Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.N1C=CC=CC=1.[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: O=C(O)C1(O)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-hydroxy-cyclopropanecarboxylic acid (100 mg, 0.98 mmol) and pyridine (100 μL) in 3 mL of DCM is cooled to 0° C. A solution of acetyl chloride (80 μL, 1.18 mmol) in 3 mL of DCM is then added dropwise to the ice cold mixture. After the addition, the resulting mixture is stirred at room temperature for 3 h. Next, the mixture is washed with saturated NH4Cl. The aqueous phase is extracted twice with DCM. The combined organic phases are combined, dried over MgSO4, filtered, and evaporated to afford the desired product that is used as such.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:24]=[C:21]([CH:22]=[O:23])[C:20]([OH:25])=[CH:19][CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:21]([CH:24]=1)[CH:22]=[O:23]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(Cl)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-chloro-salicylaldehyde (360 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. for overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 5-chloro-2-[(6,7-dimethoxy-4-quinolyl)oxy]benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16](SC)[N:15]=[C:14]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=2)[CH:13]=1.ClC1C=C(C=CC=1)[C:31](OO)=[O:32].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:32][CH3:31])[N:15]=[C:14]([C:20]2[CH:21]=[CH:22][C:23](=[O:26])[NH:24][CH:25]=2)[CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2ccc(=O)[nH]c2)n1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
To a mixture of above 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methylsulfanyl-pyrimidin-4-yl}-1H-pyridin-2-one [1 g, 2.56 mmol, Example 31] in a mixture of MeOH (30 mL) and DCM (20 mL), is added 3-chloro-peroxybenzoic acid (70%, 1.32 g, 7.68 mmol) at room temperature. After 3 hours at 20° C., a 25% solution of sodium methoxide in MeOH (12 mL) is added at 0° C. After additional 1 hour, the mixture is concentrated, diluted with water, and neutralized with 3 M hydrochloric acid (pH 7). The resulting solid is filtered, and re-dissolved in a basic solution (pH 12). After acidifying into pH 3, the precipitate is filtered, and dried to give 5-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-1H-pyridin-2-one [0.92 g, 96%, Example 32] as a solid. LCMS: RT=2.23 minutes, MS: 375 (M+H).
Reaction SMILES: ClCCl.[C:4]([C:8]1[CH:9]=[C:10]([NH:21][C:22]([NH:24][C@@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:28]([O:35][C:36]3[CH:37]=[CH:38][C:39]4[N:40]([C:42]([N:45]5[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]5[CH3:51])=[N:43][N:44]=4)[CH:41]=3)[CH2:27][CH2:26]2)=[O:23])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=2)[N:12]=1)([CH3:7])([CH3:6])[CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[C:4]([C:8]1[CH:9]=[C:10]([NH:21][C:22]([NH:24][C@@H:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:28]([O:35][C:36]3[CH:37]=[CH:38][C:39]4[N:40]([C:42]([N:45]5[CH2:50][CH2:49][CH2:48][CH2:47][C@@H:46]5[CH3:51])=[N:43][N:44]=4)[CH:41]=3)[CH2:27][CH2:26]2)=[O:23])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)[N:12]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(CO)cc4)c4ccccc43)cn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: ClCCl
Solvent: O
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C=O)cc4)c4ccccc43)cn12
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of Intermediate 176a (1.10 g, 1.70 mmol) in DCM (25 mL) at 0° C. was added Dess-Martin periodinane (791 mg, 1.86 mmol) and the resulting red-brown solution stirred at 0° C. for 45 min. Sodium metabisulfite (920 mg), water (10 mL) and sat. aq. NaHCO3 solution (10 mL) were added and the mixture stirred at RT until gas evolution ceased (15 min). The mixture was diluted with water (25 mL) and extracted with DCM (2×25 mL). The combined organics were passed through a hydrophobic fit and concentrated in vacuo to leave the title compound as a glassy orange solid (1.10 g, 100%). LCMS (Method 3): Rt 3.91 min, m/z 647 [MH+].
Reaction SMILES: C(O[CH:4]([O:12]CC)[C@H:5]([O:10][CH3:11])[CH2:6][N:7]=[N+:8]=[N-:9])C.C(OC(OCC)[C@H](O)CN=[N+]=[N-])C.[CH2:28]([OH:37])[C:29]([CH2:31][O:32]P(O)(O)=O)=[O:30].[OH-].[Na+].C(OP(O)(O)=O)[C@H]1O[C@@](O)(COP(O)(O)=O)[C@@H](O)[C@@H]1O.Cl>O>[N:7]([CH2:6][C@H:5]([O:10][CH3:11])[C@H:4]([OH:12])[C@H:28]([OH:37])[C:29](=[O:30])[CH2:31][OH:32])=[N+:8]=[N-:9]
Reactant: CCOC(OCC)[C@@H](CN=[N+]=[N-])OC
Reactant: O=C(CO)COP(=O)(O)O
Agent: CCOC(OCC)[C@H](O)CN=[N+]=[N-]
Agent: Cl
Agent: O=P(O)(O)OC[C@H]1O[C@@](O)(COP(=O)(O)O)[C@@H](O)[C@@H]1O
Solvent: O
Product: CO[C@@H](CN=[N+]=[N-])[C@H](O)[C@H](O)C(=O)CO
Temperature: 50 °C
Yield: 91.2 %

