Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12CC1CC(=O)C2.[C:8]([O:15][CH2:16][CH3:17])(=[O:14])[C:9](OCC)=O.CC(C)([O-])C.[K+].Cl.FC1C=C(F)C=CC=1NN.Cl.COC(C1[C:41]2[CH:55]3[CH2:56][CH:54]3[CH2:53][C:42]=2[N:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=2[F:52])[N:44]=1)=O>C(O)C.[Cl-].[Na+].O.C1COCC1>[CH2:16]([O:15][C:8]([C:9]1[C:41]2[CH:55]3[CH2:56][CH:54]3[CH2:53][C:42]=2[N:43]([C:45]2[CH:50]=[CH:49][C:48]([F:51])=[CH:47][C:46]=2[F:52])[N:44]=1)=[O:14])[CH3:17]
Reactant: COC(=O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: NNc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nn(-c2ccc(F)cc2F)c2c1C1CC1C2
Temperature: 40 °C
Reaction time: 18 h
Yield: 712.2 %

Procedure:
To a solution of bicyclo[3.1.0]hexan-3-one (0.30 g, 3.12 mmol) and diethyl oxalate (0.433 mL, 3.20 mmol) in denatured absolute ethanol (10 mL) was added a 1.0 M THF solution of potassium tert-butoxide (3.28 mL, 3.28 mmol). The resulting yellow solution was stirred at 20° C. for 2 h. (2,4-Difluorophenyl)hydrazine hydrochloride (0.564 g, 3.12 mmol) was added followed by a 3.0 M aqueous solution of hydrogen chloride (3.12 mL, 9.36 mmol). The reaction was stirred at 40° C., for 18 h. Brine (100 mL) was added. The mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over MgSO4, filtered, then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give a mixture of the title compound (0.672 g) and 1-(2,4-difluoro-phenyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-3-carboxylic acid methyl ester (0.090 g) as yellow solids. LCMS m/z=305.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.36 (td, J=4.5, 3.8 Hz, 1H), 1.17 (td, J=7.9, 5.0 Hz, 1H), 1.41 (t, J=7.2 Hz, 3H), 2.09-2.16 (m, 1H), 2.33-2.37 (m, 1H), 2.80 (d, J=16.9 Hz, 1H), 2.98 (dd, J=16.9, 6.7 Hz, 1H), 4.36-4.49 (m, 2H), 6.92-6.99 (m, 2H), 7.61-7.67 (m, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.CCCCCC.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([Cl:31])=[N:26][CH:27]=[N:28][C:29]=2[Cl:30])=[CH:20][CH:19]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C>O1CCCC1.O.C(O)(=O)C>[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:29]([Cl:30])=[N:28][C:27]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:26][C:25]=2[Cl:31])=[CH:22][CH:23]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: c1ccsc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(Cl)nc(-c3cccs3)nc2Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
To a solution of thiophene (1.69 g) in anhydrous tetrahydrofuran (20 ml) is added dropwise a 1.6M n-butyl lithium/n-hexane solution (11.4 ml) at 0° C. under argon atmosphere over a period of 30 minutes. To the mixture is added dropwise and gradually a solution of 5-(4-methylphenyl)-4,6-dichloropyrimidine (4.0 g) in anhydrous tetrahydrofuran (5 ml) at -60° C. The mixture is warmed to 0° C., and stirred for 1.5 hour. After the reaction is complete, to the mixture are added acetic acid (1.5 g) and water (0.25 g), and further added thereto a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.70 g) in tetrahydrofuran (5 ml), and the mixture is stirred at 0° C. for one hour. The mixture is treated with an active charcoal, and extracted with a mixture of ethyl acetate and aqueous citric acid solution. The extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate=50:1) to give 5-(4-methylphenyl)-4,6-dichloro-2-(2-thienyl)pyrimidine (2.64 g) as powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:25]=4[CH:24]=3)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O.CCOC(C)=O>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[C:31]([Cl:32])[C:25]=4[CH:24]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3cc4c(Cl)cccc4s3)cn2)CC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCNCC2)nc1)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of 4-{5-[(4-chloro-benzo[b]thiophene-2-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (75 mg, 0.16 mmol) in 15 mL of dichloromethane and 5 mL of TFA was stirred at room temperature for 2 hr. The reaction mixture was taken up in 100 mL of EtOAc and washed with 100 mL of 1N NaOH, brine and dried over anhydrous sodium sulfate. The solvent was removed and the residue was triturated with diethyl ether and hexanes (1:1 ratio), followed by filtration, to afford the product 4-chloro-benzo[b]thiophene-2-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide, (50 mg, 85% yield) as an off white solid. LCMS for C18H17ClN4OS calcd. (m/e) 372, observed 373 (M+H).
