Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[OH-].[Na+].Cl[CH2:14][CH2:15][CH2:16][NH2:17]>C(O)C.O>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[S:1][CH2:14][CH2:15][CH2:16][NH2:17]
Reactant: NCCCCl
Reactant: Sc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NCCCSc1nc2ccccc2o1
Yield: 71.6 %

Procedure:
2-Mercaptobenzoxazole (15.2 g; 0.1 mol) was dissolved in ethanol (200 ml); NaOH (4.0 g; 0.1 mol) dissolved in water was added thereto. The reaction mixture was refluxed for 30 minutes, then 3-chloropropylamine (9.3 g; 0.1 mol) dissolved in ethanol (50 ml) was added. The mixture was refluxed for 90 minutes, cooled, filtered from the salt and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with methanol/ether (1:3), (15.0 g; 71.6% yield).
Reaction SMILES: [ClH:1].[CH:2]1([C:5]2[CH:6]=[C:7]([F:21])[C:8]3[NH:12][C:11](=[O:13])[N:10]([CH:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:9]=3[CH:20]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[ClH:1].[CH:2]1([C:5]2[CH:6]=[C:7]([F:21])[C:8]3[NH:12][C:11](=[O:13])[N:10]([CH:14]4[CH2:15][CH2:16][N:17]([CH:32]5[CH2:33][CH2:34][O:29][CH2:30][CH2:31]5)[CH2:18][CH2:19]4)[C:9]=3[CH:20]=2)[CH2:3][CH2:4]1
Reactant: O=c1[nH]c2c(F)cc(C3CC3)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=c1[nH]c2c(F)cc(C3CC3)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Cyclopropyl-4-fluoro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (D29, 0.28 mmol, 86 mg), was dissolved in 1,2-dichloroethane (3 ml) and triethylamine (3 eq., 0.83 mmol, 0.086 g), tetrahydro-4H-pyran-4-one (7 eq., 1.99 mmol, 0.2 g) and sodium triacetoxyborohydride (3 eq., 0.83 mmol, 0.052 g) were added at room temperature and the mixture was stirred at room temperature for one overnight. The reaction mixture was quenched with NaHCO3 (saturated solution) and diluted with dichloromethane, then the two phases were separated by hydrophobic filter and the aqueous was washed with dichloromethane again. The organic phases were combined and the solvent was evaporated to afford the crude product which was purified by chromatography (methanol-NH3-dichloromethane) to afford the free base of the title compound, 100 mg, 98%, M++H=360. This material was dissolved in methanol (2 ml) and HCl (3 eq., 0.046 ml from a 1M solution in diethyl ether) was added at room temperature and the mixture was stirred at room temperature for 5 minutes. The solvent was subsequently evaporated to afford the title compound, 90 mg, 82%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:4]2[N:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>C(O)C>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)[N:4]3[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2nnc3c4ccccc4c(Cl)nn23)cc1
Reactant: COc1ccc(N)cc1
Solvent: CCO
Product: COc1ccc(Nc2nn3c(-c4ccc(OC)cc4)nnc3c3ccccc23)cc1
Yield: 81.3 %

Procedure:
5.0 g of 6-chloro-3-(4-methoxy-phenyl)-[1,2,4]triazolo[3,4-a]phthalazine (compound B1), and 20 g p-anisidine are stirred at 170° C. for 5 h. The reaction mixture is diluted with 40 ml ethanol and the precipitate is filtered with suction. The solid is recrystallized from N,N-dimethylformamide to yield 5.2 g of the title compound. M.p.: 301-304° C.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:26])[CH:24]([NH2:25])[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([CH2:29][CH2:30][C:31](Cl)=[S:32])#[N:28].C(N(CC)CC)C>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:26])[CH:24]([NH:25][C:31](=[S:32])[CH2:30][CH2:29][C:27]#[N:28])[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reactant: N#CCCC(=S)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCCC(=S)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reaction time: 4 h

