Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:36][CH2:37]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:37][CH2:36][C:26]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:29][C:25]=2[CH3:24])=[CH:8][C:7]=1[CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17]
Reactant: COC(=O)CCc1ccc(O)cc1CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCNC(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 48 h
Yield: 70.8 %

Procedure:
To a solution of 3-[2-(2-tert-butoxycarbonylamino-ethyl)-4-hydroxy-phenyl]-propionic acid methyl ester (0.807 g, 2.50 mmol) and toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (1.34 g, 3.74 mmol) in DMF (5 mL) was added Cs2CO3 (1.22 g, 3.74 mmol). The suspension was stirred at 65° C. for 48 h, quenched with H2O (200 mL), and extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated to a residue, which was purified on silica gel chromatography (hexanes/EtOAc 9/1 to 8/2 to 6/4) to afford the title compound as a colorless oil (0.90 g, 71%). 1H NMR (400 MHz, CDCl3): δ 1.42 (s, 9H), 2.37 (s, 3H), 2.54 (t, 2H, J=7.8 Hz), 2.77 (t, 2H, J=7.8 Hz), 2.88 (t, 2H, J=6.8 Hz), 2.96 (t, 2H, J=6.8 Hz), 3.33 (˜dt, 2H, J=6.8 Hz), 3.65 (s, 3H), 4.20 (t, 2H, J=6.8 Hz), 6.70 (br s, 1H), 6.72 (d, 1H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 7.39-7.44 (m, 3H), 7.95-7.98 (m, 2H). MS (ES+) m/z [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].S(=O)(=O)(O)O.[CH3:19]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Yield: 58 %

Procedure:
4-Hydroxy-3-nitrobenzoic acid (10.0 g, 54.6 mmol) was suspended in methanol (60 mL). After addition of conc. sulfuric acid (0.1 mL), the suspension was heated overnight under reflux. The methanol was distilled off under reduced pressure. The residue was dissolved in ethyl acetate (40 mL), washed successively with aqueous sodium hydrogen carbonate (20 mL×2) and saturated aqueous brine (20 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, to give 6.27 g (yield 58%) of the desired compound in the form of a pale brown crystalline product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C([Mg]Br)C.O1CCCC1.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C>C(OCC)C>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([B:18]([OH:23])[OH:19])[CH:7]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccnc(B(O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2-bromo-4-methylpyridine (0.5 g, 2.9 mmol) in diethyl ether (5 mL) was added a 1M solution of ethylmagnesium bromide in tetrahydrofuran (3.48 mL, 3.48 mmol) slowly at 0° C. over 10 minutes under a nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. To the above mixture was added tri-isopropyl borate (0.65 g, ˜0.8 mL, 3.48 mmol) dropwise at 0° C. The reaction mixture was slowly warmed to room temperature and stirred for another 1 hour. The reaction was quenched with saturated aqueous ammonium chloride solution (6 mL) at 0° C. and then extracted with diethyl ether (50 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-methylpyridine-2-boronic acid, which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13](=[S:15])[NH2:14])[C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23](=[O:29])[CH:24](Br)[C:25](=O)[CH3:26])([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[C:18]([O:22][C:23]([C:24]1[S:15][C:13]([C:7]2[C:8](=[O:12])[O:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([OH:1])[CH:11]=3)=[N:14][C:25]=1[CH3:26])=[O:29])([CH3:21])([CH3:20])[CH3:19]
Reactant: NC(=S)c1cc2ccc(O)cc2oc1=O
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3ccc(O)cc3oc2=O)sc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
To a suspension of 7-hydroxy-2-oxo-2H-chromene-3-carbothioic acid amide (221 mg, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) stirred at 0° C., sodium hydride (60% in oil, 44 mg, 1.1 mmol) was added portionwise. During addition a clear solution was formed with moderate effervescence. After 10 min, a solution of 2-bromo-3-oxo butyric acid tert-butyl ester (474 mg, 2.0 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added dropwise and the mixture was stirred at room temperature for 16 h. The reaction was poured into water (20 mL) and extracted with chloroform (3×10 mL). The combined organic extracts were washed with water (3×5 mL), dried over MgSO4 and concentrated. The residue was triturated with diethyl ether, the solid product was collected and washed with diethyl ether. The title compound (224 mg, 0.623 mmol, 62.3%) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].Br[CH2:13][C:14]#[N:15]>>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:13][C:14]#[N:15])[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOCCN1CCNCC1
Reactant: N#CCBr