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].O.[OH-].[Li+].OO>CO.O>[NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-Cbz-L-Leu-L-Leu-OCH3 (6.0 g, 14.6 mmol) in MeOH/H2O (3:1) (60 mL) at R. T. was added lithium hydroxide monohydrate (LiOH.H2O) (1.0 g, 43.9 mmol) and hydrogen peroxide (H2O2) (30% weight in H2O) (4.5 mL, 43.9 mmol). The reaction mixture was stirred for 3.5 h and then quenched with 10% HCl. The resulting mixture was extracted with EA (3×20 mL). The combined organic extracted were washed with sat. NaCl (2×10 mL), dried (MgSO4) and concentrated in vacuo to afford N-Cbz-L-Leu-L-Leu-OH as a white solid (5.0 g, 90.5%): 1H NMR (CDCl3, 300 MHz) δ 0.89-0.92 (t, 12H, J=3.0 Hz), 1.48-1.71 (m, 6H), 4.11-4.13 (m, 1H), 4.55-4.62 (m, 1H), 5.09 (s, 2H), 5.64 (d, 1H, J=9.0 Hz), 6.83 (d, 1H, J=9.0 Hz), 7.33-7.40 (m, 5H) ppm.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH:13]1[C:17]([OH:18])=[C:16]([C:19]([CH3:21])=[O:20])[CH2:15][S:14]1.S(Cl)(Cl)(=O)=O>O>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[C:13]1[S:14][CH:15]=[C:16]([C:19]([CH3:21])=[O:20])[C:17]=1[OH:18]
Reactant: CC(=O)C1=C(O)C(c2ccc(Cl)cc2Cl)SC1
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1csc(-c2ccc(Cl)cc2Cl)c1O
Temperature: -25 °C
Reaction time: 0.67 h
Yield: 101.1 %

Procedure:
A chloroform (3 mL) solution of 2-(2,4-dichlorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (0.3 g, 0.93 mmol, purity: 90%) was cooled to −36° C., and to this solution, a chloroform (5 mL) solution of sulfuryl chloride (0.082 mL, 1.2 equivalent amounts) was dropwise added over a period of 10 minutes, followed by stirring at −25° C. for 40 minutes. The temperature of the solution was raised to 5° C., and water (0.6 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow solid (0.27 g, yield: 91%).
Reaction SMILES: [O:1]([CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][N:31]3[CH:37]=2)[CH:25]=[CH:26][CH:27]=1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].O>O1CCCC1.C(#N)C>[OH:1][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][N:31]3[CH:37]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](OCCOc1cccc(-c2cn3cc(I)ccc3n2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: OCCOc1cccc(-c2cn3cc(I)ccc3n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
477 mg (corresponding to 0.771 mmol) of 2-[3′-(2″-t-butyldiphenylsiloxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine was dissolved in 0.98 mL of tetrahydrofuran, and 0.93 mL of a 1.0 mol/L tetrahydrofuran solution of tetrabutylammoniumfluoride was added thereto. After the reaction mixture was stirred at room temperature for 15 minutes, ammonium chloride solution was added followed by addition of 5.0 mL of water and 2.0 mL of acetonitrile to filter precipitates. The filtered precipitates were washed with water and acetonitrile in this order to obtain 120 mg (corresponding to 0.316 mmol) of 2-[3′-(2″-hydroxyethoxy)phenyl]-6-iodoimidazo[1,2-a]pyridine (FIG. 2-8, Step 5).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]3[NH:21][C:20]([CH:22]=[C:23]4[N:46]=[C:26]([C:27]([CH:39]([CH2:43][CH2:44]Br)[CH2:40][CH2:41]Br)=[C:28]5[NH:38][C:31](=[CH:32][C:33]6[CH:34]=[CH:35][C:36]=2[N:37]=6)[CH:30]=[CH:29]5)[CH:25]=[CH:24]4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:48][P:49]([O:52][CH3:53])[O:50][CH3:51]>>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]3[NH:21][C:20]([CH:22]=[C:23]4[N:46]=[C:26]([C:27]([CH:39]([CH2:43][CH2:44][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:48])[CH2:40][CH2:41][P:49]([O:52][CH3:53])([O:50][CH3:51])=[O:48])=[C:28]5[NH:38][C:31](=[CH:32][C:33]6[CH:34]=[CH:35][C:36]=2[N:37]=6)[CH:30]=[CH:29]5)[CH:25]=[CH:24]4)=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COP(OC)OC
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2c3nc(cc4ccc([nH]4)c(C(CCBr)CCBr)c4nc(cc5ccc2[nH]5)C=C4)C=C3)cc1
