Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.[C:18](#[N:21])[CH:19]=[CH2:20]>CO.[Pd]>[NH2:21][CH2:18][CH2:19][CH2:20][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:2]1
Reactant: C=CC#N
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: NCCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
Uridine is reacted with mercuric chloride (5 mmol) at pH 5.0. 5-mercurichloride-dU so produced is reacted with acrylonitrile and lithium tetrachloro-palladiate in methanol yielding 5-(2-cyanoethyl) which is reduced by hydrogenation at 3 atmospheres in the presence of 10% palladium on charcoal in methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)(=O)C.[Na].C(=O)([O-])O.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(Br)cc1CN1CCOCC1
Reaction time: 0.5 h

Procedure:
5-Bromo-2-fluorobenzaldehyde (2.5 g, 12.3 mmol) and morpholine (1.62 g, 18.5 mmol) are dissolved in 50 mL DCE and stirred for 0.5 h. Acetic acid (0.42 mL, 7.4 mmol) and sodium trisacetoxyboronhydride (3.92 g, 18.5 mmol) are added and the reaction mixture is stirred for 2 h. Then 50 mL of a saturated aqueous solution of sodium hydrogencarbonate is added and the reaction mixture is stirred for another 0.5 h. The reaction mixture is extracted with DCM and the combined organic phases are dried over MgSO4 and concentrated in vacuo. Yield: 3.02 g.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:15]1[CH2:28][CH2:27][C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:20]=3[NH:19][C:18]=2[CH2:17][CH2:16]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3c(-c4ccccc4)cccc3c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCc3[nH]c4c(-c5ccccc5)cccc4c3CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
To a solution of lithium aluminum hydride (1.27 g, 33.5 mmol) in tetrahydrofuran (10.0 mL) was added a solution of 3-benzoyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.27 g, 3.46 mmol) in tetrahydrofuran (25.0 mL) at 0° C. The mixture was stirred at room temperature overnight. Water (1.3 mL), 15% sodium hydroxide solution (1.3 mL) and water (3.9 mL) were added sequentially and the mixture was stirred for 30 min. Celite was added and the mixture was filtered through Celite. The filtrate was concentrated in vacuo to give 1.12 g (92%) of the title compound: mp 78-79° C.; 1H NMR (400 MHz, CDCl3) δ 7.92, 7.62, 7.51-7.26, 7.19-7.11, 3.83, 3.00-2.90; 13C NMR(100 MHz, CDCl3) δ 139.5, 139.3, 136.5, 132.4, 129.4, 129.1, 128.9, 128.3, 128.2, 127.2, 127.0, 124.8, 121.0, 119.8, 117.0, 113.3, 60.7, 55.7, 53.8, 28.6, 24.0; IR (drift) 2933, 2913, 2907, 2885, 2813, 1458, 1367, 1345, 1336, 1325, 796, 760, 745, 730, 700 cm−1; MS (EI) m/z 352 (M+); Anal. Calcd for C25H24N2: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.00; H, 6.89; N, 7.93.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26]O)[CH:14]=3)[O:10][N:9]=2)[CH:7]=1.[CH2:30]([N:32](C(C)C)[CH:33](C)C)C.CS(Cl)(=O)=O.CNC>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][N:32]([CH3:33])[CH3:30])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CO)c2)n1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CN(C)C)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Example 77 (115 mg; 0.29 mmol; 1 eq.) in DCM (6 mL) is added at 0° C. N-ethyldiisopropylamine (250 μL; 1.47 mmol; 5 eq.) and methanesulfonyl chloride (27 μL; 0.35 mmol; 1.2 eq.). After 15 min, dimethylamine (2M; 440 μL; 0.88 mmol; 3 eq.) was added and the reaction mixture stirred at room temperature for 2 hours. Water (5 mL) was added and the organic layer washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by mass triggered preparative HPLC (increasing amount of ACN in water) to afford the title compound as a brown oil.
Reaction SMILES: [O:1]1CC1C1C=C2C(=CC=1)C1=NOC(C3C(C(F)(F)F)=C(C4C=CC=CC=4)ON=3)=C1CC2.[C:32]1([C:38]2[C:42]([C:43]([F:46])([F:45])[F:44])=[C:41]([C:47]3[S:48][C:49]4[C:59]5[C:54](=[CH:55][C:56]([CH:60]=[CH2:61])=[CH:57][CH:58]=5)[CH2:53][CH2:52][C:50]=4[N:51]=3)[O:40][N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[O:1]1[CH2:61][CH:60]1[C:56]1[CH:55]=[C:54]2[C:59](=[CH:58][CH:57]=1)[C:49]1[S:48][C:47]([C:41]3[O:40][N:39]=[C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:42]=3[C:43]([F:46])([F:44])[F:45])=[N:51][C:50]=1[CH2:52][CH2:53]2
Reactant: C=Cc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)sc1-2
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Product: FC(F)(F)c1c(-c2ccccc2)noc1-c1nc2c(s1)-c1ccc(C3CO3)cc1CC2

