Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:6][CH:7]1[CH2:19][CH2:18][C:17]([O:21]C(OCC)C)([CH3:20])[CH:16]([OH:27])[CH:15]=[CH:14][CH:13]([CH3:28])[CH:12](/[C:29](/[CH3:50])=[CH:30]/[CH:31]=[CH:32]/[CH:33]([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([O:41]C(OCC)C)[CH2:39][CH3:40])[O:11][C:9](=[O:10])[CH2:8]1)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[OH:6][CH:7]1[CH2:19][CH2:18][C:17]([OH:21])([CH3:20])[C:16](=[O:27])[CH:15]=[CH:14][CH:13]([CH3:28])[CH:12](/[C:29](/[CH3:50])=[CH:30]/[CH:31]=[CH:32]/[CH:33]([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([OH:41])[CH2:39][CH3:40])[O:11][C:9](=[O:10])[CH2:8]1
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(=O)/C=C/C1C
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(=O)C=CC1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (8E,12E,14E)-3,6,21-tri(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (10 mg, 14 μmol) obtained in Example B39 in chloroform (0.5 mL) was added to a suspension of Dess-Martin reagent (60 mg, 140 μmol) in chloroform (2 mL), followed by stirring at room temperature for 3 hours. The reaction mixture was poured into a sodium thiosulfate aqueous solution, and the mixture was vigorously stirred. Then, ethyl acetate was added thereto, and the organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. The resulting residue was dissolved in 2 mL of methanol and pyridinium p-toluenesulfonate (3 mg, 11 μmol) was added thereto, followed by stirring at room temperature for 20 hours. The solvent was removed, and the resulting residue was dissolved in ethyl acetate. The mixture was washed with a saturated sodium bicarbonate aqueous solution and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; hexane:ethyl acetate=1:5) and preparative HPLC (Shiseido CAPCELL PAK C18, 10 mm I.D.×250 mm, eluate; acetonitrile:water=20:80–80:20) to give the title compound (0.11 mg, 2%) as a colorless oil.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH2:19]3)[CH:13]=[N:14][CH:15]=1)(C)(C)C.Cl.O1CCOCC1>CO>[OH:6][CH2:7][CH2:8][NH:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH2:19]3)[CH:13]=[N:14][CH:15]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(NCCO[Si](C)(C)C(C)(C)C)c3)ccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1C(=O)CCc2cc(-c3cncc(NCCO)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To solution of 6-{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-pyridin-3-yl}-1-methyl-3,4-dihydro-1H-quinolin-2-one (0.06 g, 0.146 mmol) in MeOH (2.5 mL) was added 4M HCl in dioxane (0.255 ml, 1.02 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, the residue dissolved in EtOAc (20 mL) and washed with aq. NaHCO3 (5 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 2% MeOH(1% NH4OH)-DCM gradient to give the title compound (0.01 g, 22%) as an off white solid. MS: 298.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.Cl>CC(O)C>[ClH:12].[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[CH2:7][CH2:8]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1ccc2c(c1)NCC2
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc2c(c1)N(c1ncnc3cc(OC)c(OC)cc13)CC2
Yield: 91 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 91% yield from 6-methoxy-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. The HCl salt was generated from the purified free base according to a procedure analogous to that given in Example 2. (M.P. 246°-247° C.(dec); LC-MS: 338 (MH+); anal. RP18-HPLC RT: 4.27 min.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH:12]O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-:12])=[CH:7][CH:6]=[CH:5]2
Reactant: Fc1ccc2ncccc2c1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc2cc(F)ccc21
Temperature: 78 °C

Procedure:
The 6-fluoroquinoline from Step A (6.0 g, 40.8 mmol) in glacial acetic acid (60 mL) is treated dropwise with hydrogen peroxide (14 mL) and heated with an oil bath to 78° C. overnight. The reaction mixture is concentrated at reduced pressure and the concentrate basified with solid sodium carbonate and extracted with dichloromethane. The extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to a light yellow solid (6.0 g). The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (5–10%) in dichloromethane to provide the title compound as a white solid (0.99 g), m.p. 105–106° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[C:11]1([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC.O.O1CCCC1>[C:17]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=[CH:19][C:20]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:21][CH:22]=1
Reactant: OCCCCCCCCBr
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCCCCCCOc1ccc(-c2ccccc2)cc1
Yield: 65.4 %