Product: COP(=O)(CCC(CCP(=O)(OC)OC)c1c2nc(cc3ccc([nH]3)c(-c3ccc(OCC(=O)OC(C)(C)C)cc3)c3nc(cc4ccc1[nH]4)C=C3)C=C2)OC
Yield: 65 %

Procedure:
A sample of 15a (38.7 mg, 0.048 mmol) was dissolved in trimethylphosphite (5.0 mL). The solution was refluxed under argon for 1.5 days. The P(OMe)3 was evaporated at reduced pressure. The residue was chromatographed (silica, CH2Cl2/MeOH, 0→5%) to yield a dark purple solid (24.6 mg, 65%): 1H NMR δ 1.64 (s, 9H), 3.15 (m, 2H), 3.32-3.36 (m, 2H), 3.43 (s, 3H), 3.47 (s, 6H), 3.50 (s, 3H), 3.81-3.87 (m, 4H), 4.84 (s, 2H), 5.44 (m, 1H), 7.35 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.1 Hz, 2H), 9.10 (s, 2H), 9.40 (s, 2H), 9.50-9.51 (m, 1H), 9.73-9.74 (m, 2H), 10.30-10.31 (m, 2H); LD-MS obsd 803.7, calcd 800.3104 (C41H48N4O9P2); λabs (log ε) 407 (4.90), 504 nm; λem(λexc 407 nm) 636 nm, 702 nm. Varying amounts of a less polar purple solid (16a-Br) were isolated along with small amounts of the starting material 15a (limited characterization). Data for 16a-Br: 1H NMR δ 0.86-0.95 (m, 1H), 1.65 (s, 9H), 1.91-2.00 (m, 1H), 3.13-3.40 (m, 6H), 3.44 (s, 3H), 3.48 (s, 3H), 3.55-3.85 (m, 2H), 4.83 (s, 2H), 5.51-5.61 (m, 1H), 7.34 (d, J=8.1 Hz, 2H), 8.17 (d, J=8.1 Hz, 2H), 9.08-9.10 (m, 2H), 9.37-9.41 (m, 2H), 9.49-9.51 (m, 2H), 9.67-9.68 (m, 1H), 9.84-9.85 (m, 1H), 10.30 (s, 2H); LD-MS obsd 773.6, calcd 773.2 [(M+H)+, M=C39H42BrN4O6P2]; λabs 407, 502 nm; λem (λexc 407 nm) 634, 702 nm.
Reaction SMILES: C([Li])CCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10]C.[Cl:12][C:13]1[C:18]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1.ICCCCCI>O.C(COC)OC>[Cl:12][C:13]1[C:18]([C:19]2([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CCCCCC
Reactant: O=S(=O)(Cc1cccnc1Cl)c1ccc(Cl)cc1
Agent: ICCCCCI
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: O=S(=O)(c1ccc(Cl)cc1)C1(c2cccnc2Cl)CCCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.66 ml, 1.03 mmol) was added dropwise to a dimethoxyethane (5 ml) solution of the 2-chloro-3-(4-chlorophenylsulfonylmethyl)pyridine (156 mg, 0.516 mmol) obtained in Example 98. At −78° C., the resulting mixture was stirred for 20 minutes, followed by the addition of 1,5-diiodopentane (0.092 ml, 0.619 mmol). The temperature of the reaction mixture was gradually elevated to room temperature, at which stirring was performed for 15 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the 15% ethyl acetate/hexane eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (72 mg, 38%) as a white solid. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:6][O:7][CH3:8])=[CH2:5].B.C1C[O:13]CC1.B(O[O-])=O.[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][CH2:3][CH:4]([CH2:6][O:7][CH3:8])[CH2:5][OH:13]
Reactant: C=C(COC)COC
Reactant: C1CCOC1
Agent: B
Agent: O=BO[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCC(CO)COC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 48 %

Procedure:
To a solution of the 3-methoxy-2-methoxymethy-1-propene (3.5 g, 30 mmol, 1.0 eq.) in THF (10 mL) at 0° C. was added BH3.THF (1M in THF, 18 mL, 0.6 eq.) and the resulting mixture was stirred for 40 min. The reaction was quenched with water followed by sodium perborate (10.6 g, 2.3 eq.), warmed to room temperature, stirred overnight, diluted with CH2Cl2 and filtered through celite. The filtrate was diluted with brine and the separated aqueous layer was extracted with CH2Cl2. The combined extracts were dried over Na2SO4 and filtered. The filtrate was didstilled at atmospheric pressure to give light yellow liquid residue. Fractional distillation of the residue at 40 milliTorr gave 3-methoxy-2-methoxymethypropan-1-ol (1.93 g, 48%). b.p.=90-110° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:14]CC1.[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[CH:25]=[C:21]2[N:20]=[C:19]([CH3:36])[C:18]=1[CH2:37][C:38]([O:40][CH3:41])=[O:39].C1(C2ON2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Cl:16][C:17]1[N:22]2[N:23]=[C:24]([C:26]3[CH:35]=[CH:34][C:33]4[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=4[CH:27]=3)[CH:25]=[C:21]2[N:20]=[C:19]([CH3:36])[C:18]=1[CH:37]([OH:14])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)Cc1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: [K+]