Procedure:
A solution of 3-azido-2(R)-methoxy-propanal diethyl acetal 24 (934 mg, 4.6 mmol) prepared by methylation of 3-azido-2(R)-hydroxy-propanal diethyl acetal obtained enzymatically; von der Osten, C. H.; Barbas, C. F.; Wong, C. H.; Pederson, R. L.; Sinskey, A. J.; Wang, Y. F. J. Am. Chem. Soc. 1989, 111, 3924) was dissolved in water (5 mL) and Dowex 50W-X8 (H+ form, 200-400 mesh) was added until pH <2. The mixture was heated at 50° C. for 8 hours, then the resin was filtered off and washed with a minimum amount of water. A solution of DHAP (262 mM, 7.6 mL, 2 mmol) was added and the mixture was adjusted to pH 6.5 with 6N NaOH. Fructose-1,6-diphosphate aldolase was added (1.4 mL, 500 units; see general section—supra) and the mixture was stirred at room temperature. After 4 h the pH was adjusted to 4.7 with HCl. Acid phosphatase (500 μL, 400 units—see general materials section, supra) was added and the mixture heated at 37° C. The enzyme was precipitated by adding acetone and these residue evaporated and chromatographed on SiO2 (CH2Cl2:MeOH 6:1), to give 400 mg (40%) of (35,4R,5S)-6-azido-5-methoxy-1,3,4-trihydroxyhexan-2-one 26: 1H-NMR (D2O, δ, ppm) 4.48 and 4.35 (1H each, J=19.8 Hz, H1 and H1′); 4.38 (1H, d, J=3 Hz, H3); 3.85 (1H, dd, J=9.2 Hz, 1.9 Hz, H4), 3.7 (1H, dd, J=13.6 Hz, 2.8 Hz, H6); 3.45, (1H, ddd, J=9.2 Hz, 2.8 Hz, 3.7 Hz, H5); 3.33 (3H, s, Me); 3.30 (1H, dd, 13.5 Hz, 3.7 Hz, H6′). 13C-NMR (D2O, δ, ppm): 213.22, 78.55, 74.85, 70.26, 65.98, 57.36, 48.97.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:15][CH3:16])[CH:12]=2)[CH2:7][NH:6]1)=[O:4]>C1(C)C=CC=CC=1.O1CCOCC1.C1COCC1.O=[Mn]=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[C:10]([O:17][CH3:18])[CH:9]=2)=[O:4]
Reactant: COC(=O)C1Cc2cc(OC)c(OC)cc2CN1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2cn1
Yield: 25.9 %

Procedure:
1.8 g (6.26 mmol) of 6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid methyl ester and 3.3 g (37.6 mmol) of MnO2 in toluene/dioxane/THF was heated under reflux overnight. After gravity filtration, the hot filtrate was evaporated to produce 0.4 g (1.62 mmol, 26%) of 6,7-dimethoxy-isoquinoline-3-carboxylic acid methyl ester. LCMS: 248 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15](Cl)[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CN(P(N(C)C)(N(C)C)=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])c(Cl)c12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc([N+](=O)[O-])c(N3CCCCC3)c12
Yield: 80.9 %

Procedure:
420 mg of 5-chloro-6-nitro-beta-carboline-3-carboxylic-acid-ethylester and 100 mg of piperidine in 10 ml of hexamethylphosphorotriamide are heated for 2 h to 80° C. After the solvent is distilled off, the residue is chromatographed on silica gel with methylene-chloride/ethanol. 350 mg of 5-piperidino-6-nitro-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 307° C. (decomposition) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][O:5][C:6]([CH3:10])([CH3:9])[C:7]#[CH:8].S(=O)(=O)(O)[OH:13]>CO.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH3:10][C:6]([CH3:9])([O:5][CH2:4][C:3]([O:2][CH3:1])=[O:11])[C:7](=[O:13])[CH3:8]
Reactant: C#CC(C)(C)OCC(=O)OC
Reactant: O=S(=O)(O)O
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: CO
Product: COC(=O)COC(C)(C)C(C)=O
Temperature: 25 °C