Procedure:
7-Amino-3-cephem-4-carboxylic acid benzhydryl ester (366 mg.) (prepared by the method of Netherlands Patent no. 7,309,135) is dissolved in methylene chloride (5 ml.), cooled in an ice bath, and cyanomethylthioacetyl chloride (149 mg.) in methylene chloride (5 ml.) is added followed by triethylamine (101 mg.). The mixture is stirred for 4 hours at 0°-5° and, after diluting with methylene chloride the reaction mixture is washed with water then with pH 4 buffer, and dried (Na2SO4). The solvent is removed in vacuo yielding the product 7-cyanomethylthioacetamido-3-cephem-4-carboxylic acid benzhydryl ester as an oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15]3[CH:16]=[C:17]([NH:21][C@H:22]([C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[N:19][CH:20]=3)=[CH:13][N:12](COCC[Si](C)(C)C)[C:9]2=[N:10][CH:11]=1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(N)CN.[OH-].[Na+]>C(Cl)Cl.CS(C)=O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15]3[CH:16]=[C:17]([NH:21][C@H:22]([C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[N:19][CH:20]=3)=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CC(C)[C@H](Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(NS(C)(=O)=O)cc23)c1)C(=O)NCC(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(C)[C@H](Nc1cncc(-c2c[nH]c3ncc(NS(C)(=O)=O)cc23)c1)C(=O)NCC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of N2-[5-(5-[(methylsulfonyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]-N-(2,2,2-trifluoroethyl)valinamide 5-3a (57 mg, 0.093 mmol) from step 1 in DCM (2 mL) was added TFA (0.714 mL, 9.27 mmol) and the resultant mixture was stirred for 2 h. The mixture was concentrated in vacuo, resuspended in MeOH (1 mL) and to this was added ethylenediamine (0.013 mL, 0.185 mmol) and sodium hydroxide (10 M aq) (0.065 mL, 0.649 mmol). After 18 h, the reaction was transferred to vial with an additional 1 mL of dimethylsulfoxide and this solution was purified by mass triggered reverse phase HLPC. The fractions containing product 5-3 were basified with NaHCO3, dried over MgSO4, filtered and concentrated.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:9])(=[O:8])=[O:7].[Cl:10][C:11]1[CH:12]=[C:13]([N:18]=[C:19]=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17].[OH-].[Na+].Cl>CC(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]([NH:9][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[O:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NS(=O)(=O)c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1cccs1
Yield: 39 %

Procedure:
2-Thiophenesulfonamide (1.55 g, 9.5 mmole) was combined with 3,4-dichlorophenyl isocyanate (1.79 g, 9.5 mmole), 1N NaOH (9.5 ml) and acetone (25 ml) followed by 1N HCl (9.5 ml) using the method of Example 4B to give the named product (1.3 g).
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([OH:21])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:4]1.C1C[O:25][CH2:24]C1>>[O:25]=[C:24]1[NH:1][CH2:2][C@@:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[O:21]1
Reactant: C1CCOC1
Reactant: N#Cc1ccc2ncn(C[C@H]3CCC[C@@](O)(CN)C3)c2c1
Product: N#Cc1ccc2ncn(C[C@H]3CCC[C@@]4(CNC(=O)O4)C3)c2c1
Temperature: 160 °C
Yield: 97 %