Product: COC(=O)C(O)c1c(C)nc2cc(-c3ccc4c(c3)CCCC4)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a stirred solution of 0.9M KHMDS/THF (9.76 mL, 8.79 mmol) in THF (25 mL) at −78° C. was added dropwise a THF (25 mL) solution of methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)acetate (2.5 g, 6.76 mmol) over 5 min. After 30 min, a THF (20 mL) solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (2.296 g, 8.79 mmol) was added to the resulting red reaction mixture and stirred for additional 30 min at −78° C. Then, the resulting orange reaction mixture was quenched with sat. NH4Cl (50 mL), diluted with EtOAc (200 mL), washed with water (100 mL), brine (100 mL), dried (Na2SO4), filtered and concentrated to give yellow solid. This was purified by flash column chromatography on silica gel column (5-40% EtOAc/hexane) to afford the 2.2 g desired methyl 2-(7-chloro-5-methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)pyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate as off-white solid. Impurities were present by NMR and LCMS. Used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ: 7.77-7.71 (m, 2H), 7.19 (d, J=7.6 Hz, 1H), 6.93 (s, 1H), 5.78 (d, J=2.7 Hz, 1H), 3.86 (s, 3H), 3.56 (d, J=2.7 Hz, 1H), 2.89-1.81 (m, 4H), 2.64 (s, 3H), 1.86 (dt, J=6.5, 3.3 Hz, 4H). LCMS (M+H)=386.3.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][C:26]([N:29]([CH3:31])[CH3:30])=[N:27][CH:28]=1)=[CH:8]2)=[O:4].[OH-].[Na+].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[CH3:50][O:51][C:52](=[O:56])[CH2:53][CH2:54][NH2:55].CCN(C(C)C)C(C)C>CO.C1COCC1>[CH3:50][O:51][C:52](=[O:56])[CH2:53][CH2:54][NH:55][C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[N:27][C:26]([N:29]([CH3:31])[CH3:30])=[N:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)CCN
Reactant: COC(=O)c1ncc2c(cc(-c3cnc(N(C)C)nc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCNC(=O)c1ncc2c(cc(-c3cnc(N(C)C)nc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
A mixture of 1-benzyl-3-(2-dimethylamino-pyrimidin-5-yl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.07 mmol), 2 M NaOH (4 mL, THF (4 mL) and MeOH (4 mL) was stirred at r.t. for 16 h. The resulting mixture was concentrated to dryness, and diluted with water (5 mL). 1 M HCl was added until pH was about 4, and the resulting precipitate was isolated by filtration and dried under high vacuum. The crude solid was dissolved in CH2Cl2, and HOBt (12 mg, 0.09 mmol) and EDC (23 mg, 0.12 mmol) were added. The resulting mixture was stirred for 10 min. β-Alanine methyl ester HCl salt (13 mg, 0.09 mmol) and Hunig's base (0.030 mL, 0.21 mmol) were then added, and the mixture was stirred for 20 h. The solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH) to give 30 mg of the title compound as a pale yellow solid. MS: (+) m/z 503.33 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[S:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][C:10]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCSc2ccc(N)cc2C1
Product: COCCN1CCSc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2C1
Yield: 26.8 %

Procedure:
Following the procedure of 512f, 8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00029 mol) and N-[(1S,2R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.099 g, 0.00029 mol) were reacted. Purification was carried out by SiO2 prep plate chromatography giving N-((1R,2R)-2-{5-chloro-2-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino]pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (0.042 g, 28%) as a grey solid. MP: 140-3° C.; 1H-NMR (DMSO-d6) 9.28 (s, 1H), 7.95 (s, 1H), 7.60-5 (s, 1H), 7.58 (d, 1H), 7.33-5 (d, 1H), 7.16-8 (d, 1H), 6.76-8 (d, 1H), 4.01 (s, 2H), 3.80-90 (m, 1H), 3.36-45 (m, 4H), 3.21 (m, 4H), 2.93 (s, 2H), 2.67 (s, 2H), 2.0010 (m, 2H), 1.65-80 (m, 2H), 1.20-45 (m, 4H); LC/MS (ESI+): 541 (M).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[C:23]#N.CO.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[CH:23]=[O:28]
Reactant: COc1cccc(OC)c1/C=C/C#N
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1/C=C/C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Add 355 mL of a 1M solution of diisobutylaluminium hydride (DIBAL-H) (355 mmol) in toluene to a solution of 61 g (322 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in 600 mL of anhydrous toluene under argon and cooled to 0° C., maintaining the temperature at 0° C. Then bring the reaction mixture to room temperature (RT) and stir for 3 h. Then add 13 mL (322 mmol) of methanol and then, dropwise, 170 g (174 mmol) of an aqueous solution of sulphuric acid at 10 wt. %. Stir the suspension for one hour, then filter on a celite bed. Wash the filtrate with 500 mL of water then dry over Na2SO4 and concentrate under reduced pressure. Take up the residue obtained in 500 mL of DCM and filter in a silica column, eluting with DCM. After concentration under reduced pressure, we obtain 37 g of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde in the form of colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CN1CCC(CN)(c2coc(-c3ccc(F)cc3)n2)CC1
Product: CN1CCC(CNC(=O)c2cccc(-c3noc(C(F)(F)F)n3)c2)(c2coc(-c3ccc(F)cc3)n2)CC1
Yield: 24 %

Procedure:
This compound was synthesized from (4-(2-(4-fluorophenyl)oxazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (50 mg, yield 24%). 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.29-8.27 (m, 1H), 8.13-8.05 (m, 3H), 7.67-7.62 (m, 2H), 7.17-7.13 (t, J=8.7 Hz, 2H), 3.85-3.84 (m, 2H), 3.14-3.00 (m, 4H), 2.67 (m, 3H), 2.43-2.42 (m, 2H), 2.24-2.23 (m, 2H). MS (ESI) m/z: Calculated for C26H23F4N5O3: 529.17. found: 530.2 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[O:5]=[CH:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8].CC1N(C)N(C2C=CC=CC=2)C(=O)C=1N.CCN(C1C=C(C)C=CC=1)CC(O)CS([O-])(=O)=O.[Na+]>[N-]=[N+]=[N-].[Na+]>[CH2:15]([OH:16])[C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@H:9]([OH:10])[C:7]([CH:6]=[O:5])=[O:8]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CC(=O)[O-]
Agent: CCN(CC(O)CS(=O)(=O)[O-])c1cccc(C)c1
Agent: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 37 °C

Procedure:
To the above reaction mixture, a mixture which has been prepared in advance by mixing 200 mM acetate buffer (pH 6.0) (750 μL), 4000-u/mL glucose oxidase (Toyobo Co., Ltd.) (450 μL), 0.15% 4-aminoantipyrine (300 μL), 0.3% TOOS (Dojindo Laboratories) (300 μL), 500-u/mL peroxidase (Toyobo Co., Ltd.: Type III) (300 μL), and 1% sodium azide (300 μL) is added, followed by heating for 10 minutes at 37° C. Thereafter, absorbance is measured at 550 nm. A control system is prepared by repeating the above procedure, except that purified water is added instead of the substrate. The amount of glucosone is obtained from the amount of the dye produced. Specifically, a calibration curve is prepared by repeating the above-described procedure, except that serially diluted glucose is employed as a substrate, and purified water is employed instead of the enzyme solution of the present invention. Thus, the amount (in micromoles) of glucosone produced in one minute is calculated, and the obtained value is used as the activity unit of the enzyme solution.