Product: CCOCCN1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of 4-(2-Ethoxy-ethyl)-piperazine (commercially available from ABCR GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=198.2; 1HNMR(DMSO-d6) 3.70 (s, 2H), 3.45 (q, 2H), 3.40 (q, 2H), 2.40-2.30 (m, 10H), 1.05 (t, 3H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([F:38])([F:37])[F:36])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH2:39])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]>C(#N)C.CN(C=O)C>[Si:1]([O:8][C@@H:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:25]=4[C:35]([F:37])([F:36])[F:38])[O:21][N:20]=3)=[CH:16][CH:17]=2)[O:12][CH2:11][C@@H:10]1[NH:39][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2OC[C@@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN[C@H]1COc2cc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)ccc2[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3S,4R)-4-(tert-Butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-amine (50 mg, 0.09 mmol) was dissolved in acetonitrile (716 μl). To this solution was added K2CO3 (12.4 mg, 0.09 mmol) and tert-butyl 2-bromoacetate (15.9 μl, 0.11 mmol). The resulting solution was stirred at room temperature overnight. This was diluted with DMF and filtered to remove solid material and was purified by preparative HPLC (PHENOMENEX® Luna 5u C18 21×250 mm, gradient elution with Method 1-MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM) to give tert-butyl 2-((3S,4R)-4-(tert-butyldimethylsilyloxy)-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetate (LCMS [M+H]+=673.3), which was dissolved in CH2Cl2 (4 mL) and TFA (1.5 mL). This solution was stirred for 2 h before it was concentrated. The resulting residue was dissolved in 4 N HCl in dioxane (1.0 mL) and 6 N HCl aqueous solution (0.5 mL) and stirred overnight. Next, the reaction was stirred at 50° C. for 4 h. After cooling, the solution was mixed with MeCN and purified by preparative HPLC (Column: PHENOMENEX® Luna C18, 5-μm particles (30×100 mm; Guard Column: none; Mobile Phase A: 5:95 acetonitrile:water with 0.1% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.1% TFA; Gradient: 15%-100% B over 10 minutes; Flow: 30 mL/min, uv detection 254 nM) to give 2-((3S,4R)-4-hydroxy-7-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)chroman-3-ylamino)acetic acid, TFA salt Ex 67 (44.5 mg): LCMS [M+H]+=503.0; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (1H, dd, J=8.03, 1.65 Hz), 7.60-7.76 (8H, m), 5.17 (1H, d, J=4.18 Hz), 4.44-4.58 (2H, m), 4.06 (2H, d, J=2.64 Hz), 3.90-3.97 (1H, m); HPLC Peak RT=7 5 min (Analytical Method A).
Reaction SMILES: FC(F)(F)C1C=CC(NS(C(C)=COCC)(=O)=O)=CC=1.[F:21][C:22]([F:31])([F:30])[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.Cl[S:33]([C:36]1[CH:37]=[N:38][O:39][C:40]=1[CH3:41])(=[O:35])=[O:34]>>[F:21][C:22]([F:30])([F:31])[C:23]1[CH:29]=[CH:28][C:26]([NH:27][S:33]([C:36]2[CH:37]=[N:38][O:39][C:40]=2[CH3:41])(=[O:35])=[O:34])=[CH:25][CH:24]=1
Reactant: Cc1oncc1S(=O)(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CCOC=C(C)S(=O)(=O)Nc1ccc(C(F)(F)F)cc1
Product: Cc1oncc1S(=O)(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
AA16 was prepared starting from 2-(4-trifluoromethylphenylaminosulfonyl)1-ethoxypropene under the same conditions as described for AA11. Alternatively, AA16 was prepared from 4-trifluoromethylaniline and 4-chlorosulfonyl-5-methylisoxazole.
Reaction SMILES: [Cl-].[Li+].[CH3:3][C:4]1([CH3:25])S[C@@H:7]2[C@H:9]([NH:12][C:13]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:14])[C:10](=[O:11])[N:6]2[C@H:5]1[C:22]([OH:24])=[O:23]>CO.C(O)(C)(C)C>[CH2:15]([O:24][C:22]([C:5]([N:6]1[C:10](=[O:11])[C@@H:9]2[C@H:7]1[O:14][C:13]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:12]2)=[C:4]([CH3:25])[CH3:3])=[O:23])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)(C)O
Solvent: CO
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)[C@H]2N=C(Cc3ccccc3)O[C@H]21
Yield: 88 %

Procedure:
A 6.2 mg quantity of lithium chloride was dissolved in a mixture of 2 ml of methanol and 0.5 ml of tert-butyl alcohol. To the solution was added 62.4 mg of benzyl ester of penicillin G to prepare an electrolyte. The electrolyte was subjected to electrolysis under the same conditions as in Example 1. The isolation and purification gives 50 mg of contemplated compound in 88% yield.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C(=O)NC1C(=O)Nc2ccccc2NC1=O
Temperature: 1.5 °C
Reaction time: 3.5 h
Yield: 76.8 %

Procedure:
Stir 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (10.0 g, 52.3 mmol) as a tan colored slurry in THF (300 mL) at 0-3° C. under nitrogen. Add triethylamine (8.00 mL, 57.0 mmol) in one portion. Add dropwise isobutyryl chloride (6.00 mL, 57.0 mmol) keeping the temperature below 3° C. Stir the resulting light yellow colored slurry at 0-3° C. for 3.5 hours until complete reaction by HPLC. Add deionized water (450 mL) over 15-20 minutes, keeping the pot temperature below 10° C. After stirring at 0-10° C. for 1.5 hours, isolate the product by filtration, rinse with cold (0-3° C.) 2:1/Water:THF (50 mL), then water (50 mL). Dry the solid in a vacuum oven at 50° C. to afford 10.5 g (77%) of the title compound: 1H NMR (500 MHz, DMSO-d6) δ 10.7 (s, 2H), 8.15 (d, 1H), 7.2 (m, 4H), 4.7 (d, 1H), 2.75 (m, 1H), 1.0 (s, 6H).