Procedure:
A suspension of 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (760 mg, 2.84 mmol) in MeOH (8 mL) was treated with 7M ammonia in MeOH (1.429 mL, 10.00 mmol) in a 20 mL microwave vial. The vial was sealed and heated in a microwave at 100° C. for 3 h. The reaction mixture was cooled to RT and blown down to dryness with nitrogen for 24 h to give crude 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile which was used without further purification. A solution of 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (808 mg, 2.84 mmol) in THF (24 mL) was sealed under nitrogen in three 20 mL microwave vials and heated with microwave at 160° C. for 3 h. The combined reaction mixture was then concentrated to dryness and 50 mL of water was added. The solid was then filtered and washed with 2×10 mL of water. The solid was air-dried under house vacuum overnight. The compound was purified under normal phase flash column chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%) to give 1-{[(5S,7S)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an off-white solid (856 mg, 97% yield). The aromatic region of the NMR spectra showed that the product contained less than 8% of the cis-diastereomer. MS (m/z) 311.1 (M+H+).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[NH:4]1.[C:17]([CH2:19][C:20](O)=[O:21])#[N:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:20](=[O:21])[CH2:19][C:17]#[N:18]
Reactant: N#CCC(=O)O
Reactant: CC1(C)N[C@H](CF)[C@@H](c2ccc(I)cc2)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a mixture of (4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyl-oxazolidine (3.5 g, 10.50 mmol), 2-cyanoacetic acid (1.34 g, 15.8 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.11 g, 15.8 mmol) in dimethylformamide (21 mL) is added triethylamine (2.12 g, 21 mmol) and stirred at room temperature for overnight. The mixture is partitioned between ethylacetate and brine. The organic solution is separated, dried over MgSO4, filtered and evaporated to give a yellow residue, which is purified on silica gel column using heptane to neat ethylacetate to give the title compound (2.75 g): 1HNMR (DMSO-d6): 1.48 (s, 3H), 1.53 (s, 3H), 3.96-4.24 (m, 2H), 4.47-4.84 (m, 3H), 5.11 (d, 1H), 7.31 (d, 2H), 7.77 (d, 2H).
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:27](OC)=[O:28])=[C:8]2[C:12]=1[N:11]=[C:10]1[N:13]([C:17]3[CH:18]=[N:19][C:20]([N:24]([CH3:26])[CH3:25])=[CH:21][C:22]=3[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]21>O1CCCC1>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:18]=[N:19][C:20]([N:24]([CH3:25])[CH3:26])=[CH:21][C:22]=4[CH3:23])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([CH2:27][OH:28])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1cnc(N(C)C)cc1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(N(C)C)ncc1N1CCCn2c1nc1c(Cl)ccc(CO)c12
Temperature: 40 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Lithium borohydride (265 mg, 12.2 mmol) was added to a stirred solution of methyl 9-chloro-1-[6-(dimethylamino)-4-methylpyridin-3-yl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (1.22 g, 3.05 mmol) in tetrahydrofuran (20 mL) at room temperature, and the mixture was stirred at 40° C. for 24 hr. The reaction was quenched by aqueous saturated ammonium chloride at 0° C., concentrated in vacuo and the precipitate was collected by filtration, washed with water, diisopropyl ether to give the title compound as a colorless powder (1.13 g, 3.04 mmol, 99%).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CCOCC>C1COCC1.C(Cl)Cl>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9]1
