Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: FC(F)(F)Oc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(OC(F)(F)F)cccc5s4)cc3CC[C@@H]12
Yield: 77.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-trifluoromethoxybenzothiazole (117 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 141 mg (77%) of the title compound as a white solid. mp 168°-173°. FDMS: m/e=478. α[D]589 =+57.89 (c=0.59, chloroform).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:14]=[C:15]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[S:16][C:17]=3[C:18](O)=[O:19])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH2:36])[CH:31]=1>>[CH3:27][O:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:18]([C:17]2[S:16][C:15]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:14][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:2][CH:3]4[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]4)[CH2:8]2)[CH2:10]3)=[O:19])[CH:31]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: O=C(O)c1sc(C2CCCCC2)nc1CCC12CC3CC(CC(C3)C1)C2
Product: COC(=O)c1cccc(NC(=O)c2sc(C3CCCCC3)nc2CCC23CC4CC(CC(C4)C2)C3)c1
Yield: 59 %

Procedure:
The product from step c was reacted with 3-amino-benzoic acid methyl ester using essentially the same method as in Example 52, step a. The product was obtained as a white solid in 59% yield. 1H NMR (300 MHz, CDCl3) 8.00 (2H, m), 7.82 (1H, d), 7.47 (2H, m), 3.93 (3H, s), 3.06 (3H, m), 2.18-1.27 (27H, m).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[C:16]2[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1.[Cl:23][C:24]1[C:25]([C:38](O)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:28][CH:29]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:25]([C:38]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][CH:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=2)=[O:39])=[N:26][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[CH:28][CH:29]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)n1
Reactant: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)ccnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4cccc(C(F)(F)F)c4)ccnc23)n1
Yield: 38.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(3-(trifluoromethyl)phenoxy)quinolin-8-amine (Intermediate-11, 100 mg, 0.327 mmol), 3-chloro-6-(pivalamidomethyl)picolinic acid (Intermediate-3, 180 mg, 0.66 mmol), oxalyl chloride (125 mg, 0.99 mmol), DMF (1 drop) and DIPEA (126 mg, 0.98 mmol) in CH2Cl2 (5 mL) to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 11.86 (s, 1H), 8.91 (d, J=6.9 Hz, 1H), 8.81 (d, 1H), 8.35 (br t, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 7.80-7.70 (m, 5H), 7.47 (d, J=7.8 Hz, 1H), 6.83 (d, J=4.8 Hz, 1H), 4.50 (d, J=6.0 Hz, 2H), 1.16 (s, 9H); MS [M+H]+: 557.26.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7](Cl)=[O:8].Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:37]=[CH:36][C:23]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([O:30][CH3:31])=[O:29])=[CH:36][CH:37]=1)=[O:8]
Reactant: COC(=O)c1ccccc1COc1ccc(CCN)cc1
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCNC(=O)c2cc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-5-phenylfuran-3-carbonyl chloride (36.4 mg, 0.165 mmol) and methyl 2-{[4-(2-aminoethyl)phenoxy]methyl}benzoate hydrochloride (53 mg, 0.165 mmol) were mixed in DCM (4 ml). PS-DIBA (3.66 mmol/g, 135 mg, 0.494 mmol) was added. The mixture was shaken at room temperature overnight. LC-MS showed there was only a trace amount of desired product and a big peak of 2-methyl-5-phenyl-3-furoic acid. TBTU (55 mg, 0.17 mmol) was added. The mixture was shaken for 2 hours and filtered. The filtrate was evaporated to dryness. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5:99.5) as eluant gave 34 mg the desired product, yield 44%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:7]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>C1COCC1.C(OCC)(=O)C>[CH2:35]([S:37]([NH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])[C:7]=1[C:8]([NH2:10])=[O:9])(=[O:39])=[O:38])[CH3:36]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1c(Nc2ccc(I)cc2F)cc(F)cc1Oc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
