined organic layers were dried (MgSO4) and concentrated to give methyl 2-(triphenylphosphoranylidene)acetate (7.5 g, 93% yield) as a white solid. A solution of 3-chloro-2-methylbenzaldehyde (0.7 g, 4.53 mmol) and 2-(triphenylphosphoranylidene)acetate (1.817 g, 5.43 mmol) in MeOH (22.6 ml) was stirred at room temperature for 2 h. The mixture was concentrated and purified by flash chromatography (0-30% ethyl acetate:hexanes) to afford the title compound (0.23 g, 24% yield) as a clear colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=15.9 Hz, 1H), 7.47-7.40 (m, 2H), 7.17-7.15 (m, 1H), 6.33 (d, J=15.9 Hz, 1H), 3.83 (s, 3H), 2.48 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:8][CH2:9][CH3:10])[CH3:7].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([N:24]([C:25]2[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH2:2][C:3]([N:8]([CH2:9][CH3:10])[CH2:6][CH3:7])=[O:4])(=[O:22])=[O:23])=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Reactant: O=C(Br)CBr
Reactant: CCNCC
Product: CCN(CC)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with diethylamine and 4-tert-butyl-N-(6-methoxy-pyridin-3-yl)-benzenesulfonamide
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[CH2:8]([OH:10])[CH3:9].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:10][CH2:8][CH3:9]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)OC(C)Cl
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
To a solution of 1-chloroethyl chloroformate (23.16 g, 0.162 mol) and ethanol (7.45 g, 0.162 mol) in methylene chloride (200 ml), pyridine (12.82 g, 0.162 mol) was added at 0° C. After 10 min at 0° C. and 21 hours at 25° C. the reaction mixture was washed with aqueous hydrochloric acid (100 ml), aqueous saturated sodium hydrogen carbonate (100 ml) and water (100 ml). The solvent was removed under reduced pressure after drying (MgSO4), giving 18.5 g (74%) of the intermediate ethyl chloroethyl carbonate as a crude product.