Reactant: N#CCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(4,4-diphenylpiperidin-1-yl)butyronitrile (4.65 g, 15.3 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 54 mL, 54 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature and concentrated to a volume of about 40 mL. Aqueous HCl (6 N, 55 mL) was added cautiously at 0° C. and stirring was continued for 2 hours at 55-65° C. The mixture was cooled to 0° C., basified to pH 10 by addition of 6 N aq. NaOH, and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. To a solution of the residue in CH2Cl2 (50 mL) was added HCl in ether (1.0 M, 30 mL, 2.0 equiv). After removal of the solvents, the residue was dissolved in CH2Cl2 (10 mL) and this solution was added dropwise into ether (150 mL) with swirling. The resulting solid was filtered and washed with ether (100 mL). This solid was taken up in water (30 mL), which was basified to pH 10 by addition of 1 M aqueous NaOH, and extracted with CH2Cl2 (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 4.51 g (95%) of light brown oil, which was characterized spectroscopically.
Reaction SMILES: C(O[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[CH2:18]([N:20]([CH2:33][CH3:34])[S:21]([C:24]1[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:23])=[O:22])[CH3:19].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:33]([N:20]([CH2:18][CH3:19])[S:21]([C:24]1[NH:25][C:26]2[C:31]([C:32]=1[CH:5]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:22])=[O:23])[CH3:34]
Reactant: CCN(CC)S(=O)(=O)c1cc2ccccc2[nH]1
Reactant: CC(=O)OC(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1[nH]c2ccccc2c1C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a solution of benzhydryl acetate (0.77 g, 3.39 mmol) and N,N-diethylindole-2-sulfonamide (0.9 g, 3.39 mmol) in 20 ml of methylene chloride was added methanesulfonic acid (0.7 ml, 10.7 mmol), followed by stirring at room temperature for one hour. A saturated aqueous solution of sodium bicarbonate was added to the reaction solution for neutralization followed by extraction with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product. The obtained crude product was crystallized from diisopropyl ether to give 0.99 g (yield: 67%) of the title compound.
Reaction SMILES: C(B1O[C:8]([CH3:10])([CH3:9])[C:5]([CH3:7])(C)O1)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=CC(Br)=C[N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]>CN(C)C=O.O>[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[N:27][N:28]([C:31]2[C:36]([Cl:37])=[CH:9][C:8]([CH:5]=[CH2:7])=[CH:10][N:32]=2)[C:29]=1[CH3:30])=[O:24])[CH3:21]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1cnc(-n2ncc(C(=O)OCC)c2C)c(Cl)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Vinylboronic acid pinacol ester (1.37 ml), tripotassium phosphate (3.85 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (301 mg) were added to a solution of 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.52 g) described in Reference Example 44(2) in N,N-dimethylformamide (36 ml), and the mixture was stirred at 100° C. for seven hours. The reaction solution was cooled to room temperature, diluted with water, filtered through Celite and the filtrate was extracted with ethyl acetate three times. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1-(3-chloro-5-vinylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (1.67 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][C:15]2([CH2:20]Cl)[O:19][CH2:18][CH2:17][O:16]2)[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].[OH-].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]([OH:11])=[O:10])[CH2:14][C:15]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:20]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(CC1(CCl)OCCO1)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)C1(c2ccc(Br)cc2)CC2(C1)OCCO2