In analogy to GP 6a, 240 mg of 2-(3-amino-phenoxy)-4-fluoro-6-(2-fluoro-4-iodo-phenylamino)-benzamide (Intermediate 1.4; 0.5 mmol, 1 eq.) were dissolved in 8 mL THF and treated with 0.1 mL triethylamine (0.75 mmol, 1.5 eq.) and 71 μL ethylsulfonyl chloride (0.75 mmol, 1.5 eq.). The reaction mixture was stirred at rt overnight, diluted with ethyl acetate, washed with saturated NaHCO3 solution, dried and concentrated in vacuo. HPLC purification of the residue provided 123 mg (0.22 mmol, 48% yield) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]#[N:8].[C:9]([N:17]=[C:18]=[O:19])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCOCC1>[C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:1][C:18]([NH:17][C:9](=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:19])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: N#CC1=C(N)CCC1
Solvent: C1COCCO1
Product: N#CC1=C(NC(=O)NC(=O)c2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of 2-aminocyclopent-1-enecarbonitrile (400 mg, 3.7 mmol) in 1,4-dioxane (20 mL) was added benzoyl isocyanate (545 g, 3.7 mmol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The precipitate was collected by filtration, washed with 1,4-dioxane, and dried to give N-(2-cyanocyclopent-1-enylcarbamoyl)benzamide (720 mg, 76%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 11.33 (s, 1H), 11.22 (brs, 1H), 7.99-7.97 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.51 (m, 2H), 3.04-3.0 (m, 2H), 2.51-2.47 (m, 2H) 1.95-1.90 (m, 2H). MS 256 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:11]=1
Reactant: C1CCNCC1
Reactant: CSc1nc(Cc2cccc(F)c2)[nH]c(=O)c1C#N
Product: N#Cc1c(N2CCCCC2)nc(Cc2cccc(F)c2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.36 mmol) of 2-(3-fluorobenzyl)-4-(methyl-sulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 309 mg (3.63 mmol) of piperidine to give 40 mg (35% of theory) of the title compound.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([S:31]([C:34]4[CH:39]=[C:38](Cl)[CH:37]=[CH:36][C:35]=4[O:41][CH3:42])(=[O:33])=[O:32])[C:26]=3[CH:43]=2)=[O:21])=[CH:15][CH:14]=1)#[N:12]>CS(C)=O.O>[OH:3][NH:2][C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([S:31]([C:34]4[CH:39]=[C:38]([Cl:1])[CH:37]=[CH:36][C:35]=4[O:41][CH3:42])(=[O:32])=[O:33])[C:26]=3[CH:43]=2)=[O:21])=[CH:17][CH:18]=1)=[NH:12]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C#N)cc3)cc21
Reactant: NO
Reactant: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of hydroxylamine hydrochloride (90 mg, 1.3 mmol) in dimethyl sulfoxide (1.25 mL) was treated with triethylamine (131 mg, 0.18 mL, 1.3 mmol) and stirred at room temperature for 5 min. The solids were filtered off, and 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid (4-cyano-phenyl)-amide (125 mg, 0.26 mmol) was added. The mixture was stirred at 75° C. for 1.5 hours. After cooling back to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted three times with 0.5N HCl. The combined acidic aqueous layer was then rebasified with 1N NaOH and extracted three times with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and evaporated. 4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide was obtained as a white solid, 97 mg (73%), MS (ISP): m/e=517.0 (M+H+.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[N:10]=[CH:11][S:12][C:13]=1[C:14](OCC)=[O:15])[CH3:8]>C1COCC1>[CH2:7]([C:9]1[N:10]=[CH:11][S:12][C:13]=1[CH2:14][OH:15])[CH3:8]
Reactant: CCOC(=O)c1scnc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ncsc1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
To a 0° C. mixture of lithium aluminum hydride (1.2 g, 31.2 mmol) in anhydrous THF (30 mL) was slowly added a solution of ethyl 4-ethyl-1,3-thiazole-5-carboxylate (3.19 g, 15.6 mmol) in anhydrous THF (40 mL). The reaction mixture was stirred at 0° C. for 1.5 hours. The reaction was quenched with 5 N NaOH. Water (100 mL) and EtOAc (100 mL) were added. The mixture was stirred for 30 minutes. The solid material was removed by filtration. The organic layer was recovered. The aqueous layer was extracted with EtOAc (1×100 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo, affording (4-ethyl-1,3-thiazol-5-yl)methanol (1.77 g, 79% yield). The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O.O>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(Oc2ncccn2)c1