Procedure:
This compound was prepared according to the procedure described for Preparation 13A, employing 100 mgs of 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydronaphtho[2,1-d]thiazol-2-yl)isoxazole (82E). Yield: 100 mgs (96%)
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=Cc1cncc(Br)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cncc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
5-Bromo-4-chloro-pyridine-3-carbaldehyde (500 mg, 2.27 mmol) is dissolved in MeOH (20 mL) and sodium borohydride (257 mg, 6.80 mmol) is added. The mixture is stirred for 1 hr at room temperature and the solvent is removed in vacuo. Then saturated NH4Cl aqueous solution (20 mL), water (50 mL) and EtOAc (50 mL) are added and the mixture is stirred for 10 min. The aqueous layer is separated and extracted with EtOAc (2×50 mL). The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography affords 400 mg of (5-bromo-4-chloro-pyridin-3-yl)-methanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[C:8]2=[O:23])=[O:4].[OH-].[Na+]>CO>[O:23]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[CH2:10][N:9]1[CH2:14][CH2:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2

Procedure:
A methanol solution (50 ml) of 4-2 (2.6 g, 8.4 mmol) and 1 N NaOH (25.2 mL, 25.2 mmol) was stirred under ambient conditions for 18 h. The reaction was concentrated and the residue acidifed with 1 M NaHSO4 solution to provide 4-3 as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2.Cl.CN(C)CCCCl.Cl.C(N(C(C)C)CCCl)(C)C.[CH3:38][S:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=[CH2:45])=[CH:42][CH:41]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C.CS(C)=O>[CH3:38][S:39][C:40]1[CH:47]=[CH:46][C:43](/[CH:44]=[CH:45]/[C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[N:6]=[CH:5]3)=[CH:42][CH:41]=1
Reactant: CN(C)CCCn1ncc2cc(Br)ccc2c1=O
Reactant: C=Cc1ccc(SC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)N(CCCl)C(C)C
Solvent: CC#N
Solvent: CS(C)=O
Product: CSc1ccc(/C=C/c2ccc3c(=O)n(CCCN(C)C)ncc3c2)cc1

Procedure:
6-Bromo-2-[3-(dimethylamino)propyl]phthalazin-1(2H)-one (8.5 gm) (prepared as in Example I, except that 3-(dimethylamino)propyl chloride hydrochloride was substituted for the 2-(diisopropylamino)ethyl chloride hydrochloride) was stirred into 4 ml DMSO plus 4 ml acetonitrile. To the resulting mixture was added 3.7 gm 4-methylthiostyrene, 0.2 gm tri(O-tolyl)phosphine, and 0.04 gm palladium acetate. The reaction mixture was stirred at reflux (95°-100° C.) for 24 hours. The solution was concentrated to dryness on a rotovap and the residue recrystallized from 95% ethanol yielding 5.5 gm of product melting at 210° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4].[C:26]([Cu])#[N:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccccc3OC)cccc2c1O
Reactant: N#C[Cu]
Product: COC(=O)c1nc(C#N)c2c(Oc3ccccc3OC)cccc2c1O

Procedure:
The title compound was synthesized from 1-bromo-4-hydroxy-8-(2-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=351.4.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4](Cl)=[CH:3][CH:2]=1.[C:9](=O)([O:13]CC)[O:10][CH2:11][CH3:12]>S1(CCCC1)(=O)=O.CC1C(CN2CCC(N3CCC(N4C(=O)NC5C4=CC=CC=5)CC3)CC2)=CC=CC=1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([C:9]([O:10][CH2:11][CH3:12])=[O:13])=[CH:3][CH:2]=1
Reactant: CCOC(=O)OCC
Reactant: Cc1ccc(Cl)cc1
Agent: Cc1ccccc1CN1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Solvent: O=S1(=O)CCCC1
Product: CCOC(=O)c1ccc(C)cc1
Temperature: 170 °C
Reaction time: 44 h
Yield: 77.9 %