Procedure:
A mixture of 37.8 g of 8-bromo-1-octanol, 30.77 g of 4-phenylphenol, 8.31 g of sodium hydroxide and 34 g of N--methyl-N,N--dioctyl-1-octanaminium chloride in 100 ml of water and 175 ml of tetrahydrofuran was refluxed for 17 hours. The tetrahydrofuran was removed and the residue extracted with warm chloroform. The chloroform extract was washed with water, dried and the solvent removed. The residue was recrystallized from methanol, giving 35.26 g of the desired compound as a white solid, mp 101°-103° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25](=[O:42])[C@@H:26]([N:28]([C:31](=[O:41])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[N+]=[N-])[CH:29]=O)[CH3:27])([CH3:23])([CH3:22])[CH3:21]>C1(C)C(C)=CC=CC=1>[C:20]([O:24][C:25](=[O:42])[C@@H:26]([N:28]1[C:31](=[O:41])[C:32]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:38]=[CH:29]1)[CH3:27])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N(C=O)C(=O)c1ccccc1N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: C[C@@H](C(=O)OC(C)(C)C)n1cnc2ccccc2c1=O
Temperature: 25 °C
Yield: 75 %

Procedure:
Triphenylphosphine (3.41 g, 13.0 mmol) was added portionwise to a solution of (2S)-2-(N-(2-azido-benzoyl)-N-formylamino)-propionic acid tert-butyl ester (3.437 g, 10.80 mmol) in xylene (70 mL) at room temperature. The reaction mixture was stirred at room temperature until the evolution of nitrogen ceased (approx. 1 h), and then refluxed for 20 h. The volatiles were evaporated and the residue was purified by flash chromatography (30% ethyl acetate in hexane) to afford the sub-title compound as a colorless oil (2.221 g, 75%). 1H NMR (400 MHz C6D6) δ 1.30 (3H, d), 1.34 (9H, s), 4.97 (1H, q), 7.08 (1H, m), 7.31 (1H, m), 7.81 (1H, s), 7.86 (1H, d), 8.55 (1H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:23][OH:24])=[C:20]([OH:22])[CH:21]=2)=[CH:10][C:9]=1[C:25]([F:28])([F:27])[F:26]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:23]=[O:24])=[C:20]([OH:22])[CH:21]=2)=[CH:10][C:9]=1[C:25]([F:26])([F:27])[F:28]
Reactant: OCc1ccc(COc2ccc(-c3ccccc3F)c(C(F)(F)F)c2)cc1O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(COc2ccc(-c3ccccc3F)c(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.8 %

Procedure:
To a solution of 5-({[2′-fluoro-2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-2-(hydroxymethyl)phenol (520 mg) in chloroform (10 mL) was added manganese dioxide (1 g) at room temperature. The reaction liquid was stirred at room temperature for 16 hours, and then filtered through celite. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane:EtOAc=95:5 to 80:20) to obtain 4-({[2′-fluoro-2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-2-hydroxybenzaldehyde (180 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Nc1ccc(CO)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Product: OCc1ccc(Nc2nc(Cl)ncc2F)cc1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 4-aminobenzylalcohol were reacted to yield 2-chloro-5-fluoro-N4-[4-(hydroxymethyl)phenyl]-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.08 (d, 1H, J=2.7 Hz), 7.62 (d, 2H, J=9.0 Hz), 7.40 (d, 2H, J=8.1 Hz), 6.99 (bs, 1H), 4.70 (s, 2H); 19F NMR (CDCl3): −44570 (s, 1F); LCMS: ret. time: 19.57 min.; purity: 99%; MS (m/e): 254 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]([C:19]1[N:23]([CH3:24])[C:22]([C:2]2[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: CC(C)NS(=O)(=O)c1cc(F)c(Br)cc1F
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)NS(=O)(=O)c1cc(F)c(-c2ccc(C#N)n2C)cc1F
Reaction time: 16 h
Yield: 14.1 %

