Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=S)[CH:8](C)[CH2:9][NH:10][C:4]=2[CH:3]=1.[C:15]([NH:18][NH2:19])(=O)C>C(O)CCC>[CH:15]1[N:6]2[C:5]3[CH:13]=[CH:14][CH:2]=[CH:3][C:4]=3[N:10]=[CH:9][CH2:8][C:7]2=[N:19][N:18]=1
Reactant: CC1CNc2cc(Br)ccc2NC1=S
Reactant: CC(=O)NN
Solvent: CCCCO
Product: C1=Nc2ccccc2-n2cnnc2C1

Procedure:
A solution of 7-bromo-3-methyl-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (1.5 g, 5.5 mmol) and acetohydrazide (693 mg, 9.36 mmol) in n-butanol (20 mL) was heated at 130° C. for 12 hours. The reaction mixture was concentrated in vacuo, diluted with water (20 mL), extracted with ethyl acetate (15 mL×3) and washed with brine (10 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and then filtered. The filtrate was concentrated to give a crude product, which was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to afford 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine, 5,6-dihydro-1,4-dimethyl-8-bromo as a white solid (1 g, 62%). 1H NMR (300 MHz, CDC13): δ 7.19-7.14 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 3.74-3.64 (m, 1H), 3.43-3.36 (m, 1H), 3.13-3.05 (m, 1H), 2.49 (s, 3H), 1.50 (d, J=6.9 Hz, 3H). LRMS (M+H)+: calcd 292.03. found 292.
Reaction SMILES: [O:1]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].N1C(C)=CC=CC=1C.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38].O>CC(C)=O.C(OCC)(=O)C>[CH2:40]([O:39][C:37]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])=[O:38])[CH3:41]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(Cc2ccccc2O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(OC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 4 h

Procedure:
To a stirred solution of 2-(4-methoxybenzyl)phenyl β-D-glucopyranoside (220 g) and 2,6-lutidine (136 mL) in acetone (834 mL) was added ethyl chloroformate (84 mL) at about 5 to about 10° C. Thereafter the mixture was stirred at about 10 to about 20° C. for 4 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed successively with a 10% aqueous solution of citric acid, brine, a 10% aqueous solution of sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the solvent of the filtrate was removed under reduced pressure. The residue (326 g) was dissolved in ethanol (1039 mL) under heating, and the resulting solution was treated with activated charcoal (11 g). After the mixture was stirred for 5 minutes, insoluble materials were filtered through celite. To the filtrate was added n-hexane (2046 mL) at about 30 to about 40° C. over about 45 minutes, and the resulting mixture was allowed to stand at room temperature for 17 hours. Thereafter, the mixture was stirred under ice-cooling for 2 hours, and the precipitated crystals were collected by filtration to afford crude crystals of 2-(4-methoxybenzyl)phenyl 6-O-ethoxycarbonyl-β-D-glucopyranoside (202 g).
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([OH:29])[CH2:23]2)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[OH-:33].[Ca+2].[OH-]>O>[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@@H:22]([OH:27])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:33])=[C:9]([CH:30]([CH3:31])[CH3:32])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: [OH-]
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H]1C[C@@H](O)CC(=O)O1
Agent: [Ca+2]
Solvent: O
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
E-6-{2-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (4.0 g), water (20.0 mL), and calcium hydroxide (0.64 g) was added to a reactor. The reaction mixture was stirred at room temperature for 3 hours and then filtered under reduced pressure. The resulting white solid was dried to obtain E-7-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid 1/2 calcium salt (4.1 g, yield 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][CH:14]([O:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH2:13][CH:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH:16]([CH3:17])[CH2:15][CH:14]([O:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:13][CH:12]1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(OCC(=O)OC(C)(C)C)CC(C)N1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CC(OCC(=O)O)CC(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
1.11 g of N-benzyloxycarbonyl-4-tert-butoxycarbonylmethyloxy-2,6-dimethylpiperidine was dissolved in 5 ml of methylene chloride, and 2 ml of trifluoroacetic acid was added. The solution was stirred overnight at room temperature, and the resulting solution was concentrated under reduced pressure. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. From the fractions eluted with chloroform-methanol (9:1 v/v) was obtained 0.61 g of N-benzyloxycarbonyl-4-carboxymethyloxy-2,6-dimethylpiperidine, which was an oily product with no color (yield: 65%).