Procedure:
A mixture of 7.73 g of p-toluyl chloride, 5.91 g of diethyl carbonate, and 0.85 g of TBPB in 25 ml of sulfolane was heated at 170° C. under reflux. After 44 hours, the reaction mixture was added to 200 g of crushed ice and this was extracted twice with 25-ml portions of hexane. The combined extracts were dried over anhydrous Na2SO4 and distilled to obtain 6.4 g (78 percent yield) of ethyl p-toluate, b.p. 120°-1° C./20 mm.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41](=[O:43])[CH3:42])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:45])[C:23]([CH3:44])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41](=[O:43])[CH3:42])=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 16.9 %

Procedure:
Piperidine (0.027 g, 0.321 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.062 g, 0.321 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.040 g, 0.107 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.008 g, 0.0181 mmol, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:12]O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12][Br:33])[CH:3]=1
Reactant: OCc1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.3 mmol) and triphenylphosphine (3.3 g, 12.6 mmol) were combined in tetrahydrofuran (30 mL) and cooled to 0° C. N-Bromosuccinimide (2.4 g, 13.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (100% hexanes) gave 1.53 g (76%) as a light brown oil. 1H-NMR (CDCl3, 500 MHz) δ 7.73 (s, 1H), 7.70 (s, 1H), 7.58 (s, 1H), 4.44 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([N:17]([CH3:19])[CH3:18])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:3].[C:20]([OH:25])(=[O:24])[C:21]([OH:23])=[O:22]>CO>[CH3:3][CH:2]([CH2:4][CH:5]([N:17]([CH3:18])[CH3:19])[C:6]1([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1)[CH3:1].[C:20]([O-:25])(=[O:24])[C:21]([O-:23])=[O:22]
Reactant: O=C(O)C(=O)O
Agent: CC(C)CC(N(C)C)C1(c2ccc(Cl)cc2)CCC1
Solvent: CO
Product: O=C([O-])C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
15 g of sibutramine was dissolved in 60 ml of methanol. Oxalic acid (5.07 g) dissolved in 20 ml methanol was slowly added in droplets to the sibutramine solution at room temperature and agitated for 2 hrs. The resulting solution was cooled to 0° C., agitated for about 2 hrs, and filtered to collect deposited crystals. The crystals were washed with 50 ml of isopropyl ether and vacuum-dried at 50° C., thus obtaining 18 g (yield: 89.7%) of a white target compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=O)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.C(=O)(O)[O-].[Na+].C([O-])(=O)C.[Na+].Cl.[O:36]([NH2:38])[CH3:37]>O>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:38][O:36][CH3:37])[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CON
Reactant: Nc1nc(C(=O)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 6.9 %

Procedure:
A solution of 7-[2-(2-amino-4-thiazolyl)glyoxyloylamino]-3-cephem-4-carboxylic acid hydrochloride (1.78 g) in water (100 ml) was adjusted to pH 6.0 with sodium bicarbonate under ice-cooling with stirring. Sodium acetate (0.38 g) and methoxylamine hydrochloride (1.37 g) were added to the solution adjusted to pH 7.0 with sodium bicarbonate and then stirred at 48° C. for an hour. The resultant solution was washed with ethyl acetate (200 ml) and diethyl ether (100 ml) in turn, and then nitrogen gas was bubbled into the solution to remove diethyl ether. The aqueous solution was adjusted to pH 3.5 with 10% hydrochloric acid under ice-cooling with stirring. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 120 mg). The mother liquor was subjected to column chromatography on macroporous, nonionic adsorption resin "Diaion HP-20" (Trademark: manufactured by Mitsubishi Chemical Industries Ltd.) and eluted with 40% aqueous acetone. The eluate was concentrated under reduced pressure, lyophilized, and then dried over phosphorus pentoxide to give the same object compound (950 mg). Total yield 1070 mg.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[S:12][C:13]([CH2:16]O)=[CH:14][N:15]=1.N1C=CC=CC=1>O1CCCC1>[Cl:10][C:11]1[S:12][C:13]([CH2:16][O:5][S:6]([CH3:9])(=[O:7])=[O:8])=[CH:14][N:15]=1
Reactant: OCc1cnc(Cl)s1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.28 g of methanesulfonic anhydride are added to 1.0 g of 2-chloro-5-hydroxymethyl-thiazole and 0.63 g of pyridine in 10 ml of tetrahydrofuran and the mixture is stirred for three hours at room temperature. Concentration of the solution yields the title compound in the form of a solid (compound 1.3). 1H-NMR (DMSO-d6, 250 MHz): s, 1H, 7.87 ppm; s, 2H, 5.52 ppm; s, 3H, 2.43 ppm.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:20]/[N:21]=[C:22]1\[NH:23][CH:24]=[CH:25][C:26]([I:28])=[CH:27]\1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([I:28])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(/C=N/N=c3/cc(I)cc[nH]3)nc12
Solvent: C1CCOC1
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(-c3nnc4cc(I)ccn34)nc12
Reaction time: 0.08 h

