Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]3[O:14][C:17](=[O:19])[NH:15][C:10]=3[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(c2ccc3oc(=O)[nH]c3c2)CC1
Yield: 89.3 %

Procedure:
To a solution of 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 9.6 mmol) in THF (40 mL) was added triphosgene (4.2 g, 14 mmol) at room temperature. The mixture was stirred for 20 minutes at this temperature before water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give 1-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-cyclopropanecarboxylic acid methyl ester (2.0 g, 91%), which was directly used in the next step. 1H NMR (CDCl3, 300 MHz) δ 8.66 (s, 1H), 7.13-7.12 (m, 2H), 7.07 (s, 1H), 3.66 (s, 3H), 1.68-1.65 (m, 2H), 1.24-1.20 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1N)C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
N-Methyl-N-(2-(2-nitrophenyl)ethyl)carbamic acid tert-butyl ester (924 mg, 3.3 mmol) was dissolved in ethanol (60 ml). 10% palladium on carbon (200 mg) was added. The mixture was hydrogenated at room temperature at 1 atmosphere for 16 h. The catalyst was filtered off through a plug of celite. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (60 g), using ethyl acetate/heptane (1:2) as eluent, to give 723 mg of N-(2-(2-aminophenyl)ethyl)-N-methylcarbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([F:17])[C:11]([C:12](O)=[O:13])=[C:10]([C:18]#[N:19])[CH:9]=2)=[CH:6][C:5]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[C:15]([F:17])[C:11]([C:12]([NH:33][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:13])=[C:10]([C:18]#[N:19])[CH:9]=2)=[CH:6][C:5]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:4][N:3]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1cc(-c2cc(C3CCOCC3)cnc2N)cc(F)c1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(-c2cc(C3CCOCC3)cnc2N)cc(F)c1C(=O)NCc1ccccc1

Procedure:
To 4-(2-amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-cyano-6-fluorobenzoic acid were added DCM (1 mL), followed by benzylamine (0.017 mL, 0.153 mmol), triethylamine (0.053 mL, 0.383 mmol) and T3P (50% in EtOAc, 0.084 mL, 0.141 mmol). After 1 h more benzylamine (0.017 mL, 0.153 mmol) and T3P (50% in EtOAc, 0.084 mL, 0.141 mmol) were added and at 2 h the reaction was completed. Saturated NaHCO3 solution was added and extracted twice with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (heptane:EtOAc 1:0 to 0:1) to give the product as a colorless solid (17 mg). LCMS (m/z) 431.1 (MH+), 0.65 min. 1H NMR (400 MHz, CDCl3)) δ ppm 8.03 (s, 1H), 7.74 (s, 1H), 7.54 (d, 1H, J 12 Hz), 7.43-7.30 (m, 4H) 7.26 (s, 1H), 7.23 (s, 1H) 6.57 (br s, 1H), 4.74 (d, J 5.53 Hz, 2H), 4.10-4.06 (m, 2H), 3.55-3.46 (m, 2H), 2.77-2.67 (m, 1H), 1.80-1.70 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23]2[CH:27]=[C:26]([CH:28]3[CH2:30][CH2:29]3)[NH:25][N:24]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH3:31][C:32](OC(C)=O)=[O:33]>C1COCC1.O>[C:32]([N:25]1[C:26]([CH:28]2[CH2:29][CH2:30]2)=[CH:27][C:23]([NH:22][C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]([C:8]3[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][N:19]([CH3:20])[CH3:21])(=[O:14])=[O:15])=[CH:10][CH:9]=3)[N:4]=2)=[N:24]1)(=[O:33])[CH3:31]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(-c2ncc(Br)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)n1nc(Nc2nc(-c3ccc(S(=O)(=O)NCCN(C)C)s3)ncc2Br)cc1C1CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To the mixture of 5-(5-bromo-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (200 mg, 0.39 mmol) in THF/H2O (2 mL/2 mL), Ac2O (0.2 mL, 1.95 mmol, 5.0 eq) was added dropwise. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was filtered, and the solid was concentrated with ethanol to bring residual water off to afford crude 5-(4-(1-acetyl-5-cyclopropyl-1H-pyrazol-3-ylamino)-5-bromopyrimidin-2-yl)-N-(2-(dimethylamino)ethyl)thiophene-2-sulfonamide (used for the next step without further purification). LC-MS (m/z)=556.0, 558.0 [M+H]+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:30])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26]C(=O)C)[CH:19]=2)[CH2:10][CH2:9]1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C(O)C>[CH3:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:30])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:19]=2)[CH2:10][CH2:9]1
Reactant: COc1ccc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)cc1OC(C)=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2.07 g of potassium carbonate was added to a solution of 4.97 g of N-(trans-4-methylcyclohexyl)-3-acetoxy-4-methoxycinnamamide (Example 193) in 200 ml of ethanol. The solution was stirred for 20 minutes, while it was refluxed. Next, 2.0 ml of ethyl bromoacetate was slowly added dropwise to the solution .by means of a dropping funnel. Thereafter, the solution was stirred for 2 hours. After reaction, the solution was allowed to cool to room temperature. The crystal and the potassium carbonate, both precipitated from the reaction solution, were filtered out, and the solvent was removed in vacuo from the filtrate. The product obtained was recrystallized from methylene chloride/ether, yielding 1.46 g of N-(trans-4-methylcyclohexyl)-3-(ethoxycarbonylmethoxy)-4-methoxycinnamamide (a compound the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:17]([O-])=O)=[C:6]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9](OC)=[O:10])[CH:7]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:17][C:9](=[O:10])[CH:8]2[C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)C(C(=O)OC)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1C(=O)Nc2ccc(F)cc21
Temperature: 42.5 °C
Yield: 118.4 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet tube and having an inner volume of 500 ml were charged 60.0 g (0.22 mol) of dimethyl 2-(5-fluoro-2-nitrophenyl)malonate synthesized according to Example 1 with a purity of 98% and 228 g of methanol under argon atmosphere. Under stirring, while maintaining the temperature of the mixture to 40 to 45° C., 3.0 g (0.72 mmol in terms of the palladium atom) of 5% by weight palladium/carbon (49% hydrated product) was added to the mixture. Then, while blowing hydrogen with a flow rate of 123 ml/min. and a normal pressure, the mixture was reacted at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered to remove the catalyst, the filtrate was concentrated under reduced pressure, and 80 ml of methanol and 240 ml of water were added to the resulting concentrate and cooled to 10° C. Then, after filtration of the precipitated crystals, they were dried to obtain 54.5 g (isolation yield: 94%) of 5-fluoro-3-methoxycarbonyloxindole as white crude crystals with a purity of 80% (analytical value by high performance liquid chromatography).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([O:12][CH3:13])[CH:6]=[N:7]2.[C:14]([O:18]CC)(=[O:17])[CH:15]=[CH2:16]>C1COCC1.CO.[Pd]>[CH3:13][O:12][C:5]1[CH:6]=[N:7][C:8]2[C:3]([CH:4]=1)=[C:2]([CH2:16][CH2:15][C:14]([OH:18])=[O:17])[CH:11]=[CH:10][CH:9]=2
Reactant: C=CC(=O)OCC
Reactant: COc1cnc2cccc(Br)c2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cnc2cccc(CCC(=O)O)c2c1

Procedure:
This compound was synthesised from 5-bromo-3-methoxy-quinoline (5.0 g, 21 mmol; prepared as in DE 10316081) and ethyl acrylate (5 eq.) according to method G followed by hydrogenation over Pd/C in THF/MeOH 4:1. The hydrolysis was carried out according to method F. The product was isolated as a colourless solid (0.1 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[C:6]([N:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C:9]2=[O:14])[CH:7]=1.[NH:32]1[CH2:36][CH2:35][CH2:34][C:33]1=[O:37]>>[CH3:13][N:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:7]=[C:2]([N:32]3[CH2:36][CH2:35][CH2:34][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:21][CH2:22]2)=[O:16])[C:9]1=[O:14]
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Cl)cc3N3CCN(C)C3=O)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3N3CCN(C)C3=O)CC2)nc1C
Yield: 49.1 %

Procedure:
Using 1-{5-chloro-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-3-methylimidazolidin-2-one (55 mg) described in Preparation Example 259 and pyrrolidin-2-one (16 mg) and by the reaction and treatment in the same manner as in Example 666, the title compound (30 mg) was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>CCCCCCC.C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C@H:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: CC(CBr)c1ccccc1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Solvent: CCO
Solvent: CCCCCCC
Product: Cc1nc(-c2ccn(C[C@@H](C)c3ccccc3)n2)sc1C(=O)NCc1cccnc1
Yield: 15 %

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-bromo-1-methyl-ethyl)benzene as described in Example 49 and isolated by chiral separation (80/20 heptane/ethanol) (0.0033 mg, 15% yield). 1HNMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.18-7.34 (m, 4H), 7.13 (d, J=8 Hz, 2H), 7.04 (d, J=2 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.12-6.20 (m, 1H), 4.63 (d, J=4 Hz, 2H), 4.18-4.38 (m, 2H), 3.37-3.46 (m, 1H), 2.75 (s, 3H), 1.30 (d, J=8 Hz, 3H); MS (M+H)+=418.4; Rt=1.31 min; HRMS (M+H)+=418.17.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:5]=1)[CH3:3].C1C(=O)N([Cl:21])C(=O)C1>>[Cl:21][C:5]1[N:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:8][C:4]=1[CH:2]([CH3:1])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ncc(C(C)C)[nH]1
Product: CCOC(=O)c1nc(Cl)c(C(C)C)[nH]1
Yield: 76.9 %

Procedure:
The same operation as in Example (1c) was performed using ethyl 5-(propan-2-yl)-1H-imidazole-2-carboxylate obtained in Example (35d) (0.82 g, 4.50 mmol) and NCS (0.60 g, 4.51 mmol), to obtain 0.75 g of the title compound as a white solid (77%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([CH2:8][Br:17])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)cc1Br

Procedure:
Synthesized from 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.3 mmol), NBS (3.79 g, 21.3 mmol) and DBPO (233 mg, 0.97 mmol) in CCl4 according to Method A. Yield: 2.38 g, 8.34 mmol, 43%. This compound was directly used in the next step without further purification.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([N:16]1[CH2:20][C:19]([CH2:22]Br)([CH3:21])[CH:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[C:17]1=[O:31])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8].C[O-].[Na+]>CO>[CH3:6][C:7]([N:16]1[CH2:20][C:19]2([CH3:22])[C:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])([CH2:21]2)[C:17]1=[O:31])([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[CH3:8]
Reactant: CC1(CBr)CN(C(C)(C)c2cccc(Cl)c2)C(=O)C1c1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(c1cccc(Cl)c1)N1CC2(C)CC2(c2ccccc2F)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To 20 ml of tetrahydrofuran were added 0.7 g of 1-[1-methyl-1-(3-chlorophenyl)ethyl]-4-bromomethyl-4-methyl-3-(2-fluorophenyl)pyrrolidine-2-one and 0.35 g of a 28% methanol solution of sodium methoxide, and the solution was then stirred at room temperature for 1 hour. After the solvent was distilled off, ice water was added to the solution, and extraction was then made with ethyl acetate. Next, the resultant extract was dried over anhydrous sodium sulfate, and after concentration, column chromatography was done to obtain 0.5 g of the desired 3-[1-methyl-1-(3-chlorophenyl)ethyl]-5-methyl-1-(2-fluorophenyl)-3-azabicyclo[3.1.0]hexane-2-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:35]([F:38])([F:37])[F:36])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28][C:29](=O)[C:30]([F:33])([F:32])[F:31])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:39][OH:40].Cl.CC([O-])=O.[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:35]([F:36])([F:37])[F:38])[O:14][N:13]=[C:12]([C:15]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]([C:25]([NH:27][CH2:28]/[C:29](=[N:39]\[OH:40])/[C:30]([F:33])([F:31])[F:32])=[O:26])=[CH:17][CH:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: O=C(NCC(=O)C(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(NC/C(=N\O)C(F)(F)F)c1ccc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 130 °C
Yield: 51 %