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([C:33](OC)=[O:34])[CH:27]=2>C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][C:6]=1[NH:5][C:33]([C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:24]([C:18]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=3[Cl:16])[NH:25]2)=[CH:30][CH:29]=1)=[O:34]
Reactant: Nc1ccc2ccccc2n1
Reactant: COC(=O)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2cc(-c3c(Cl)cccc3Cl)[nH]c2c1
Temperature: 100 °C
Reaction time: 0.42 h

Procedure:
To 10 mL of ice-cold toluene was added 844 μL of 2 M trimethylaluminum in toluene then 2-aminoquinoline (233 mg, 1.62 mmol) was added in one portion and the mixture was stirred for 25 min. To this was added a solution of methyl 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylate (470 mg, 1.47 mmol) (from Example 3-5) in toluene (7 mL) dropwise and the resulting solution was heated at 100° C. for 18 h. A second aliquot of trimethylaluminum was added and the mixture heated another 18 h, after which it was cooled to ambient temperature, quenched with 1N HCl, and basified by stirring with 8% NaHCO3. This mixture was filtered, and the filtrate separated. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were dried, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed using a gradient of 20-50% heptane/ethyl acetate to give 2-(2,6-dichlorophenyl)-1H-indole-6-carboxylic acid quinolin-2-ylamide. 1H NMR (DMSO-d6, 400 MHz) δ 11.85 (s, 1H), 11.06 (s, 1H), 8.40 (s, 2H), 8.22 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.81 (dd, J=8.3, 1.5 Hz, 1H), 7.74 (td, J=6.8, 1.5 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.66 (s, 1H), 7.53 (m, 2H), 6.62 (s, 1H). MS (m/z) 432.0 (M+1); retention time=1.57 min (Method 10).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[N:6]=1.[CH3:23]I>>[CH3:23][N:19]1[CH:20]=[CH:21][C:16]([N:3]2[CH:4]=[C:5]([C:7]#[C:8][C:9]3[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=3)[N:6]=[C:2]2[CH3:1])=[CH:17][C:18]1=[O:22]
Reactant: CI
Reactant: Cc1cccc(C#Cc2cn(-c3cc[nH]c(=O)c3)c(C)n2)c1
Product: Cc1cccc(C#Cc2cn(-c3ccn(C)c(=O)c3)c(C)n2)c1

Procedure:
The title compound, light brown solid, MS: m/e=304.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-(2-Methyl-4-m-tolylethynyl-imidazol-1-yl)-1H-pyridin-2-one and methyl iodide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:12]2[CH:22]=[C:23]([OH:28])[C:24]([OH:27])=[C:25]([Cl:26])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl-].O.CN([CH:36]=[O:37])C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[C:12]2[CH:22]=[C:23]([OH:28])[C:24]([O:27][CH2:10][C:11]3[CH:25]=[CH:24][C:23]([O:37][CH3:36])=[CH:22][CH:12]=3)=[C:25]([Cl:26])[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(O)c(O)c2Cl)C(c2ccc(O)cc2)C1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2c(O)cc3c(c2Cl)CCN(C(=O)OC(C)(C)C)CC3c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
10.0 g of 3-t-butyloxycarbonyl-6-chloro-7, 8-dihydroxy-1-(4'-hydroxyphenyl) 2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 100 ml of DMF. To this was added 1.25 g of a 50% sodium hydride mineral oil dispersion under an argon atmosphere. The reaction was stirred at ambient temperature for 15 minutes and 3.59 g of 4-methozybenyl chloride was added. The reaction was stirred for 16 hours at ambient temperature then poured into a large volume of water. The mixture was then extracted with ethyl acetate. The extracts were washed with water dried over magnesium sulfate and concentrated to yield an oil. The crude product was dissolved in 100 ml. of acetonitrile and the solution washed with several portions of petroleum ether. The acetonitrile solution was concentrated