Reaction SMILES: Cl.[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:3]1.C(N(CC)CC)C.[C:28](#[N:31])[CH:29]=[CH2:30]>CO>[O:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]([CH2:12][CH2:13][N:14]([CH2:30][CH2:29][C:28]#[N:31])[CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:3]1
Reactant: C=CC#N
Reactant: COC(=O)CCNCCC1COc2ccccc2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCN(CCC#N)CCC1COc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
30 g (0.1 mol) of N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 5.84 g (0.11 mol) of acrylonitrile are added to the solution and the whole is stirred for 15 hours at room temperature. The reaction mixture is then concentrated under a water-jet vacuum, the residue is taken up in diethyl ether and the ethereal solution is washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-N-(2-methoxycarbonylethyl)-amine is thus obtained in the form of a yellow oil.
Reaction SMILES: [C:1](Cl)(=O)C.[Na+].[Cl-].[Cl:7][C:8]1[CH:9]=[C:10]([C:15]2[CH2:19][CH:18]([CH2:20][C:21]([OH:23])=[O:22])[O:17][N:16]=2)[CH:11]=[CH:12][C:13]=1[Cl:14].Cl>CO>[CH3:1][O:22][C:21](=[O:23])[CH2:20][CH:18]1[O:17][N:16]=[C:15]([C:10]2[CH:11]=[CH:12][C:13]([Cl:14])=[C:8]([Cl:7])[CH:9]=2)[CH2:19]1
Reactant: O=C(O)CC1CC(c2ccc(Cl)c(Cl)c2)=NO1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC1CC(c2ccc(Cl)c(Cl)c2)=NO1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Acetyl chloride (5 eq) was added to MeOH (50 vol) externally cooled with a mixture saturated aqueous NaCl solution and ice. After 10 minutes the solution was warmed to room temperature. After a further 90 minutes, [3-(3,4-dichloro-phenyl)-4,5-dihydro-isoxazol-5-yl]-acetic acid (1.0 eq) in MeOH (25 vol) was added to the hydrogen chloride methanolic solution and stirred for 16 hours. The solvent was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluent: [3:7] EtOAc:heptane) to afford [3-(3,4-dichloro-phenyl)-4,5-dihydro-isoxazol-5-yl]-acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31][S-:32].[Na+]>CN(C=O)C.C(OCC)(=O)C>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([S:32][CH3:31])=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccncc23)cn1
Temperature: 130 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.120 g, 0.285 mmol) in 2 mL of DMF was added sodium thiomethoxide (0.100 g, 1.43 mmol). The mixture was heated in a sealed tube at 130° C. for 18 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 432.9 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.73-8.63 (m, 2H), 8.39 (s, 1H), 8.29-8.19 (m, 1H), 8.09 (s, 1H), 7.32-7.26 (m, 1H), 7.08 (d, J=8.3 Hz, 1H), 4.61 (br s, 1H), 4.50 (s, 2H), 4.05 (br s, 1H), 2.53 (s, 3H), 2.40-2.27 (m, 2H), 2.13-1.75 (m, 3H), 1.55-1.35 (m, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.[OH2:29]>O1CCCC1>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])=[CH:7][CH:8]=1)(=[O:26])=[O:29]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2oncc2CCCO)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2oncc2CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 3-[5-(4-methylthiophenyl)-4-isoxazolyl]propan-1-ol (500 mg) in tetrahydrofuran (30 ml) was gradually added m-chloroperbenzoic acid (870 mg) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give crystals (480 mg, yield 85%) of 3-[5-(4-methylsulfonylphenyl)-4-isoxazolyl]propan-1-ol from a fraction eluted with acetone-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-isopropyl ether to give a colorless needle. melting point: 125–126° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=O)=[CH:6][N:5]=[C:4]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[N:3]=1.[CH:17]1[CH:18]=[CH:19][C:20]2[N:25](O)N=N[C:21]=2[CH:22]=1.CCN=C=NCCCN(C)C.Cl.[Cl:39]NC1C=CC=CC=1>CN(C=O)C.O>[Cl:39][C:17]1[CH:18]=[CH:19][C:20]([NH:25][C:9](=[O:11])[CH2:8][C:7]2[C:2]([OH:1])=[N:3][C:4]([N:12]3[CH:16]=[CH:15][CH:14]=[N:13]3)=[N:5][CH:6]=2)=[CH:21][CH:22]=1