Procedure:
8-(tert-butyldimethylsilyloxy)-2-((E)-((Z)-(4-iodopyridin-2(1H)-ylidene)hydrazono)methyl)quinoline was weighed into a 1 neck flask and dissolved in THF. Iodobenzene diacetate (IBD) (4.199 g) was added portionwise, and the reaction was stirred for 5 minutes. The reaction was quenched with saturated Na2S2O3 (20 mL). The phases were separated, followed by extraction of the aqueous phase with DCM. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting with a 2:1 mixture of Hexanes/ethyl acetate), affording the desired product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P(Cl)(Cl)(Cl)=O>>[C:15]1([O:13][C:12]([C:3]2[C:2]([OH:1])=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cc2ccccc2cc1O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Oc1ccccc1)c1cc2ccccc2cc1O
Temperature: 100 °C
Yield: 37.6 %

Procedure:
A mixture of 50 g (0.266 mole) 3-hydroxy-2-naphthoic acid, 27.3 g (0.29 mole) phenol, and 21.4 g (0.14 mole) phosphorus oxychloride was stirred and heated at 100° C. for 3.5 hrs. Then 200 ml alcohol was added, and the mixture was heated one hour longer and cooled. The yellow product was collected and recrystallized from benzene to give 26.4 g (38%) of phenyl-3-hydroxy-2-naphthoate, m.p. 126°-130° C.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16](=[O:22])[CH2:15]2)=O.FC(F)(F)C(O)=O>>[Cl:8][CH2:9][CH2:10][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[Cl:21])[NH:17][C:16](=[O:22])[CH2:15]2
Reactant: O=C1Cc2cc(C(=O)CCl)c(Cl)cc2N1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(CCCl)c(Cl)cc2N1
Temperature: 42.5 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
Triethylsilane (57.2 gm) was added slowly to the reaction mixture of 5-(2-Chloro acetyl)-6-chloro oxindole (50.0 gm) and trifluoroacetic acid (175 mL) below the temperature of 45° C. The reaction was maintained at 40-45° C. for 6 hours. The reaction mass was cooled to 0° C. to −5° C. and maintained stirring for 90 minutes. The separated solid was filtered and washed with water (50 mL). Then the wet compound was further slurred in water (250 mL) for 90 minutes. The resultant solid was filtered, washed with water (50 mL) and dried at a temperature of 70-75° C. to afford 5-(2-chloroethyl)-6-chloro oxindole (43.5 gm).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1.[OH:24][CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:26](O)=[O:27]>>[OH:24][CH:25]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:26]([N:1]1[CH2:6][CH2:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]3=[O:23])=[CH:9][CH:8]=2)=[CH:3][CH2:2]1)=[O:27]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: CCCCCCCCC(O)C(=O)O
Product: CCCCCCCCC(O)C(=O)N1CC=C(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)CC1

Procedure:
Using an analogous procedure to that described in Example 20, the TFA salt of Example 2 was reacted with 2-hydroxydecanoic acid in place of N-acetylglycine, to give the title compound. Yield=252 mg, 65%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1.[H-].[Na+].Cl[C:21]1[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([O:16][C:21]4[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:33])[CH3:31])[C:24]5[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=5[N:22]=4)=[CH:12][CH:11]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:17]=1
Reactant: Cc1cn2cccc(-c3ccc(O)cc3)c2n1
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn2cccc(-c3ccc(Oc4nc5ccccc5n4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
To a solution of 4-(2-methylimidazo[1,2-a]pyridin-8-yl)phenol (0.40 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.086 g), and the mixture was stirred at room temperature for 5 min. To the reaction mixture was added 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.50 g), and the mixture was stirred under microwave irradiation at 150° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.57 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10](O)=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1.C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.CCN(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:29]=[N+:30]=[N-:31])=[O:11])=[C:4]([O:13][CH3:14])[CH:3]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cc(F)ccc1/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1cc(F)ccc1/C=C/C(=O)N=[N+]=[N-]
Reaction time: 16 h
Yield: 76.5 %

Procedure:
(E)-3-(4-fluoro-2-methoxyphenyl)acrylic acid (1.22 g, 6.22 mmol), diphenylphosphinyl azide (1.273 mL, 5.91 mmol), and Et3N (1.734 mL, 12.44 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give (E)-3-(4-fluoro-2-methoxyphenyl)acryloyl azide (1.0 g, 73% yield).