Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1)=O.[CH3:19][O:20][C:21]1[CH2:25][NH:24][C:23](=[O:26])[CH:22]=1>CS(C)=O>[CH3:19][O:20][C:21]1[C:25](=[CH:1][C:3]2[NH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=2)[NH:24][C:23](=[O:26])[CH:22]=1
Reactant: COC1=CC(=O)NC1
Reactant: CCCCCCCCCCCc1ccc(C=O)[nH]1
Solvent: CS(C)=O
Product: CCCCCCCCCCCc1ccc(C=C2NC(=O)C=C2OC)[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-formyl-5-undecylpyrrole (4 g; 16.03 mmols) and 4-methoxy-3-pyrrolin-2-one (3.63 g; 32.06 mmols) in DMSO (53 ml) 2N sodium hydroxyde (45 ml) is added under nitrogen atmosphere and the mixture is stirred at 60° C. for 8 hours. After dilution with water (200 ml) the yellow suspension is extracted with dichloromethane (600 ml). The organic phase is shacked with water and brine, anhydrified over anhydrous sodium sulphate and evaporated to dryness. The crude material is taken up in hexane and filtered to give 4-methoxy-5-(5-undecyl-1H-pyrrol-2-yl-methylene)-1,5-dihydro-pyrrol-2-one (4.86 g; 14.11 mmols) as a yellow crystalline solid. Yield: 88%.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:14][N:15]3[CH:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(c2csc(Cn3cc([N+](=O)[O-])cn3)c2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC1(c2csc(Cn3cc(N)cn3)c2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-4-nitro-1H-pyrazole (110 mg, 0.37 mmol), iron powder (63 mg, 1.12 mmol) and NH4Cl (102 mg, 1.89 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by water (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a red oil. TLC: rf (EA)=0.47. LC-MS-conditions 02: tR=0.62 min; [M+H]+=266.01.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][C:14]=2[O:25][CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[CH2:29]([O:31][SiH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[CH3:30]>C([Si](C=C)(C)O[Si](C)(C)C)=C.[Pt].C1(C)C=CC=CC=1>[CH2:29]([O:31][Si:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[CH2:4][CH2:3][CH2:2][CH2:1][O:5][C:6]1[CH:28]=[CH:27][C:9]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])=[CH:15][C:14]=2[O:25][CH3:26])=[O:11])=[CH:8][CH:7]=1)[CH3:30]
Reactant: C=CCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2OC)cc1
Reactant: CCO[SiH](OCC)OCC
Agent: [Pt]
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCCCOc1ccc(C(=O)Oc2ccc(/C=C/C(=O)OC)cc2OC)cc1)(OCC)OCC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Air was conducted for 30 min. into a mixture of 1 g of 2-methoxy-4-[(E)2-methoxycarbonyl-vinyl]phenyl 4-(3-butenyloxy)benzoate, 0.480 ml of triethoxysilane, 10 ml of toluene and 0.017 ml of platinum divinyltetramethyldisiloxane (3-3.5% in toluene) and the mixture was then stirred at 60° C. for 1 hr. Then, a further 0.1 ml of triethoxysilane was added and the mixture was left to react at 60° C. for 16 hrs. The reaction mixture was thereafter cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was thereupon dried over magnesium sulphate, filtered and evaporated to dryness. Chromatography on 150 g of silica gel with toluene/ethyl acetate (19:1 to 9:1) gave 0.60 g of 2-methoxy-4-[(E)2-methoxycarbonyl-vinyl]phenyl 4-(4-triethoxysilanylbutyloxy)benzoate as a colorless liquid, λmax. (CH2Cl2): 279 nm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH:13]1[CH2:15][CH:14]1[C:16](O)=O.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:32][N:33]1[C:38]([CH3:39])=[CH:37][N:36]=[C:35]([CH3:40])[C:34]1=[NH2+:41].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:39][C:38]1[N:33]2[N:32]=[C:16]([CH:14]3[CH2:15][CH:13]3[C:3]3[N:2]([CH3:1])[CH:6]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[N:4]=3)[N:41]=[C:34]2[C:35]([CH3:40])=[N:36][CH:37]=1
Reactant: Cn1cc(-c2ccccc2)nc1C1CC1C(=O)O
Reactant: Cc1ncc(C)n(N)c1=[NH2+]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(C)n2nc(C3CC3c3nc(-c4ccccc4)cn3C)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropanecarboxylic acid (70 mg, 0.289 mmol) in DMF (2.0 mL) was added 1-amino-3,6-dimethylpyrazin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (98 mg, 0.289 mmol) followed by O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (93 mg, 0.289 mmol) and triethylamine (0.040 mL, 0.289 mmol) at rt. After 2 h stirring at rt, the reaction mixture was stirred at 70° C. for 12 h. The crude was purified by prep HPLC using Phenomenex column and MeOH—H2O-TFA as eluent (20% to 100% over 12 min gradient; flow: 40 mL/min). Collected the pure fractions and removed solvent. Obtained 5,8-dimethyl-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)cyclopropyl)-[1,2,4]triazolo[1,5-a]pyrazine in 44% yield. Prepared hydrochloride salt by adding 1.0 M HCl (3 mL) and MeOH (3 mL) and removing solvent. 1H NMR (500 MHz, METHANOL-d4) δ 6.63 (s, 1H), 6.24 (s, 1H), 6.15-6.11 (m, 2H), 5.90-5.85 (m, 2H), 5.84-5.79 (m, 1H), 2.33 (s, 3H), 1.74-1.71 (m, 1H), 1.50-1.44 (m, 4H), 1.28 (s, 3H), 0.63-0.58 (m, 1H), 0.56-0.51 (m, 1H); MS (ESI) 345 (M+H); Rf=1.61 (Condition A).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([OH:24])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:28])[CH:12]=[CH:11][CH:10]=[CH:9]3.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]3[C:13](=[C:14]([C:15]4[CH:20]=[C:19]([CH:21]([CH3:23])[CH3:22])[C:18]([O:24][C:29](=[O:31])[CH3:30])=[C:17]([CH:25]([CH3:27])[CH3:26])[CH:16]=4)[C:4]=2[C:3]=1[CH3:28])[CH:12]=[CH:11][CH:10]=[CH:9]3
Reactant: Cc1sc2cc3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)C)cc(-c2c3ccccc3cc3sc(C)c(C)c23)cc1C(C)C

Procedure:
Using 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (5.0 g, 13.7 mmol), acetic anhydride (1.68 mL, 17.8 mmol), and pyridine (85 mL) the title compound was prepared according to the procedure in Example 2, step 3 to give 5.37 g (91%) as a white solid, mp 243-245° C.; NMR (DMSO-d6) δ 8.49 (s, 1 H), 7.98 (d, 1 H), 7.49-7.39 (m, 3 H), 7.16 (s, 2 H), 3.01 (septet, 2 H), 2.43 (s, 3 H), 2.41 (s, 3 H), 1.56 (s, 3 H), 1.16 (d, 12 H). MS(EI), [M+] 430; Anal. Calc. for C28H30O2S: C, 78.10, H, 7.02, N, 0.00. Found: C, 77.95, H, 7.04, N, 0.07.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17]C(C#N)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:22]([OH:25])(=[O:24])[CH3:23]>>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][C:23]([C:22]([OH:25])=[O:24])=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(N2CCC(c3ccccc3)CC2)cc1
Agent: Cl
Product: O=C(O)c1ccc(N2CCC(c3ccccc3)CC2)cc1

Procedure:
To 4-phenyl-1-(4-cyanophenyl)piperidine (0.39 g) are added acetic acid (10 ml) and conc. hydrochloric acid (10 ml), and the mixture is refluxed for five hours. The reaction solution is concentrated, and to the residue is added diethyl ether/methanol. The insoluble crystals are collected by filtration, and dried under reduced pressure to give 4-phenyl-1-(4-carboxyphenyl)piperidine (0.39 g) as white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(OCC)(=O)C>C(#N)C>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=2)=[CH:7][N:6]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)nc1)c1cccc(C(F)(F)F)c1
Temperature: 55 °C
Yield: 94.5 %

Procedure:
To a stirring solution of 5-amino-2-chloropyridine (129 mg, 1 mmol) and N,N-diisopropylethylamine (209 μL, 1.2 mmol) in dry acetonitrile (5 mL) was added 3-(trifluoromethyl)benzoyl chloride (151 μL, 1 mmol). The resulting solution was heated at 55° C. for 3h. After cooling to room temperature ethyl acetate (10 mL) was added and the solution was washed with water (2×10 mL) and dried (Na2SO4). The solvent was removed under reduced pressure and the crude material was purified by column chromatography (4:1, hexane/ethyl acetate) to afford the desired product as a white solid (284 mg, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH3:13]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:13]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc([N+](=O)[O-])cn1
Temperature: -25 °C
Yield: 80.2 %

Procedure:
To a solution of 4-nitro-1H-pyrazole (5.0 g, 44.2 mmol) in anhydrous DMF (100 mL) was NaH (60% in oil) (1.94 g, 48.6 mmol) while being stirred at −25° C. under nitrogen. The mixture was stirred for 30 min before bromoethane (5.30 g, 48.6 mmol) was added. The mixture was continued to stir under nitrogen at −25° C. for 6 h. The solution was diluted with ethyl acetate (100 mL), washed with water (2×50 mL) and brine solution (50 mL), dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to afford crude 123a (5.0 g, 80%), which was used in next step without further purification. MS-ESI: [M+H]+ 142.0
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:22]([O-])=O>C(O)(=O)C.[Zn]>[NH2:22][C:3]1[CH:4]=[C:5]([S:8]([NH:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:16][CH2:17]2)(=[O:9])=[O:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c(N)c2)CC1
Temperature: 50 °C

Procedure:
Zinc dust (1345 mg, 20.57 mmol) was added to a room temperature solution of methyl trans-4-(4-chloro-3-nitrophenylsulfonamido)cyclohexanecarboxylate (Intermediate 1, 775 mg, 2.057 mmol) in acetic acid (15.200 ml). The reaction was heated to 50° C. overnight, the filtered over celite and rinsed with acetic acid. The acetic acid was removed in vacuo at 60° C., and the residue was partitioned between EtOAc/sat'd NaHCO3. The aqueous layer was extracted with a second portion EtOAc, and the organic layers were combined then rinsed 1× brine, dry over MgSO4, filter, and concentrated to give the title compound as a solid (670 mg, 1.932 mmol, 94% yield). MS MH+ 347.1
Reaction SMILES: C1(C)C=CC=CC=1.C[N+]1([O-])[CH2:14][CH2:13][O:12]CC1.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([S:24][CH2:25][C:26]([F:29])([F:28])[F:27])=CC=1B(O)O.Cl>C(OCC)(=O)C.CCCCCC>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([S:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:14][C:13]=1[OH:12]
Reactant: C[N+]1([O-])CCOCC1
Reactant: OB(O)c1cc(SCC(F)(F)F)c(Cl)cc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Oc1cc(SCC(F)(F)F)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 95.3 %

Procedure:
To 150 ml of toluene was added 29.0 g (50% aqueous solution, 124 mmol) of N-methylmorpholine-N-oxide, and dehydration was conducted by heating under reflux for 1 hour. To the reaction mixture was dropwise added 31.5 g (103 mmol) of 2,4-dichloro-5-(2,2,2-trifluoroethylthio)phenylboronic acid dissolved in ethyl acetate, and the mixture was refluxed for 3 hours under heating. Then, the mixture was allowed to cool to room temperature, and 10% aqueous hydrochloric acid was added, followed by extraction with ethyl acetate. The organic phase obtained was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: a mixed solvent of n-hexane:ethyl acetate=10:1), to obtain 27.2 g (yield: 95%) of an intended product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:12]([C:15]#[N:16])([CH3:14])[CH3:13]
Reactant: COC(=O)c1ccc(Cl)c(C(C)(C)C#N)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a solution of methyl 4-chloro-3-(1-cyano-1-methylethyl)benzoate (8.0 g, 34 mmol) in tetrahydrofuran (30 mL) were added lithium hydroxide•monohydrate (2.13 g, 51 mmol), methanol (100 mL) and water (5 mL), and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with water (200 mL). The mixture was adjusted to pH 3 by slowly adding 1N hydrochloric acid. The resulting white precipitate was collected by filtration, washed with water, and dried to give the title compound (7.40 g, 99%) as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH2:6][CH3:7])[C:3](O)=[O:4].[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][NH:14][C:15]([C:17]2[N:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][N:26]([C:3](=[O:4])[C:2]([CH3:8])([CH3:1])[CH2:6][CH3:7])[CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CCC(C)(C)C(=O)O
Product: CCC(C)(C)C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,2-dimethylbutyric acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (46% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 8.01, 6.98, 3.86-3.73, 3.57, 1.68, 1.52, 0.92, 0.80-0.72, 0.49-0.45, 0.14-0.08. MS (ES+) m/z 374.3 (M+1).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]([OH:34])[CH:31]([CH3:33])[CH3:32].[OH-].[Na+]>ClCCl.C(OCC)C>[Br:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](=[O:34])[CH:31]([CH3:32])[CH3:33]
Reactant: CC(C)C(O)c1ccccc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
To a suspension of [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (2.2 g, 5.19 mmol) in dichloromethane (18 mL) at room temperature under nitrogen was added dropwise a solution of 1-(2-bromophenyl)-2-methylpropan-1-ol of Step A (1.00 g, 4.36 mmol) in dichloromethane (18 mL) over ca. 5 minutes. After 2 hours, additional [1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one] (0.20 g, 0.47 mmol) was added and the reaction mixture stirred at room temperature for 4 days. The reaction mixture was then diluted with diethyl ether (100 mL) and the resulting suspension added to 1.3 M aqueous sodium hydroxide solution (40 mL) with stirring. After 10 minutes the organic phase was separated, washed with 1.3 M sodium hydroxide (40 mL) and water (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (0.89 g, 90%) as a clear, pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br[CH2:25][C:26]([C:28]1[S:29][C:30]([CH3:33])=[CH:31][N:32]=1)=[O:27]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:25]=1[C:26]([C:28]1[S:29][C:30]([CH3:33])=[CH:31][N:32]=1)=[O:27]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cnc(C(=O)CBr)s1
Product: COC(=O)Cc1c(C(=O)c2ncc(C)s2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-5-methylthiazole (Preparation is described in Example 232).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=O)[CH2:17][CH3:18])[CH:3]=1.Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][NH2:27].CC([O-])=O.[Na+]>CCO>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:29]=[CH:28][C:24]=1[CH2:25][O:26][N:27]=[C:16]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:17][CH3:18]
Reactant: CCC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: NOCc1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCC(=NOCc1ccc(C(F)(F)F)cc1C(F)(F)F)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Yield: 65.3 %

Procedure:
A solution of N-(4-chloro-2-propionylphenyl)trifluoromethanesulfonamide 22 (3.21 mg, 10.17 mmol), O-(2,4-bistrifluoromethylbenzyl)hydroxylamine hydrochloride (3.16 mg, 10.68 mmol) and anhydrous NaOAc (876 mg, 10.68 mmol) in EtOH (120 mL) was stirred for 15 h at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 2:3). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded a pale yellow solid which was recrystallized from CH2Cl2/PE to give N-{2-[1-(2,4-bistrifluoromethylbenzyloxyimino)propyl]-4-chlorophenyl}trifluoromethanesulfonamide 76 (3.70 g, 65%), as a pale yellow oil. 1H n.m.r. (200 MHz, CDCl3) δ 10.96, br s, 1H; 7.96, s, 1H; 7.85, d, J=8.4 Hz, 1H; 7.72, d, J=8.4 Hz, 1H; 7.61, d, J=8.8 Hz, 1H; 7.49, d, J=2.4 Hz, 1H; 7.33, dd, J=2.4 and 8.8 Hz, 1H; 5.45, s, 2H; 2.88, q, J=7.6 Hz, 2H; 1.21, t, J=7.6 Hz, 3H. HRMS (M+) 556.0254.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-])=O)=[C:5]([C:10]([NH2:12])=[O:11])[NH:4][N:3]=1.[CH2:13]([OH:15])C.O>C(O)=O.[Pd]>[CH:13]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:10]([NH2:12])=[O:11])=[O:15]
Reactant: Cc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Solvent: O=CO
Solvent: O
Product: Cc1n[nH]c(C(N)=O)c1NC=O
Reaction time: 8 h

Procedure:
A mixture of 3-methyl-4-nitropyrazole-5-carboxamide (17.0 g, 0.1 mol) in a mixture of 20 ml of 97-100% formic acid, 160 ml of ethanol and 30 ml of water was hydrogenated overnight at 40°-60° using 150 mg of 5% palladium-on-charcoal at 50 psi. Filtration of the hot solution through Celite and evaporation gave 17.8 g of crude, ochre-colored product which was recrystallized from ethanol: 1st crop 9.3 g colorless, 2nd crop 6.7 g brownish, total yield, 16.0 g (95%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH2:14]([O:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1)[CH3:15]>>[CH2:14]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:1][CH2:2][C:3]3[NH:4][C:5](=[O:13])[C:6]4[CH2:12][O:11][CH2:10][CH2:9][C:7]=4[N:8]=3)=[O:31])[CH2:25][CH2:24]2)=[O:22])=[CH:33][CH:34]=1)[CH3:15]
Reactant: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Product: CCOc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1
Yield: 19.9 %

Procedure:
The title compound (150 mg) was prepared following the general procedure of Example 1 from 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (300 mg, 1.66 mmol) and 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid (603 mg, 1.66 mmol). 1H NMR (400 MHz, CDC3) δ 10.67 (s, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 2H), 6.94 (t, J=9.0 Hz, 2H), 4.56 (s, 2H), 4.37 (d, J=6.0 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.20-3.29 (m, 1H), 2.91-3.00 (m, 2H), 2.66-2.72 (m, 2H), 2.30-2.40 (m, 2H), 1.80-1.90 (m, 4H), 1.45 (t, J=7.0 Hz, 3H). HRMS calculated for C24H30N4O5 455.2294. found (ESI, [M+H]+), 455.2308. MS m/z 455.2 (M+1), retention time=2.70 min.
Reaction SMILES: [CH3:1][C:2]([S:29]([CH3:32])(=[O:31])=[O:30])([CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:17]([CH3:27])[C:16]1=[O:28])[C:3]([NH:5][O:6]C1CCCCO1)=[O:4].Cl.CO>C(Cl)Cl>[OH:6][NH:5][C:3](=[O:4])[C:2]([CH3:1])([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:13][CH2:14][N:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:17]([CH3:27])[C:16]1=[O:28]
Reactant: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)NOC2CCCCO2)S(C)(=O)=O)c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1c(-c2ccccc2)ccn(CCC(C)(C(=O)NO)S(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (137 mg, 0.296 mmol) was dissolved in methylene chloride (2 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 2.22 mL, 8.88 mmol) and the slurry was stirred at ambient temperature for 15 minutes. Methanol (1 mL) was added followed by silica gel and the mixture was concentrated to dryness. Crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford N-hydroxy-2-methyl-4-(3-methyl-2-oxo-4-phenylpyridin-1(2H)-yl)-2-(methylsulfonyl)butanamide as a solid. 65.8 mg