Procedure:
The product from Example 66A (10.0 g, 64 mmol) in methanol (320 mL) was treated with mercury(II) acetate (2.0 g, 6.4 mmol) and sulfuric acid (0.5 mL). After refluxing for 1.5 hours, the mixture was allowed to cool to ambient temperature, concentrated to a volume of 100 mL, poured into 1N HCl (300 mL) and extracted with dichloromethane (3×300 mL). The organic layers were combined, washed with aqueous NaHCO3, washed with brine, dried over Na2SO4 and concentrated to provide the title compound (10.3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)([CH3:20])[CH2:15][C:16]([NH:18][NH2:19])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([CH3:20])[CH2:15][C:16](=[O:17])[NH:18][NH:19]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(O)(CC(=O)NN)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CN(C)C=O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
28.8 g of 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid hydrazide [obtainable by Friedel-Crafts acetylation of 4-fluorobiphenyl to give 4-p-fluorophenylacetophenone, reaction with bromoacetic acid ethyl ester/zinc to give 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and reaction with hydrazine hydrate in ethanol] in 200 ml of DMF is heated and worked up in the customary manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH2:13].Br[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(C(C)C)CC)(C)C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][NH:13][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(OC)c(CCN)c1
Reactant: CCOC(=O)CCCBr
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCNCCc1cc(OC)ccc1OC
Yield: 93.7 %

Procedure:
(2,5-Dimethoxyphenyl)ethylamine 3 (8.33 gm, 0.046 moles), ethyl 4-bromobutyrate (11.64 gm, 0.060 moles) and diisopropylethylamine (7.76 gm, 0.060 moles) were stirred at 110-120° C. for 18 hours, cooled, and partitioned between 50 ml DCM and 50 ml water. The aqueous layer was extracted thrice with 50 ml portions of DCM. The combined organic extracts were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated by rotary evaporation under reduced pressure. The crude product was purified by flash chromatography on silica gel, eluting with a gradient mixture of ethyl acetate and hexane. Ethyl 4-[(2,5-dimethoxyphenyl)ethylamino]butanoate 4 (12.73 gm, 94% yield) was isolated after removing the solvent. 1H NMR (CDCl3) δ 6.44-6.78, 3H, m; 4.11, 2H, q; 3.79, 3H, s; 3.76, 3H, s; 3.08-3.19, 4H, m; 2.30, 2H, t; 1.79, 2H, m; 1.24, 3H, t; 1.03, 3H, t.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:29][CH3:30])=[C:16]2[C:20]=1[N:19]([CH3:21])[CH:18]=[C:17]2[C:22](=[O:28])[C:23]([N:25]([CH3:27])[CH3:26])=O>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:29][CH3:30])=[C:16]2[C:20]=1[N:19]([CH3:21])[CH:18]=[C:17]2[CH:22]([OH:28])[CH2:23][N:25]([CH3:26])[CH3:27]
Reactant: COc1ccc(Br)c2c1c(C(=O)C(=O)N(C)C)cn2C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Br)c2c1c(C(O)CN(C)C)cn2C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
To a slurry of LiAlH4 (419 mg, 11.03 mmol) in anhydrous THF at 0° C. under a nitrogen atmosphere was added AlCl3 (488 mg, 3.67 mmol) and the reaction mixture was stirred for 10 min. To this slurry was then added compound 6-3 (500 mg, 1.47 mmol) and stirring continued for 30 min by which time MS showed no starting material. The reaction was quenched by adding water, extracted by ether, dried, and concentrated. The crude material was purified by column chromatography to give compound 6-4 (480 mg, 90%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ (ppm) 2.42 (s, 6H), 2.58 (dd, 1H, J=12.4, 9.6), 2.71 (dd, 1H, J=12.4, 3.3), 3.89 (s, 3H), 4.08 (s, 3H), 5.28 (dd, 1H, J=9.2, 3.0), 6.33 (d, 1H, J=8.5), 6.97 (s, 1H), 7.20 (d, 1H, J=8.3). APCI [M+1]: 309, 311, 327, 329.
Reaction SMILES: C([O-])([O-])=[O:2].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[Br:19][CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:26][C:27]([C:31]#[N:32])=[N:28]2)=[CH:23][CH:22]=1>O.CC(C)=O>[Br:19][CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:26][C:27]([C:31]([NH2:32])=[O:2])=[N:28]2)=[CH:23][CH:22]=1
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(CBr)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Sodium percarbonate (2.98 g, 9.50 mmol, 3.0 equiv.) in water (52.8 ml) was added dropwise to a solution of 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carbonitrile (2-1, 1.08 g, 3.17 mmol, 1.0 equiv.) in acetone (106 ml) and the reaction stirred for 1 hour at rt. The reaction was quenched with saturated KH2PO4 and the mixture was extracted with EtOAc (3×). The combined organic fractions were dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography (120 g SiO2, 0-100% EtOAc/hexanes) to afford 7-(bromomethyl)-4-(4-fluorophenyl)quinoline-2-carboxamide (3-1, 650 mg, 57%) as a white solid. LRMS m/z (M+H)+ 359.05 found, 359.19 required.
Reaction SMILES: C([N:3]([CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17](OC)[CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:6][N:5]=1)C.C(NC1N=CC(C2SC3C=[C:38]([OH:40])C=CC=3N=2)=CC=1)C>>[CH3:38][O:40][C:16]1[CH:17]=[CH:18][C:12]2[S:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:3][CH3:21])=[N:5][CH:6]=3)=[N:14][C:13]=2[CH:15]=1
Reactant: CCN(C)c1ccc(-c2nc3ccc(OC)cc3s2)cn1
Reactant: CCNc1ccc(-c2nc3ccc(O)cc3s2)cn1
Product: CNc1ccc(-c2nc3cc(OC)ccc3s2)cn1