Reactant: ClNc1ccccc1
Reactant: O=C(O)Cc1cnc(-n2cccn2)nc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1cnc(-n2cccn2)nc1O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-(4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidin-5-yl)acetic acid, 12-d, (150 mg, 0.68 mmol) and HOBt (101.2 mg, 0.75 mmol) in DMF (5 ml) was added EDC.HCl (144 mg, 0.75 mmol) and DIEPA (264 mg, 2.05 mmol). The solution was stirred at room temperature for 5 mins before the addition of the chlorophenyl amine (0.75 mmol) (Sigma-Aldrich). The mixture was stirred at room temperature for 24 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was concentrated under vacuum and the residue was purified by silica gel column or Prep-HPLC to give the final compound 12-1. 1H NMR (DMSO-d6, 300 MHz): δ 10.23 (s, 1H), 8.56 (d, 1H), 7.92 (s, 1H), 7.63 (d, 2H), 7.37 (d, 2H), 6.64 (s, 1H), 3.53 (s, 2H). (M+H)+=330.1.
Reaction SMILES: Cl.C(OCC)(=O)C.[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25](OC(C)(C)C)=O)[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.ClC1[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=1)[C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[CH2:8]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:36]=[CH:37][C:38]([N+:45]([O-:47])=[O:46])=[C:39]([CH:44]=2)[C:40]([O:42][CH3:43])=[O:41])[CH2:21][C@H:20]1[O:32][CH3:33])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methanol (15 ml) and a 4 N hydrochloric acid/ethyl acetate solution (30 mL) were added to tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (1.5 g, 4.12 mmol), and the mixture was stirred at room temperature for two hours. The reaction solution was concentrated under reduced pressure, azeotropically dehydrated by adding toluene, and dissolved in DMF (10 ml). Methyl 5-chloro-2-nitrobenzoate (900 mg, 4.17 mmol) and potassium carbonate (2.1 g, 15.2 mmol) were added, and the mixture was stirred at 175° C. for 24 hours. The reaction solution was diluted with ethyl acetate, washed with water, and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to obtain the title compound. The total resulting compound was used for the next reaction.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1.C(O)(=O)C>CO.[Pd]>[F:13][CH:2]([F:1])[O:3][C:4]1[N:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)F)nc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(OC(F)F)nc1
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To 2-(difluoromethoxy)-5-nitropyridine (4.7 g, 24.7 mmol) in degassed methanol (100 mL) was added 10% palladium on carbon (500 mg, 0.47 mmol) and the reaction was hydrogenated at atmospheric pressure for 1 hour. To this was added acetic acid (2.83 mL, 49.4 mmol) and the reaction was filtered through Celite and concentrated in vacuo to afford 6-(difluoromethoxy)pyridin-3-amine (6.33 g, 25.9 mmol, 105% yield) as an olive green liquid. 1H NMR (400 MHz, MeOD-d4) δ ppm 7.60 (d, J=2.76 Hz, 1 H), 7.37 (s, 0.5 H), 7.15 (dd, J=8.66, 2.89 Hz, 1 H), 7.00 (s, 0.5H), 6.71 (d, J=8.78 Hz, 1 H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[N:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[NH:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1CCCC1=NN(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCC1NN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude ethyl 2-(2,2-dimethylhydrazono)cyclopentanecarboxylate (6.91 mmol) was dissolved in acetic acid (10 mL) and water (10 mL). Sodium cyanoborohydride was added and the reaction was stirred at 25° C. for 16 h. The mixture was neutralized with saturated aqueous sodium bicarbonate solution until pH=8 was reached and was diluted with ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, ethyl 2-(2,2-dimethylhydrazinyl)cyclopentanecarboxylate as a clear oil, which was used directly in the next step without any further purification. LC-MS (ESI) calcd for C10H20N2O2 200.28, found 201.3 [M+H+].