Temperature: 150 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl 3-hydroxybenzoate (3.4 g), 2-chloropyrimidine (2.29 g) and potassium carbonate (3.04 g) in dimethylsulfoxide (30 ml) was stirred at 150° C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give methyl 3-(pyrimidine-2-yl)oxybenzoate (3.66 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:25]([O:27]C)=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][NH:15][C:14](=[O:24])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:25]([OH:27])=[O:26])=[N:11][N:12]2[CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][N:15]([CH3:32])[C:14](=[O:24])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(c2ccccc2)n2nc(C(=O)O)c(OCc3ccccc3)c2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-benzyloxy-4-oxo-7-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (28 mg, 0.074 mmol) in anhydrous DMF under inert atmosphere was added sodium hydride (3 mg, 0.111 mmol, 95% dispersion in oil). The mixture was treated with iodomethane (6 μL, 0.089 mmol) and stirred at room temperature for 1 hour. When the methylation was complete, several drops of H2O were added and the mixture stirred at room temperature for 1 hour. The mixture was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions yielded the title product as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 12.90 (s, 1H), 7.51-7.49 (m, 2H), 7.39-7.31 (m, 6H), 7.01-7.00 (m, 2H), 5.80 (s, 1H), 5.27 (dd, J=11.2, 25.2 Hz, 2H), 4.21 (d, J=4.8 hz, 1H), 4.18 (d, J=4.4 Hz, 1H), 2.92 (s, 3H); ES MS (M+1)=378.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16](O)=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>O1CCCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH3:29])[CH:20]=3)[CH2:15][C:16]([NH:45][OH:46])=[O:17])[C:9](=[O:10])[C:8]2=[CH:30][CH:31]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Reactant: NO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3ccc(C(C)(C)C)cc3C2=O)ccc1OC
Yield: 85.5 %

Procedure:
3-(4-tert-Butylphthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide was prepared by the procedure of Example 1 from 3-(4-tert-butylphthalimido)-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (2.0 g, 4.7 mmol), carbonyldiimidazole (800 mg, 4.93 mmol) and hydroxylamine hydrochloride (377 mg, 5.43 mmol) in tetrahydrofuran (10 mL) to afford 3-(4-tert-butylphthalimido)-3-(3-ethoxy-4-methoxyphenyl)-N-hydroxypropionamide as a white solid (1.77 g, 85% yield): mp, 127.5-129.5° C.; 1H NMR (DMSO-d6) δ1.24-1.44 (m, 12H, 4CH3), 3.09 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 3.97 (q, J=6.9 Hz, 2H, CH2), 5.66 (t, J=7.8 Hz, 1H, NCH), 6.89 (br s, 2H, Ar), 7.01 (br s, 1H, Ar), 7.76-7.87 (m, 3H, Ar), 8.79 (br s, 1H, OH), 10.59 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.73, 30.76, 34.29, 35.48, 50.14, 55.46, 63.72, 111.69, 112.27, 119.59, 119.98, 123.07, 128.75, 131.28, 131.45, 131.55, 147.69, 148.49, 158.32, 166.07, 167.53, 167.85; Anal Calcd for C24H28N2O6: C, 65.44; H, 6.41; N, 6.36. Found: C, 64.34; H, 6.29; N, 7.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[O:9])=[CH:4][CH:3]=1.CN(C)C=O.[Br:31]N1C(=O)CCC1=O>O.C(=O)(O)[O-].[Na+]>[Br:31][C:13]1[S:12][C:11]([C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccsc1-c1ncn(C2CCCCO2)n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Temperature: 25 °C

Procedure:
To a mixture of (4-chlorophenyl){2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanone (20.2 g, 54.0 mmol) in N,N-dimethylformamide (350 mL, 4500 mmol) was added dropwise a solution of N-bromosuccinimide (14.42 g, 81.05 mmol) in N,N-dimethylformamide (50 mL, 600 mmol) under argon. The mixture was stirred at rt with care taken to block the reaction from exposure to ambient light. After 3 h reaction, LCMS showed both starting material and product. Additional N-bromosuccinimide (6.732 g, 37.82 mmol) was added and the mixture was stirred at rt again. After stirring overnight, the mixture was diluted with water and sodium bicarbonate solution and then the mixture was extracted with EtOAc. The organic layer was washed with water and brine. The EtOAc layer was dried and evaporated in vacuum to a residue, which was purified by chromatography to afford (5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanone as a white solid (18.0, 73.5%). LCMS: (FA) ES+ 451.9, 453.9
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]Cl.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]>>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20]
Reactant: [O-][n+]1ccccc1S
Reactant: ClCc1c(Cl)ccc(Cl)c1Cl
Agent: [Na]
Product: [O-][n+]1ccccc1SCc1c(Cl)ccc(Cl)c1Cl

Procedure:
The intermediate 2-(2,3,6-trichlorophenylmethylthio)pyridine N-oxide is prepared from 2,3,6-trichlorobenzylchloride and 2-mercaptopyridine N-oxide sodium salt by the procedure employed in Example 3. Melting point 232° - 234°C. Yield quantitative. Structure confirmed by IR and NMR.