Procedure:
To a solution of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-oxopropyl)-1-naphthamide (Preparation 11, 100 mg, 0.2 mmol) in EtOH (5 mL) was added hydroxylamine.HCl (30 mg, 0.4 mmol), water (1 mL), and KOAc (40 mg, 0.4 mmol). Reaction was heated to 130° C. for 40 minutes in a microwave. Water was added to the crude reaction and extracted with EtOAc (2×75 mL). The combined organics were dried (Na2SO4) and concentrated under vacuum. The crude material was chromatographed (24 g Redi-Sep column) eluting from 100% EtOAc to 50:50 EtOAc:heptane to afford (E)-4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3-trifluoro-2-(hydroxyimino)-propyl)-1-naphthamide (52 mg, 51%) as a solid. 1HNMR (CDCl3) δ ppm: 9.06 (1H), 8.81 (1H), 8.26 (1H), 7.71-7.57 (4H), 7.51 (1H), 6.48 (1H), 4.64 (2H) 4.28 (1H), 3.89 (1H); m/z (Cl) 596 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]3[C:13]=2[C:14]2[CH:29]=[C:28]([CH3:30])[CH:27]=[N:26][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2[C:47]3C4C=C(C)C=NC=4[NH:50][C:46]=3[C:45]([O:56]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][C:45](=[O:56])[C@@H:46]([NH2:50])[CH3:47])=[C:17]3[C:13]=2[C:14]2[CH:29]=[C:28]([CH3:30])[CH:27]=[N:26][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCOC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 216 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3 H) 1.39 (d, J=7.07 Hz, 3 H) 2.20-2.24 (m, 2 H) 2.26 (s, 3 H) 4.14 (m, 1 H) 4.32 (t, J=5.68 Hz, 2 H) 4.56 (m., 2 H) 7.08-7.11 (m, 1 H) 7.12-7.16 (m, 1 H) 7.55 (s, 1 H) 7.85 (t, J=7.83 Hz, 1 H) 7.98 (dd, J=10.23, 8.46 Hz, 2 H) 8.06 (s, 1 H) 8.28 (br. s., 3 H) 12.07 (s, 1 H); [M+H] calc'd for C26H30N3O5S, 496.2.; found, 496.4.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:17][O:18][CH2:19][CH2:20][OH:21])[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O[C:25]1[CH:57]=[CH:56][C:28]([CH2:29][CH:30]2[S:34][C:33](=[O:35])[N:32]([C:36]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]2=[O:55])=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:17][O:18][CH2:19][CH2:20][O:21][C:25]3[CH:57]=[CH:56][C:28]([CH2:29][CH:30]4[S:34][C:33](=[O:35])[N:32]([C:36]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:31]4=[O:55])=[CH:27][CH:26]=3)[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CC(=NOCCO)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 87.6 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 647 mg of 2-[1-(4'-trifluoromethylbiphenyl-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 28), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.35 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CO.[C:9]([NH:17][C:18]1[CH:27]=[C:26]([C:28]#[C:29][Si](C)(C)C)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:9]([NH:17][C:18]1[CH:27]=[C:26]([C:28]#[CH:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)OC)c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.68 g of potassium carbonate was added, to a solution of 17 mL of methanol and 17 mL of tetrahydrofuran containing 3.5 g of methyl 2-(benzamido)-4-(2-(trimethylsilyl)ethynyl)benzoate and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and ethyl acetate and 1.0 mol/L hydrochloric acid were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=8:1] to obtain 1.6 g of methyl 2-(benzamido)-4-ethynylbenzoate as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][O:10][Si:16]([CH3:18])([CH3:17])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: ONCc1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)ONCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
A stirred solution of 10.0 grams (0.063 mole) of N-(2-chlorophenyl)methylhydroxylamine (Example 1, Step A-2) and 12.9 grams (0.19 mole) of imidazole in 50 ml of dry dimethylformamide was cooled in an ice-water bath. To this stirred solution was added dropwise during a 20 minute period 10.6 grams (0.07 mole) of tert-butyldimethylsilyl chloride in 25 ml of dry dimethylformamide. During the addition the reaction mixture temperature was maintained at 5°. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature at which it was stirred for 18 hours. Most of the dimethylformamide was removed from the reaction mixture under water aspirator pressure. The residue was taken up in 300 ml of methylene chloride and washed with three 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give on cooling a semi-solid residue. A sample of the semi-solid was slurried with hexane and the insolubles collected by filtration. The filtrate was concentrated to give an oil residue. The above procedure was repeated on the remainder of the semi-solid using 75 ml of hexane. The hexane filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled under reduced pressure to give 10.2 grams of [(2-chlorophenyl)methyl]-[dimethyl(1,1-dimethylethyl)silyloxy]amine; bp 88°-89°/0.7 Pa.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23](C(OC)=O)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CC(C)([O-])C.[K+].Cl.CN([CH:44]=[O:45])C>C1COCC1>[CH2:1]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:20]([O:22][CH:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:44]=2[OH:45])=[O:21])=[CH:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCOc1ccc(CC(=O)OC(C(=O)OC)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCOc1ccc(C2=C(O)C(c3ccccc3)OC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
In a mixture of THF (10 ml) and DMF (1 ml) was dissolved methoxycarbonylphenylmethyl 4-undecyloxyphenylacetate (1.4 g, 3 mmol.). To the solution was added at room temperature potassium tertiary butoxide (1.5 g, 0.012 mol.) The mixture was stirred at room temperature for one hour, to which was added 2N HCl (30 ml), followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure Resultant crude crystals were recrystallized from IPE-ethyl acetate to give 2-(4-undecyloxyphenyl)-3-hydroxy-4-phenyl-2-buten-4-olide (4-g, 0.9 g, 69%). Physico-chemical properties and NMR spectrum of this compound are shown in Table 7.