Procedure:
N-Ethyl-5-(6-methoxy-1,3-benzothiazol-2-yl)-N-methylpyridin-2-amine (55.4 mg, 0.185 mmol) was subjected to the procedure described for 2-[6-(ethylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol. Recrystallization from methanol gave 23.7 mg of the title compound as a pale yellow solid. 1H NMR δ ppm 9.75 (s, 1 H) 8.67 (d, 1 H) 8.03 (dd, 1 H) 7.75 (d, 1 H) 7.35 (d, 1 H) 6.93 (dd, 1 H) 6.75 (d, 1 H) 3.63 (q, 2 H) 3.07 (s, 3 H) 1.11 (t, 3 H); MS m/z (M+H) 286.
Reaction SMILES: [OH:1][C:2]1[C:9](I)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2[O:1][C:2]3[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][C:9]=3[CH:20]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: O=Cc1cccc(I)c1O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2cc3cccc(C=O)c3o2)c1
Yield: 143 %

Procedure:
A mixture of 11 g of 2-hydroxy-3-iodo benzaldehyde, 8.6 g of (3-methoxy-phenyl) acetylene and 150 ml of pyridine was refluxed for 45 minutes and then allowed to return to ambient temperature. Ethyl acetate was added, and washing was carried out with an acid solution, followed by drying and concentrating to obtain 16 g of product which was chromatographed on silica (eluant: hexane-isopropyl ether (7-3)) to obtain 9 g of the desired product melting at 55° C. to 60° C.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:53])[CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:51]([OH:53])[CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1F
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl) methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octane-1-yl]ethanol 19c (2.16 g, 2.92 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 20 mL) were added o-dichlorobenzene (1.64 mL, 14.6 mmol) and 10% Pd/C (0.5 g, 0.42 mmol) in turn at room temperature. The mixture was stirred at room temperature for 3 hours under H2 and filtered. The filter cake was washed with a tetrahydrofuran/methanol mixture (v/v=1/4, 10 mL×2). The filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound 19 as a white solid (0.5 g, 36.5%, HPLC: 96.7%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: MS (ESI, pos. ion) m/z: 469.2[M+H]+; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.42 (m, 1H), 7.39 (s, 1H), 7.31 (dd, 1H), 7.05 (d, 1H), 7.02 (m, 1H), 6.92 (d, 1H), 5.27 (d, 1H), 4.98 (d, 1H), 4.89 (d, 1H), 4.60 (d, 1H), 4.02 (m, 2H), 3.99 (m, 3H), 3.84 (m, 1H), 3.76 (d, 1H), 3.53 (m, 1H), 3.43 (m, 1H), 3.38 (m, 1H), 1.31 (t, 3H), 1.16 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH:11]1([C:14](=[O:21])[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])[CH2:13][CH2:12]1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14]([CH:11]2[CH2:13][CH2:12]2)=[O:21])[C:16]([CH:18]2[CH2:20][CH2:19]2)=[O:17])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Product: COc1ccc(C=C(C(=O)C2CC2)C(=O)C2CC2)cc1