Reaction SMILES: [CH2:1]([S:4]([O:7]C)(=[O:6])=[O:5])[CH:2]=[CH2:3].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:1]([S:4]([O-:7])(=[O:6])=[O:5])[CH:2]=[CH2:3].[CH3:1][N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CCS(=O)(=O)OC
Reactant: c1ccncc1
Product: C=CCS(=O)(=O)[O-]
Product: C[n+]1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Methyl allylsulfonate (21.4 g, 0.157 mol) synthesized by the conventional method and pyridine (13.1 g, 0.166mol, 1.05 eq) were reacted by stirring for 2 hours at 80° C. After completed the reaction, unreacted pyridine was removed under reduced pressure, crude substance was washed with ethyl acetate several times. The desired product of 1-methylpyridinium allylsulfonate (31.4 g, 0.146 mmol, 93% yield) was obtained by drying by heating under reduced pressure. Melting point was 39° C. Measurement result of 1H NMR was shown as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][C:17]1[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=1)=[O:8]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: Cc1ccc(O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(OC(=O)c2cc(Cl)c(F)cc2F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 69.8 %

Procedure:
5-Chloro-2,4-difluorobenzoic acid (1.17 g, 6.08 mmol) was dissolved in thionyl chloride (5.0 mL) and heated at 60° C. under a nitrogen atmosphere for 5 hours. The reaction mixture was concentrated in vacuo and azeotroped with DCM (2×10 mL) and toluene (10 mL). Then the crude was dissolved in DCM (15 mL) and cooled to 0° C. 4-Methylphenol (0.665 g, 6.15 mmol) and triethylamine (1.05 mL, 7.53 mmol) in DCM (10 mL) were added dropwise and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated in vacuo and the residue dissolved in EtOAc (10 mL), then washed with saturated aqueous solution of sodium hydrogencarbonate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to yield the crude solid. The solid was triturated in the minimum amount of heptanes to afford the title compound as a white solid (1.20 g, 69%):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:25][C@@H:26]1[CH2:30][CH2:29][O:28][CH2:27]1.O1CCOCC1.[OH-].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=3)[N:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[O:25][C@@H:26]1[CH2:30][CH2:29][O:28][CH2:27]1
Reactant: COC(=O)c1ccc(Cn2nccc2-c2ccc(OC)c(O[C@@H]3CCOC3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccnn2Cc2ccc(C(=O)O)cc2)cc1O[C@@H]1CCOC1
Temperature: 90 °C
Yield: 81.6 %

Procedure:
Into a 1-neck round-bottom flask was added methyl 4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoate (330 mg, 0.808 mmol), 5 mL of 1,4-dioxane, 20 mL of water and 8 mL of 2 M aqueous sodium hydroxide. The reaction was heated at 90° C. for 1.5 hours, acidified with 1N HCl until pH˜3 and extracted with 3×20 mL CH2Cl2. The combined organic fractions were dried over sodium sulfate, filtered and concentrated under reduced pressure to yield 4-[(5-{4-methoxy-3-[(3R)-tetrahydrofuran-3-yloxy]phenyl}-1H-pyrazol-1-yl)methyl]benzoic acid (260 mg, 81%) as a brown solid. LCMS M+1=395.2
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.C(N(CC)CC)C.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>C(#N)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][OH:25])=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1ccc(CBr)cc1[N+](=O)[O-]
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(CN(C)CCO)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 5 mL round bottom flask was charged with 4-(bromomethyl)-1-methoxy-2-nitrobenzene (0.6 g, 2.44 mmol) and acetonitrile (2 mL). The solution was treated with triethylamine (1 mL, 7.32 mmol) and 2-(methylamino)ethanol (0.585 mL, 7.32 mmol) and the reaction was stirred at ambient temperature for 16 hours. The reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated to provide the title compound. MS (DCI(+)) m/e 241.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][C@H:5]1[CH:14]=O.[OH2:16].Cl.[NH2:18]O.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][CH2:3][CH:4]1[O:8][C:7]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:6][CH:5]1[CH:14]=[N:18][OH:16]
Reactant: NO
Reactant: COC[C@@H]1OC2(CCCCC2)O[C@H]1C=O
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COCC1OC2(CCCCC2)OC1C=NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
Crude (2R,3S)-3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (31 g, 145 mmol) was dissolved in 1:1 methanol:water (600 mL), and hydroxylamine hydrochloride (10.1 g, 145 mmol) and Na2CO3 (7.67 g, 72.3 mmol) were added. The reaction was stirred at ambient temperature for 3 hours. The methanol was removed under reduced pressure and the remaining material was extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated to afford 3-(methoxymethyl)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (33.6 g, 147 mmol, 101% yield) which was taken forward without purification.