and seeded with crystals of the product. The solution was allowed to stand in a freezer overnight with a resultant of white solid. Additional solid was obtained after concentration of the mother liquor. The solid (5.57 g) was heated for 10 minutes in 100 ml of dichloromethane on a steam bath. The suspension was filtered and the solid washed with warm dichloromethane to yield 3-t-butyloxycarbonyl-6-chloro-8-hydroxy-7-(4-methoxybenzyloxy)-1-(4 -hydroxyphenyl)-2,3,4,5 tetrahydro-1-H-3-benzazepine, M.P. 190°-192° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])(O)[O:4][N:3]=1.OS(O)(=O)=O.[OH-].[Na+]>>[CH3:1][C:2]1[CH:6]=[C:5]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[O:4][N:3]=1
Reactant: CC1=NOC(O)(C2CCCN2C)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc([C@@H]2CCCN2C)on1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To the solution of the product from step 25c above was added 12 mL of conc H2SO4, and the mixture was warmed to 70° C. and stirred for 2 hr. The solution was cooled in an ice-water bath, and adjusted to pH 12 by slow addition of 50% aqueous NaOH (40 g). The mixture was extracted twice with ethyl acetate, and the combined extracts were dried over Na2SO4. The solid were removed by filtration, and the filtrate was distilled, first at atmospheric pressure to remove the solvent and, finally, under vacuum to provide the title compound as a nearly colorless liquid (4.74 g, 57%). b.p. 115°-117° C./20 mm Hg. 1H NMR (CDCl3) δ: 1.8-2.1 (m, 3H), 2.32 (s, 3H), 2.21 (m, 1H), 2.29 (s, 3H), 2.36 (m, 1H), 3.17 (m, 1H), 3.53 (t, J=8 Hz, 1H), 6.01 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-])=O.C(OCC)(=O)C>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccccc2)nc1
Yield: 86 %

Procedure:
3-Nitro-6-phenoxypyridine (8.77 g, 40.6 mmol), 10% palladium on carbon (1.20 g) and 1:1 mixed solvent (250 mL) of ethyl acetate with ethanol were mixed and hydrogenation was performed at room temperature under an initial pressure of 196 kPa. After the catalyst was removed by filtration and washed with ethanol, the filtrate was concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 6.50 g (86%) of the title compound as faintly yellow needle-like crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.Br[CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:32]([O:31][CH2:30][CH2:29][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCCOCc1ccccc1
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(c2c(F)cccc2OCCOCc2ccccc2)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (preparation described in example 413; 50 mg; 0.13 mmol), ((2-bromoethoxy)methyl)benzene (28 mg; 0.13 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Water was added, and the separated aq. layer was extracted with Et2O. The mixed organic layers were washed with water, dried over anh. MgSO4, filtered and concentrated to dryness under reduced pressure affording 5-(2-(2-(benzyloxy)ethoxy)-6-fluorophenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=1.04 min.; [M+H]+: 518.47 g/mol. A mixture of 5-(2-(2-(benzyloxy)ethoxy)-6-fluorophenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one 55 mg; 0.10 mmol), and platinum (IV) oxide hydrate PtO2 (24 mg; 0.10 mmol) in anh. MeOH (2 ml) was stirred at rt, under hydrogen atmosphere (1 atm), for 16 h. Filtration over a pad of celite, concentration to dryness under reduced pressure, and subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.84 min.; [M+H]+: 427.92 g/mol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.O.CCO.COCCOC>[CH3:18][O:17][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2cccnc2)cc1
Temperature: 110 °C
Yield: 50 %

Procedure:
Procedure H′: 750 mg of pyridine-3-boronic acid (6.14 mmol), 1.34 g of methyl 4-bromobenzoate (6.22 mmol) are put in the reaction vessel with 25 ml of DME: water: EtOH=7:3:2.). 6.25 ml of aqueous 2M Na2CO3 is added to the mixture and 250 mg of tetrakis(triphenylphosphine is added. The vessel is sealed and heated at 110° C. for 40 min in Microwave machine (MARS). After cooling, water and CH2Cl2 are added. The CH2Cl2 layer is separated, washed by brine, dried over Na2SO4 and evaporated. The crude product is applied to silica-gel column chromatography (Hexane:AcOEt=3:1) to give 4-pyridin-3-yl-benzoic methyl ester. Yield 50%: mass spectrum (m/e): 214(M+1); 1H-NMR(CDCl3): 8.92(m, 1H), 8.68(m, 1H), 8.18(d, 2H, J=7.6 Hz), 7.95(m, 1H), 7.69(d, 2H, J=7.6 Hz), 7.43(m, 1H), 3.99(s, 3H).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][O:35][CH2:36][CH2:37][CH3:38])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([O:12]CCC)=[O:11])([CH3:4])[CH3:3]>O.[OH-].[Li+].O1CCOCC1>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:34][O:35][CH2:36][CH2:37][CH3:38])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[NH:33][N:32]=[N:31][N:30]=3)=[CH:19][CH:18]=2)[C:9]=1[C:10]([OH:12])=[O:11])([CH3:4])[CH3:3]
Reactant: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCOCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
394 mg of propyl 4-(1-hydroxy-1-methylethyl)-2-propoxymethyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 90(b)] were dissolved in a solution of 88 mg of lithium hydroxide monohydrate in 10 ml of a 50% v/v aqueous Solution of dioxane, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction solution was concentrated by distillation under reduced pressure, and the dioxane was removed by distillation under reduced pressure. The concentrate was then cooled with ice, and 2.1 ml of 1N aqueous hydrochloric acid were added. The crystals which precipitated were collected by filtration, to give 235 mg of the title compound, melting at 166°-168° C.
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][C:8]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[CH:19][C:9]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)=O)(=O)C.O.[NH2:29][NH2:30]>C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[CH:19]=[C:20]([O:25][CH3:26])[C:21]([O:23][CH3:24])=[CH:22][C:8]=3[CH2:7][C:6]([CH2:5][OH:4])=[N:30][N:29]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(CC(=O)COC(C)=O)c(C(=O)c2cccc(Cl)c2)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1OC)C(c1cccc(Cl)c1)=NN=C(CO)C2
Reaction time: 8 h
Yield: 77.8 %

Procedure:
6.7 g (17.3 mmoles) of 2-(3-acetoxyacetonyl)-3'-chloro-4,5-dimethoxybenzophenone [(IV), R=CH3 ] are suspended in 70 ml of 99.5% ethanol, then 5.2 l (104 mmoles) of 100% hydrazine hydrate are added under stirring. The reaction mixture is stirred at room temperature for 72 hours, treated with activated carbon, filtered and 82 ml of distilled water are added to the filtrate. Then 4 ml of glacial acetic acid are dropped to the pale yellow solution under cooling with ice-cold water. Upon scratching crystals get separated. The suspension is kept overnight at 1° to 5° C., filtered, washed five times with 5 ml of ice-cold 50% ethanol solution each and the product is dried at a temperature between 80° and 100° C. Thus 4.64 g of crude product are obtained.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH2:16][CH3:17])=[CH:14][C:13](=[O:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC[C@@H]1C=C(C)[C@H](O)CN1C(OC(C)(C)C)=O)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][C@@H:10]1[C:15]([CH2:16][CH3:17])=[CH:14][C@H:13]([OH:18])[CH2:12][N:11]1[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CCC1=CC(=O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Product: CCC1=C[C@H](O)CN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
The title compound was prepared from (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-3-ethyl-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 207, 5.146 g, 13.92 mmol) according to the procedure described for Intermediate 8, except the mixture was stirred at ambient temperature for 1 h. The mixture was concentrated and diluted with aqueous NH4Cl, water and EtOAc. The organic layer was separated and washed three times with brine, dried over Na2SO4, filtered and concentrated to afford the title compound (5.19 g, 100%) as a cloudy oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=O)=[CH:31][CH:30]=1>O1CCCC1>[F:27][C:28]([F:38])([F:39])[C:29]1[CH:30]=[CH:31][C:32]([C:33]2[O:5][C:4](=[O:6])[C:3]3[CH:7]=[C:8]([C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)([CH3:13])[CH3:12])[CH:9]=[CH:10][C:2]=3[N:1]=2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)c1ccc2nc(-c3ccc(C(F)(F)F)cc3)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
To a solution of 2-amino-5-α-cumylbenzoic acid (13.5 g, 0.53 mol, prepared in Example 20) and triethylamine (7.8 g, 0.56 mol) in tetrahydrofuran (200 mL) is added dropwise at room temperature a solution of 4-trifluoromethylbenzoyl chloride (11 g, 0.53 mol). The resulting suspension is stirred at room temperature overnight, then filtered and concentrated to a solid that is then suspended in acetic anhydride and heated to 115° C. for three hours. The resulting solution is cooled and concentrated to an oil. The oil is taken up in ethanol (100 mL) and allowed to stand. The resulting solid formed is colled and dried to give 15.4 g of the title compound melting at 104–105° C. The structure of the compound is confirmed by 1Hnmr (CDCl3) 500 MHz: δ 1.78 (s, 6H); 7.23 (t, 1H); 7.23 (d, 2H); 7.31 (t, 2H); 7.60 (d, 1H); 7.64 (dd, 1H); 7.78 (d, 2H); 8.26 (d, 1H). 19Fnmr (fluorinated species at −69.57 ppm).
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:12]1([S:15]([NH:18][C:19]2[C:27]3[O:26][CH:25]=[CH:24][C:23]=3[C:22]([F:28])=[C:21]([F:29])[C:20]=2[NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=2[F:38])(=[O:17])=[O:16])[CH2:14][CH2:13]1)[CH:10]=C.C(OCC)(=[O:41])C>O1CCOCC1.O.CCCCCC.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[F:28][C:22]1[C:23]2[CH:24]=[CH:25][O:26][C:27]=2[C:19]([NH:18][S:15]([C:12]2([CH2:9][CH:10]=[O:41])[CH2:13][CH2:14]2)(=[O:16])=[O:17])=[C:20]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([I:37])=[CH:33][C:32]=2[F:38])[C:21]=1[F:29]
Reactant: CCOC(C)=O
Reactant: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(F)c(F)c3ccoc23)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: CCCCCC
Product: O=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(F)c(F)c3ccoc23)CC1
Temperature: 30 °C
Reaction time: 14 h
Yield: 43 %

Procedure:
2,6-Lutidine (0.077 g, 0.7188 mmol) and NaIO4 (0.307 g, 1.4376 mmol) were added to a solution of 1-allyl-N-(4,5-difluoro-6-(2-fluoro-4-iodophenylamino)benzofuran-7-yl)cyclopropane-1-sulfonamide (I-35a: 0.190 g, 0.3594 mmol) in dioxane (10 mL). This was followed by the addition of osmium tetroxide (0.0045 g, 0.0179 mmol) in water (2 mL). The reaction mass was stirred for 12-16 hours at 20-40° C. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mass was diluted with DCM (50 mL) and partitioned between water and DCM. The organic layer was washed with 2N HCl (20 mL), water, brine solution and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (50% ethyl acetate in hexane) afforded 0.086 g of the product (43% yield). LCMS: 74%, m/z=548.9 (M−1).