Procedure:
According to general procedure B, 4-bromo-2,5-difluoro-N-isopropylbenzenesulfonamide (150 mg, 0.5 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.3 mL) was added. Tri-t-butylphosphine (75 μL, 0.026 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-isopropylbenzenesulfonamide (24 mg) HPLC purity 97.2% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C15H15F2N3O2S−H+, 338.07803; found (ESI-FTMS, [M−H]1−), 338.07811
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:8]=1)=O.[NH:22]([C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1)N>>[F:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:22]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(F)c2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(F)c3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-fluoro-phenyl)-1H-pyridazin-4-one (A-13) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=348.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1>C(OC(=O)CCC)(=O)CCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[O:9][CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:7]([CH2:2][CH2:3][CH3:4])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ncn2c1COC(=O)c1c(Cl)cccc1-2
Agent: CCCC(=O)OC(=O)CCC
Product: CCCc1nc(-c2ncn3c2COC(=O)c2c(Cl)cccc2-3)no1
Yield: 99.5 %

Procedure:
7-Chloro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a]-[4,1]benzoxazepine-3-amidoxime (2 g, 7 mmole) in n-butyric anhydride (6 ml) was heated at 150° C. for 1 hour. The crude product was chromatographed on silica, initially with ethyl acetate:hexane (1:1) and then changing to ethyl acetate. The purified product was crystallised from ethyl acetate:cyclohexane (4:1) to give the product (1.2 g, 50%), m.p. 130°-132° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC.CCOC(C)=O>[C:20]1([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:18]#[N:19])[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#CC(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CC(c1ccccc1)(c1ccccc1)c1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a mixture of 1.0 g 2-chloro-5-nitropyridine (6.3 mmol), 1.33 g diphenylacetonitrile (6.9 mmol, 1.1 equiv) and 700 mg tetrabutylammonium fluoride (3.15 mmol, 0.5 equiv) in 3 mL toluene was added dropwise 1.5 mL 50% aqueous NaOH. After 30 min, no starting materials remained by TLC (hexane/EtOAc). The mixture was filtered through a short plug of silica to remove tars, evaporated and chromatographed (SiO2; hexane/EtOAc). The crude product was a slightly yellow oil which was recrystallized from MeOH to furnish the title compound (1.7 g, 86%) as colorless plates. mp 94-9° C. 1H NMR (CDCl3; 300 MHz) 7.20-7.29 (5H, m), 7.35-7.42 (5H, m), 7.54 (1H, d, J=8.7 Hz, H-3), 8.49 (1H, dd, J=3 and 9 Hz, H-4), 9.60 (1H, d, J=2.4 Hz, H-6). 13C NMR (CDCl3; 300 MHz) 60.19, 121.65, 123.77, 128.87, 129.09, 129.33, 132.52, 138.46, 143.49, 145.31, 164.99. Elemental analysis calculated for C19H13N3O2: C, 72.38; H, 4.13; N, 13.33. Found: C, 72.35; H, 4.08; N, 13.25.
Reaction SMILES: [OH:1][CH:2]([CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[CH3:3].N1C=CC=CC=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30].C(Cl)(=O)C(Cl)=O>C1(C)C=CC=CC=1.O>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:29]([O-:1])=[O:30].[OH:1][CH:2]([CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH:7]=1)[CH3:3]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: COc1ccc2cc(CCC(C)O)ccc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)[O-])cc(OC)c1OC
Reaction time: 48 h

Procedure:
To a stirred mixture of 2-hydroxy-4-(6-methoxy-2-naphthyl) butane (1.15 g:0.005 mole) in toluene (45 ml) containing dry pyridine (3 ml) was added 3,4,5-trimethoxy-benzoyl chloride, prepared from the corresponding acid (1.06 g:0.005 mole) and oxalyl chloride (1 ml). After standing for 48 hours at room temperature, the resulting mixture was added to water and extracted with ether. The organic extract was washed twice with water, dried (Na2SO4) and concentrated. The crude oil was chromatographed on alumina (100 g) using 10% ethereal hexane as eluant to afford the 3,4,5-trimethoxybenzoate of 2-hydroxy-4-(6-methoxy-2-naphthyl)butane as a pale yellow oil.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([NH:28][CH2:25][CH2:26][CH3:27])=[O:22])[N:16]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CCCN
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 125 °C
Yield: 69.8 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(ethoxycarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 4) (107 mg, 0.31 mmol) in toluene (2 ml) was treated with n-propylamine (250 μl, 3.10 mmol) and the mixture was heated at 125° C. in a sealed vessel for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with aqueous citric acid solution (5% w/v), water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (80:20) gradually changing to dichloromethane:ethyl acetate (60:40) then to dichloromethane:methanol (90:10) to afford the title compound as an oil (76 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH2:24])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1.[N:32]1[CH:37]=[CH:36][C:35]([C:38](O)=[O:39])=[CH:34][N:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([F:17])[CH:16]=2)[CH:13]([NH:18][C:19]([C:21]2([NH:24][C:38]([C:35]4[CH:36]=[CH:37][N:32]=[N:33][CH:34]=4)=[O:39])[CH2:23][CH2:22]2)=[O:20])[CH2:12][CH2:11]3)[CH:7]=1
Reactant: O=C(O)c1ccnnc1
Reactant: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(N)CC2)no1
Product: Cc1nc(-c2c(F)cc(Cl)cc2-c2cc(F)c3c(c2)CCC3NC(=O)C2(NC(=O)c3ccnnc3)CC2)no1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B], 1-amino-cyclopropanecarboxylic acid{(rac)-5-[5-chloro-3-fluoro-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-7-fluoro-indan-1-yl}-amide (example 32) has been coupled with pyridazine-4-carboxylic acid to yield the title compound as light yellow solid. MS: 551.1 (MH+, 1Cl).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl.O1CCOCC1>O1CCCC1.CO>[F:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)N1CCc2cc(F)c([N+](=O)[O-])cc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc2c(cc1F)CCN2
Yield: 90.8 %

Procedure:
A solution of 1-acetyl-5-fluoro-6-nitro-2,3-dihydro-1H-indole (1.22 g, 5.44 mmol) and 4.0 M HCl/dioxane (6.80 ml, 27.2 mmol) in tetrahydrofuran (50 ml) and methanol (100 ml) was heated overnight at 50 C. The reaction was quenched with saturated NaHCO3 (200 ml), solvent removed, aqueous layer extracted with dichloromethane (250 ml), organic layer adsorbed to silica gel and purified by LC (20-75% ethyl acetate/hexanes) to afford the indoline (0.9 g, 91%). ESIMS (M+H)+=183.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[N:11]1([CH2:16][CH:17]([CH3:20])[CH2:18][NH2:19])[CH:15]=[CH:14][N:13]=[CH:12]1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:19][CH2:18][CH:17]([CH3:20])[CH2:16][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CC(CN)Cn1ccnc1
Reactant: O=C(O)c1ccc(Cl)nc1
Product: CC(CNC(=O)c1ccc(Cl)nc1)Cn1ccnc1

Procedure:
When 6-chloronicotinic acid was reacted with 3-(1H-imidazol-1-yl)-2-methylpropanamine by the procedure of Example 20, the compound of the Example was obtained, mp 102°-104° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:25](=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:24][C@:6]1([C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]1=[O:23])[CH2:5]2.[Cl-].[C:32]([O:36][C:37](=[O:40])[CH2:38][Zn+])([CH3:35])([CH3:34])[CH3:33]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[N+:28]([C:27]1[CH:26]=[C:25]2[C:4]([CH2:5][C@:6]3([CH2:24]2)[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:7]3=[O:23])=[CH:3][C:2]=1[CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:40])([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc(I)c([N+](=O)[O-])cc3C2)c2cccnc21
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: CC(C)(C)OC(=O)Cc1cc2c(cc1[N+](=O)[O-])C[C@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Temperature: 40 °C

Procedure:
To a flask containing (2R)-5-iodo-6-nitro-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step B (4.02 g, 7.48 mmol), tris(dibenzylideneacetone)dipalladium (349 mg, 0.38 mmol), and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (532 mg, 0.75 mmol) was added 2-tert-butoxy-2-oxoethylzinc chloride (Rieke, 0.5 M in Et2O; 15.7 mL, 7.85 mmol) and the resulting solution was heated to 40° C. for 1 h. The reaction was quenched with dilute aqueous NaHCO3 (100 mL) and the mixture was extracted with EtOAc (200 mL). The organic layer was washed with brine, dried over Na2 SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=526 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[Mg+2].[Cl-].[Cl-]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [Mg+2]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 60 °C

Procedure:
The immobilized enzyme composite was then packed in a column and a 45% weight by volume solution of fructose with 5×10-3M MgCl2 was passed over the beads while maintaining the temperature at 60° C. for a period of 2 hours. At the end of the 2 hour period the amount of glucose formed and the flow rate were assayed. It was found that the activity of the enzyme was 227 units/gram at a flow rate of 2 ml/min.; the term "unit" being defined as the grams of glucose formed per hour per gram of immobilized enzyme conjugate. In addition, it was found that the coupling efficiency of the conjugate was 54%.