Procedure:
The procedure described in Example 19 was repeated by using 0.68 g 4-methoxybenzaldehyde and 0.77 g 1,3-dicyclopropyl-1,3-propanedione. Yield 0.46 g, mp 60.5°-61.5° C.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:39]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O>C(OCC)(=O)C.Cl>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:38])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[O:30][C:31]([O:34][C:35](=[O:37])[CH3:36])=[CH:32][CH:33]=1)=[O:28])[C:23]([O:25][CH3:39])=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)Oc1ccc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)o1
Agent: Cl
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@]1(OC(=O)c2ccc(OC(C)=O)o2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (721 mg) is dissolved in ethyl acetate (25 mL). DBU (242 mg) is added, followed by dimethyl sulfate (201 mg) and the reaction is stirred at room temperature for 2 hours, then diluted with 0.2 M HCl. The organic phase is washed with water and brine, then dried over magnesium sulfate and evaporated. Purification by flash chromatography on silica gel eluting with hexanes-ethyl acetate (2:1) affords 5-acetoxyfuran-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected NMR signals (CDCl3) δ 0.96 (3H, d), 0.98 (3H, s), 1.40 (3H, s), 2.18 (3H, s), 2.76 (3H, s).
Reaction SMILES: C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:43]=[CH:44][C:45]=1[OH:46])[C:17]([NH:19][NH:20][S:21]([NH:24][C:25]([N:27]1[CH2:30][C@H:29]([NH:31]C(=O)OCC2C=CC=CC=2)[C:28]1=[O:42])=[O:26])(=[O:23])=[O:22])=[O:18].[H][H]>C(#N)C.[Pd]>[NH2:31][C@H:29]1[CH2:30][N:27]([C:25]([NH:24][S:21]([NH:20][NH:19][C:17](=[O:18])[C:16]2[CH:43]=[CH:44][C:45]([OH:46])=[C:14]([OH:13])[CH:15]=2)(=[O:22])=[O:23])=[O:26])[C:28]1=[O:42]
Reactant: O=C(N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)c2ccc(O)c(O)c2)C1=O
Reaction time: 0.25 h
Yield: 83.5 %

Procedure:
7.4 ml of bis(trimethylsilyl)acetamide (0.03 mol) was added to a suspension of 2.47 g (0.005 mol) of (S)-[1-[[[[2-(3,4-dihydroxybenzoyl)hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (see Example 3A) in 40 ml of acetonitrile. After stirring for 15 minutes, a clear solution was obtained. One gram of palladium on charcoal (10%) was added and hydrogen was passed through the solution with stirring. The catalyst was filtered off and 2 ml of methanol were added to the solution, followed by a few drops of acetic acid. The mixture was stirred for 2 hours with cooling (ice/water) and the precipitate was filtered off, washed with acetonitrile and petroleum ether to yield 1.5 g of (S)-3-amino-N-[[2-(3,4-dihydroxybenzoyl)hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide.
Reaction SMILES: COC[C@@H]1[C@H](C=O)[C@]1(C)C1C=C(C(C)C)C=C(C(C)C)C=1.CC12C(C)(C)[C:26]([C:32]([O:34][CH2:35][C@H:36]3[C@H:38]([CH2:39][O:40]CC)[C@@:37]3([CH3:55])[C:43]3[CH:48]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:46]=[C:45]([CH:52]([CH3:54])[CH3:53])[CH:44]=3)=O)(CC1)OC2=O>>[CH2:32]([O:34][CH2:35][C@H:36]1[C@H:38]([CH:39]=[O:40])[C@:37]1([CH3:55])[C:43]1[CH:44]=[C:45]([CH:52]([CH3:53])[CH3:54])[CH:46]=[C:47]([CH:49]([CH3:51])[CH3:50])[CH:48]=1)[CH3:26]
Reactant: CCOC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Agent: COC[C@@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Product: CCOC[C@H]1[C@H](C=O)[C@]1(C)c1cc(C(C)C)cc(C(C)C)c1
Yield: 83 %

Procedure:
Following a procedure similar to that for the preparation of Intermediate 45 but using Intermediate 43b as the starting material afforded the title compound (30 mg, 83% yield) as a colorless oil: