Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].C1(C)C=CC=CC=1.[CH3:17][N:18](C=O)C>[C-]#N.[C-]#N.[Zn+2].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:17]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9])#[N:18]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)c(F)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a deoxygenated solution of 4-bromo-3-fluorotoluene (25.0 g, 132 mmol) in DMF (500 mL) was added Zn(CN)2 (10.1 g, 86 mmol) and Pd(PPh3)4 (15 g, 13 mmol). The reaction was stirred at 100° C. for 18 hrs, then cooled to room temperature. The solution was poured into toluene (1 L), washed with 30% aq. NH4OH (2×1 L), then brine (800 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography, eluting with a gradient of hexane—0% to 7% EtOAc, yielded the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[F:9].[CH3:10][N:11](C=O)C>C(OCC)(=O)C>[F:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[C:10]#[N:11]
Reactant: CN(C)C=O
Reactant: Cc1ccc(Br)c(F)c1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#N)c(F)c1
Yield: 70 %

Procedure:
A mixture of 4-bromo-3-fluorotoluene (2 g, 10.6 mmol) and cuprous cyanide (1.4 g, 15.9 mmol) in DMF (15 mL) was heated at reflux for 4 h. The reaction mixture was diluted with ethyl acetate, washed with aqueous ammonia, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (EtOAc:n-hexane, 1:4) to give the title compound (1.0 g, 70%).
Reaction SMILES: [CH:1]1([SH:4])[CH2:3][CH2:2]1.[H-].[Na+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O>C1COCC1.C(OCC)C>[CH:1]1([S:4][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: SC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
A 4% strength solution of 3.00 g (40.5 mmol) of cyclopropanethiol (preparation according to: E. Block et al., J. Am. Chem. Soc. 1992, 114, 3492) in THF/diethyl ether (1:1) was admixed in portions with 1.78 g (44.6 mmol) of sodium hydride (60%) and stirred for 30 minutes at room temperature. The portionwise addition of 6.00 g (38.7 mmol) of 1-fluoro-4-nitrobenzene was then carried out. The mixture was stirred at 40° C. for 2 hours. After cooling, the mixture was added to water and extracted (3×) with benzene. The combined organic phases were concentrated by evaporation and the residue was purified chromatographically (hexane/ethyl acetate 95:5). This gave 4.6 g (23.6 mmol; yield: 61%) of the product.
Reaction SMILES: [Si:1]([O:8][NH2:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([S:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[C:32](O)=[O:33])(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>C(Cl)Cl>[O:8]([NH:9][C:32]([CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][N:26]1[S:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([Cl:10])=[CH:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:25])=[O:24])=[O:33])[Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)[Si](C)(C)ON
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)ONC(=O)C1CCCCN1S(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
O-(tert-butyldimethylsilyl)hydroxylamine (57 mg, 0.39 mmol) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (59 mg, 0.31 mmol) were added to a solution of 1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxylic acid (100 mg, 0.26 mmol), [prepared as described above] in methylene chloride (4 ml). The reaction mixture was stirred overnight at RT and then diluted with methylene chloride. The solution was washed with water, 10% citric acid, and brine, and dried over MgSO4. After the organics were removed the residue was chromatographed (SiO2, 2030% ethyl acetate/hexane) to give N-tert-butyldimethylsiloxy-1-[4-(4-chlorophenyl)piperazine-1-sulfonyl]piperidine-2-(RS)-carboxamide as a colorless foam (56%).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:15]1Br)(=[O:12])[CH3:11]>[O-2].[Zn+2]>[C:10]([O:13][C@@H:14]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:15]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:12])[CH3:11]
Reactant: N#Cc1ccccc1S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: [O-2]
Agent: [Zn+2]
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C#N)SC[C@H]1OC(C)=O
Yield: 60 %

Procedure:
If the procedure described in Preparation IV is followed starting from 10.7 g (79.2.10-3 mol) of 2-mercaptobenzonitrile, 30.2 g (85.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.3 g (77.4.10-3 mol) of zinc oxide (ZnO), 19.3 g (yield: 60%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([CH2:21][CH2:22][CH3:23])(=O)=O)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:24][C:25](=[O:29])[O:26][CH2:27][CH3:28].[NH4+]>CO.[Pd]>[CH2:27]([O:26][C:25](=[O:29])[NH:24][CH:7]1[CH2:8][CH2:9][C:10]2[C:15](=[CH:14][C:13]([CH2:16][CH2:17][S:18][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)[CH:6]1[CH2:5][C:4]1[CH:3]=[CH:2][CH:32]=[CH:31][CH:30]=1)[CH3:28]
Reactant: CCCS(=O)(=O)CCc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(NC(=O)OCC)CC2
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: CCCSCCc1ccc2c(c1)C(Cc1ccccc1)C(NC(=O)OCC)CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
Ethyl 1-(3-chlorobenzyl)-7-(2-(propylsulfonyl)ethyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (27.1 mg, 0.057 mmol) and ammonium form late (71.5 mg, 1.134 mmol) were dissolved in 5 ml MeOH. Pd/C (0.845 mg, 7.94 μmol) was added and stirred at 80° C. for 4 h. The mixture was filtered, the solvent evaporated, the residue re-dissolved in ethyl acetate, which was subsequently washed with water, NaHCO3 and brine, dried, filtered. Solvent was evaporated to obtain white solid which was purified by chromatography affording 12.7 mg of product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[F:28][C:29]1[CH:30]=[C:31]([C:41](=[O:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>CN(C=O)C>[C:41]([C:31]1[CH:32]=[CH:33][C:34]([N:35]2[CH2:36][CH2:37][N:38]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[Br:1])[C:11]#[N:12])=[O:6])[CH2:39][CH2:40]2)=[C:29]([F:28])[CH:30]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: N#Cc1ccc(Br)c(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
To a solution of 2-bromo-5-cyano-benzoic acid (200 mg, 0.885 mmol) in DMF (3 ml) was added dropwise 1,1′-Carbonyldiimidazole (148 mg, 0.885 mmol). When the CO2 evolution ceased, the mixture was heated to 50° C. for 15 minutes. The mixture was cooled to room temperature. 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (198 mg, 0.885 mmol) was added portionwise. The mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed twice with water, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was purified on SiO2 (Heptane/AcOEt 0%-30% (10 minutes)) to provide 3-[4-(4-acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-bromo benzonitrile (185 mg, 49%) as white solid (M+ 430.3).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O1CCOCC1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CC(C)([O-])C.[Na+]>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>[Br:8][C:6]1[CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:3]=[N:4][CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1cncc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 41.1 %

Procedure:
To a solution of [3,5-dibromopyridine (1000 mg, 0.004 mol) in 1,4-dioxane (8 mL, 0.1 mol), morpholine (400 mg, 0.004 mol) and sodium tert-butoxide (400 mg, 0.004 mol) were added. The reaction was bubbled with nitrogen. Tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.0002 mol) was added and nitrogen was bubbled through for couple of minutes. The mixture was heated at 80° C. overnight. The reaction was allowed to cool to rt and was then partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give a crude residue. The crude product was purified by FCC on silica gel eluting with 1:1, EtOAC:Hexane gave to give 4-(5-bromopyridin-3-yl)morpholine as a viscous oil (400 mg, 40%). 1H NMR (400 MHz, CDCl3): δ 8.2 (s, 1H), 8.1 (s, 1H), 7.2 (s, 1H), 3.8 (m, 4H), 3.2 (m, 4H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1.Cl>CO>[CH3:1][O:2][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Br)cn1
Yield: 83.6 %

Procedure:
Sodium methylate (4.05 g, 21 mmol) was added to a methanol solution (20 mL) of 2,5-dibromopyridine (1 g, 4.2 mmol), followed by refluxing for 13 hours. The reaction solution was poured into dilute hydrochloric acid for neutralization and the mixture was extracted with a chloroform/methanol mixed solvent (chloroform/methanol=9/1). The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with chloroform/methanol=99/1) to obtain 2-methoxy-5-bromopyridine (660 mg; yield: 87%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+]>CS(C)=O.CCOCC>[CH3:9][O:10][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COc1ccc(Br)cn1
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 92.4 %

Procedure:
To a solution of 2,5-dibromopyridine (20 g, 84 mmol) in DMSO (84 mL) is added (25 wt %) sodium methoxide (21.2 mL, 93 mmol). The resulting solution is heated to 80° C. and stirred for 45 min then cooled to 20° C., diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ether in hexanes) to give 14.6 g of title compound as a colorless oil. 1H NMR (CDCl3) δ 3.90 (s, 3H), 6.66 (d, J=9 Hz, 1H), 7.63 (dd, J=9, 3 Hz, 1H), 8.20 (d, J=3 Hz, 1H). MS (EI) m/z 187/189 (M+, Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C#N)ccc1OC
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(C#N)cc1C(=O)O

Procedure:
Hydrolyze methyl 2-methoxy-5-cyanobenzoate by the method of Preparation 24 using 1.1 equivalents of lithium hydroxide to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Brc1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.4 %

Procedure:
In a 3-neck 1 L round-bottom flask fitted with a condenser, nitrogen inlet, and 2 stoppers was added 2,6-dibromopyridine (15.3 g, 64.58 mmol), phenylboronic acid (7.87 g, 64.58 mmol), and potassium carbonate (17:85 g, 129.16 mmol) in 228 mL of dimethoxyethane and 150 mL of water. Nitrogen was bubbled directly into the mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) was added (1.85 g, 1.60 mmol) and the reaction mixture was heated to reflux. The reaction was complete after 3 h of heating. It was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous layer extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and evaporated. The material was purified by column chromatography eluting with 2% ethyl acetate/hexanes followed by vacuum distillation using a Kugelrohr collecting product at 150° C. 5.2 g of product was obtained (34%)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[F:15][CH:16]([F:33])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[S:29](Cl)(=[O:31])=[O:30].N1C=C(C)C=C(C)C=1>CS(C)=O>[F:33][CH:16]([F:15])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=1[S:29]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1c(OCC(F)F)cccc1C(F)(F)F
Reactant: COc1cnc(OC)n2nc(N)nc12
Agent: Cc1cncc(C)c1
Solvent: CS(C)=O
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Reaction time: 8.5 h
Yield: 93.1 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (7.8 g, 0.040 mol) and 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride (13 g, 0.040 mol) were combined in 3,5-lutidine (31 g, 0.29 mol, 7.2 eq). The slurry was treated with methyl sulfoxide (0.040 g, 0.0005 mol, 0.012 eq) and stirred at ambient conditions for 8.5 hours. The reaction slurry was filtered, and the wet cake solids were slurried in a mixture of 15% sulfuric acid (80 mL) and acetonitrile (20 mL). The mixture was stirred for 25 minutes, then filtered, and the solids washed with water. After drying under vacuum at 55° C., 18 g of product was obtained as a white solid assaying at 97.4 wt % (91% yield).
Reaction SMILES: CSC.ClCl.[NH2:6][C:7]1[N:15]=[C:14]2[N:9]([C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]2[O:16][CH3:17])[N:8]=1.N1C=CC=C(C)C=1.[F:27][CH:28]([F:45])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:32]=1[S:41](Cl)(=[O:43])=[O:42].S(Cl)(Cl)(=O)=O>C(#N)C.O>[F:45][CH:28]([F:27])[CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[C:32]=1[S:41]([NH:6][C:7]1[N:15]=[C:14]2[N:9]([C:10]([O:18][CH3:19])=[N:11][CH:12]=[C:13]2[O:16][CH3:17])[N:8]=1)(=[O:42])=[O:43]
Reactant: O=S(=O)(Cl)c1c(OCC(F)F)cccc1C(F)(F)F
Reactant: COc1cnc(OC)n2nc(N)nc12
Agent: ClCl
Solvent: O=S(=O)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Temperature: 8 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
A solution of methyl sulfide (0.34 g, 0.0055 mol) in acetonitrile (40 mL) was cooled to −25° C. To the cold solution was added a cold, freshly prepared 17 wt % solution of chlorine in acetonitrile (2.4 g, 0.0057 mol) over several minutes. While still cold, 1.1 g of 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (1.1 g, 0.0056 mol) and 3-picoline (0.95 g, 0.010 mol) were added. The mixture was allowed to warm to 8° C. 3-Picoline (48 g, 0.52 mol), 2-amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (18.4 g, 0.094 mol), and 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride (32.5 g, 0.10 mol) were added in order to the reactor. The mixture was stirred and heated at ˜40° C. for 24 hours, then at room temperature for 48 hours. The reaction slurry was converted into a solution by the addition of acetonitrile (600 mL) and water (100 mL). The solution was assayed for product by HPLC and determined to contain 42 g (86% yield, in situ, from sulfonyl chloride).
Reaction SMILES: [CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]>C([O-])(=O)C>[CH2:1]([OH:34])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:29][OH:30])[C@H:5]([OH:31])[C@@H:4]([OH:32])[C@@H:3]1[OH:33]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O[C@H]3[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]3CO)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Product: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
The two types of enzymatic activities described above were measured as following. The activity of α-isomaltosylglucosaccharide-forming enzyme was measured by the following assay: A substrate solution was prepared by dissolving maltotriose in 100 mM acetate buffer (pH 6.0) to give a concentration of 2% (w/v). A reaction mixture was prepared by mixing 0.5 ml of the substrate solution and 0.5 ml of an enzyme solution, and incubated at 35° C. for 60 minutes. After stopping the reaction by boiling for 10 minutes, the amount of maltose formed in the reaction mixture was determined by high-performance liquid chromatography (HPLC). One unit of α-isomaltosylglucosaccharide-forming activity was defined as the amount of the enzyme that forms one μmole of maltose per minute under the above conditions. HPLC was carried out using “SHODEX KS-801 column”, Showa Denko K. K., Tokyo, Japan, at a column temperature of 60° C. and a flow rate of 0.5 ml/minutes of water, and using “RI-8012”, a differential refractometer commercialized by Tosoh Corporation, Tokyo, Japan.
Reaction SMILES: OS(O)(=O)=O.[I:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[OH-].[Na+].[CH3:19]O>>[I:6][C:7]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:8]=1[C:9]([O:11][CH3:19])=[O:10]
Reactant: CO
Reactant: Cc1ccc(I)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(C)ccc1I

Procedure:
H2SO4 95-98% (2.54 mL, 0.048 mol) was added to a solution of 2-iodo-5-methylbenzoic acid (25.0 g, 0.095 mol) in MeOH (220 mL) and refluxed for 20 h. The rxn mixture was cooled with an ice bath, and 1N aq. NaOH was added dropwise until pH 8 was reached. The org. solvent was removed in vacuo and the aq. layer was extracted with DCM (2×). The combined org. extracts were washed with sat. aq. NaHCO3 (1×) and H2O (1×), dried (Na2SO4), filtered and concentrated in vacuo to give methyl 2-iodo-5-methylbenzoate as a pale yellow liquid which was used in the next step without further purification. LC-MS A: tR=0.87 min; [M+H]+=259.22.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>O1CCCC1.C1CCCCC1>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[S:15][CH2:14][CH2:13][CH2:12][S:11]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(c1ccc(Br)cc1)C1SCCCS1
Reactant: BrCCCCBr
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(c1ccc(CCCCBr)cc1)C1SCCCS1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-bromo-1-(1,3-dithian-2-yl)ethylbenzene (27.2 g, 94 mmol) in tetrahydrofuran (200 ml) was charged with sec-butyl]ithium (99 ml, 1.3M in cyclohexane, 0.13 mole) dropwise at -78° C. under nitrogen. The mixture was stirred at ambient temperature for 1.5 hours, and then quenched with 1,4-dibromobutane (42 g, 0.2 mole). After being stirred for 3 hours, the mixture was poured into ethyl acetate, and then washed with water and brine. The organic solution was then dried (Na2SO4) and concentrated to an oil. The crude product was purified by flash chromatography over a silica gel column. The 4-(4-bromobutyl)-1-(l,3-dithian-2-yl)-ethylbenzene thus purified was a light oil, 22.3 g.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[C:19](Cl)=[O:20])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[Cl:9][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([Cl:8])[C:2]=1[NH:1][C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:16]([O:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:17]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reaction time: 0.17 h
Yield: 20 %

Procedure:
4-Amino-3,5-dichloropyridine (4.0 g) and 3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimately ground together in a mortar with a pestle, and transferred to a round-bottomed flask. The mixture is melted, using a hot air gun external to the flask, stirring with a magnetic stirrer. After 10 minutes, heating is ceased and the melt is allowed to cool. The resulting material is triturated with dichloromethane and the residual solid is filtered off. The filtrate is concentrated to give a fawn solid, which is subjected to flash chromatography on silica gel, eluting with diethyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87 g), m.p. 155°-157° C. [Elemental analysis: C,56.3; H,4.7; N,7.2; Cl,18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum: 1661 cm-1, 3244 cm-1 ].
Reaction SMILES: [C:1]([C:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([CH3:13])=O.CO.N1CCCC1>C(O)(=O)C.CCOCC.O>[C:1]([C:5]1[CH:9]=[CH:8][C:7](=[C:11]([CH3:13])[CH3:10])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1=CC=CC1
Reactant: CC(C)=O
Solvent: C1CCNC1
Solvent: CCOCC
Solvent: CO
Product: CC(C)=C1C=CC(C(C)(C)C)=C1
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a mixed solution of 1.40 g (11 mmol) of tert-butylcyclopentadiene, 8.4 ml (114 mmol) of acetone and 20 ml of methanol, 9.5 ml (114 mmol) of pyrrolidine was added with ice cooling, followed by stirring at room temperature for one night. To the reaction solution, 50 ml of water, 100 ml of ether and 3 ml of acetic acid were added with ice cooling. The separated organic phase was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was subjected to column chromatography (silica gel, developing solvent: hexane) to obtain 1.62 g of a yellow liquid (yield: 88%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH:8]=[N:7]1>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Yield: 64.5 %

Procedure:
1-(3-Fluorobenzyl)-5-nitro-1H-indazole from Example 7A (500 mg) was dissolved in ethanol (40 mL) and was hydrogenated in an H-Cube™ (room temperature, 1 bar, 1 mL/min, 10% Pd/C catalyst). After removal of the solvent and trituration with tert-butyl methyl ether, 287 mg (64%) of the title compound were obtained.