Procedure:
To a solution of ethyl 2-(4-bromophenyl)-3-[2-(chloromethyl)-1,3-dioxolan-2-yl]propanoate (1-3) (27 g, 71.5 mmol) cooled to −78° C. in DMF (200 mL) was added NaH (8.58 g, 214 mmol) and the reaction was allowed to slowly warm from −78° C. to rt. Once at rt, 1N NaOH (100 mL) was added and the reaction mixture was stirred over night. The crude reaction mixture was poured into saturated sodium bicarbonate and washed with chloroform. The aqueous layer was acidified with HCl, extracted with chloroform, dried over sodium sulfate filtered and concentrated. The crude residue was purified by column chromatography eluting with 1-50% EtOAc/Hexane. The appropriate fractions were concentrated and recrystallized from EtOAc/hexane to give 2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octane-2-carboxylic acid (1-4) as a white solid. MS (M+H)+: 314.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[N:20][NH2:21])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH2:33][C:34](O)=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2/[CH:19]=[N:20]/[NH:21][C:34](=[O:35])[CH2:33][C:31]2[CH:30]=[CH:29][C:28]3[O:24][CH2:25][O:26][C:27]=3[CH:32]=2)(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: NN=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccc2c(c1)OCO2)N/N=C/c1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h

Procedure:
A solution of 2-[hydrazonomethyl]phenyl 4-(trifluoromethyl)benzenesulfonate (150 mg, 0.44 mmol) and 1,3-benzodioxol-5-ylacetic acid (1.2 equiv) in DMF (1 mL) is treated with a solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (167 mg, 0.87 mmol) and 4-dimethylaminopyridine (DMAP) (106 mg, 0.87 mmol) in CH2Cl2 (10 mL). The solution is shaken overnight on an orbital shaker. The solution is evaporated to dryness using a speed. Water is added to the mixture, which is then sonicated to give a solid. The solid is filtered and washed with a large amount of water. A small amount of methanol is added and the mixture sonicated. The resulting solid is filtered and washed with more methanol to yield pure 2-((E)-{2-[2-(1,3-benzodioxol-5-yl)acetyl]hydrazono}methyl)phenyl 4-(trifluoromethyl)benzenesulfonate. The yield is 169 mg, 77%. 1H NMR (400 MHz, DMSO) □ 11.48 (2s, 1H), 8.01 (m, 6H), 7.12 (m, 6H), 5.99 (2s, 2H), 3.62 (2s, 2H). ESI− for C23H17F3N2O6S, m/z 505, (M−H)−.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].C(O)C(N)(CO)CO.Cl.[Mg+2].[Cl-].[Cl-].N[C@H](C(O)=O)CS.S(=O)(=O)(O)O.C1C2NC3C(=CC=CC=3)C=2C=CC=1.OCC([C@H]([C@H]([C@@H](CO)O)O)O)=O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: N[C@@H](CS)C(=O)O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The isomerization of galactose was performed with a mixture of 25 μl of 100 mM galactose and 100 μl of the crude enzyme solution as a substrate at 60° C. for 1 hour. To measure the activity of galactose isomerization, 100 μl of the crude enzyme solution containing 40 mM of galactose as a substrate was mixed with 1 Ml of reaction buffer (50 mM Tris-HCl, pH 7.0), followed by reaction at 65° C. for 20 minutes. At that time, 5 mM of MgCl2 and 1 mM of MnCl2 were added to the reaction mixture. The activity of the isomerase was measured by the cystein-carbazol-sulfuric acid method (Dische, Z., and E. Borenfreund., A New Spectrophotometric Method for the Detection and Determination of Keto Sugars and Trioses, J. Biol. Chem., 192:583-587, 1951). The protein contained in the crude enzyme solution was quantified with a Bradford assay kit (Biorad, U.S.A.). As a result, the isomerase activity was 0.2045±0.0078 (mg-tagatose/mg-protein·h), indicating that the product of galactose isomerization, tagatose, was successfully generated (FIG. 3).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=3)[CH2:13][CH2:14][O:15][CH2:16][CH2:17][C:18]([OH:20])=O)[CH:7]=[N:6]2)[CH2:3][CH2:2]1.[CH3:24][O:25][CH:26]([O:34][CH3:35])[CH2:27][NH:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([N:28]([CH2:27][CH:26]([O:34][CH3:35])[O:25][CH3:24])[C:18](=[O:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[C:10]([C:8]3[CH:7]=[N:6][N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH:9]=3)[CH:11]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)CCOCCc1cccc(-c2cnn(CC3CC3)c2)c1
Reactant: COC(CNC1CCCC1)OC
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(CC3CC3)c2)c1)C1CCCC1)OC

Procedure:
The subtitled compound (246 mg) was prepared from 3-(3-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 19, Step iii)] and N-(2,2-dimethoxyethyl)cyclopentanamine, prepared as in Preparation 9 using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=438 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.79 (s, 1H), 7.40 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.7 Hz, 1H), 4.56 and 4.37 (2×t, J=5.4 Hz, 1H), 4.26-4.15 (m, 1H), 4.00 (d, J=6.9 Hz, 2H), 3.76-3.65 (m, 4H), 3.35 and 3.22 (2×d, J=4.8 Hz, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 2.85 (t, J=6.4 Hz, 2H), 2.65 (t, J=6.3 Hz, 2H), 1.82-1.44 (m, 8H), 1.38-1.23 (m, 1H), 0.65-0.57 (m, 2H), 0.44-0.33 (m, 2H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19]CCC[CH:15]([N:20]([CH3:30])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:14][CH:15]([N:20]([CH3:30])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:19]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN(c1ncnc2[nH]ccc12)C1CCCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Solvent: CO
Solvent: ClCCl
Product: CN(c1ncnc2[nH]ccc12)C1CN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Yield: 23 %

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichloro-phenylamino)-1-{3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-azepan-1-yl}-ethanone to give a residue that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (10 mg, 23%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.88 (bs, 1H), 8.18 (s, 1H), 7.22 (d, J=4.0 Hz, 1H), 6.66 (s, 2H), 6.60 (s, 1H), 6.50-6.22 (m, 1H), 5.58-5.42 (m, 1H), 4.54 (t, J=8.0 Hz, 2H), 4.40-4.28 (m, 1H), 4.24 (t, J=8.0 Hz, 1H), 4.16-4.08 (m, 1H), 3.36 (s, 3H) 3.80 (d, J=2.0 Hz, 1H). LC-MS: m/z [M+1]=405.