Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[CH:18]=[C:19]([O:22][CH2:23][C@@H:24]([NH:29]C(=O)OC(C)(C)C)[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]=[CH:21][C:16]=3[C:15]3[C:10](=[C:11]([CH3:37])[N:12]=[CH:13][CH:14]=3)[C:9]2=[O:38])=CC=1>C(#N)C.C(OCC)(=O)C.O>[NH2:29][C@@H:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]2[C:15]3[C:10](=[C:11]([CH3:37])[N:12]=[CH:13][CH:14]=3)[C:9](=[O:38])[NH:8][C:17]=2[CH:18]=1
Reactant: COc1ccc(Cn2c(=O)c3c(C)nccc3c3ccc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc32)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cc1nccc2c1c(=O)[nH]c1cc(OC[C@@H](N)CC(C)C)ccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.2 %

Procedure:
To a solution of (S)-tert-butyl (1-((6-(4-methoxybenzyl)-4-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (500 mg, 0.192 mmol) (prepared as described in Example 49), in acetonitrile (5 mL) and water (5 mL) was added ceric ammonium nitrate (527 mg, 0.962 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was diluted with ethyl acetate (5 mL) and water (5 mL). The organic layer was separated, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to afford (S)-8-(2-amino-4-methylpentyloxy)-4-methylbenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.154 mmol, 80% yield) as an off-white solid. LC/MS (ESI) m/e 326.2 [(M+H)+, calcd for C19H24N3O2 326.2] LC/MS retention time (method C): tR=1.56 min. HPLC retention time (method A): tR=6.98 min; HPLC retention time (method B): tR=6.96 min. 1H NMR (400 MHz, CD3OD) δ ppm 6.32 (m, 1H), 8.44 (m, 2H), 7.13 (m, 1H), 6.94 (d, J=2.4 Hz, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 3.75 (m, 1H), 3.2 (s, 3H), 1.75 (m, 3H), 1.10 (m, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)[C:8](=[O:29])[CH:7]=[N:6]2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[NH2:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=3)[N:6]=[CH:7][C:8]2=[O:29])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)cnc3cc(C#N)ccc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of tert-butyl {1-[2-(6-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 198, 0.38 g) in methylene chloride (4 mL) was added at 0° C. TFA (2 mL). After 1 hour, the reaction was diluted with chloroform, washed with saturated solution of Na2CO3, dried (Na2SO4), filtered and concentrated yielding 0.25 g of crude product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[CH:35]=[CH:34][C:25]2[N:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:28][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][C:22]2[CH:35]=[CH:34][C:25]3[N:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:28][C:24]=3[CH:23]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nc2ccc(CBr)cc2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)cc2o1
Temperature: 70 °C

Procedure:
0.8 g of 4-(2-quinolinylmethyloxy)phenol, 0.89 g of ethyl 6-bromomethylbenzoxazole-2-carboxylate and 0.44 g of potassium carbonate are combined in 15 ml of dimethylformamide and heated at 70° C. for 18 hours. The mixture is poured into water and the aqueous mixture extracted with ethyl acetate. The organic solution is dried and evaporated and the resulting crude product is purified by column chromatography on silica gel to give ethyl 6-(4-(quinolin-2-ylmethyloxy)phenoxymethyl)-benzoxazole-2carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:25]2[CH2:26][CH2:27][NH:28][CH2:29][C:24]=2[C:5]2[C:6]([OH:23])=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:9][C:4]=2[O:3]1.[ClH:31].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][CH2:40][C:41]([OH:43])=O)[CH2:34][CH2:33]1.[CH:44]1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[ClH:31].[CH3:1][C:2]1([CH3:30])[C:25]2[CH2:26][CH2:27][N:28]([CH3:44])[CH2:29][C:24]=2[C:5]2[C:6]([O:23][C:41](=[O:43])[CH2:40][CH2:39][CH2:38][N:35]3[CH2:36][CH2:37][O:32][CH2:33][CH2:34]3)=[CH:7][C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=3)=[CH:9][C:4]=2[O:3]1
Reactant: CC1(C)Oc2cc(CCCCCc3ccc(F)c(F)c3)cc(O)c2C2=C1CCNC2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)CCCN1CCOCC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCC2=C(C1)c1c(OC(=O)CCCN3CCOCC3)cc(CCCCCc3ccc(F)c(F)c3)cc1OC2(C)C

Procedure:
5,5-Dimethyl-10-hydroxy-8-(3,4-difluorophenyl-n-pentyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine, γ-morpholino-butyric acid hydrochloride and dicyclohexylcarbodiimide are combined in equimolar amounts in methylene chloride and reacted as in Example 7 to give the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.4 %

Procedure:
A flask charged with 1H-imidazole-2-carboxylic acid ethyl ester (1.03 g, 7.36 mmol), K2CO3 (2.00 g, 14.5 mmol), SEM-Cl (1.56 mL, 8.89 mmol), and 20 mL of acetone was stirred for 10 h at RT. The reaction was diluted with EtOAc (100 mL), washed with NaHCO3 (2×100 mL), brine (100 mL), and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 1.50 g (76%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H22N3O3Si, 271.1 (M+H). found 271.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:14]([NH2:16])=[O:15])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=2)[N:6]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33](F)[CH:32]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[C:35]([NH:1][C:2]3[S:3][C:4]([C:14](=[O:15])[NH2:16])=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[CH:8]=4)[N:6]=3)[CH:36]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: NC(=O)c1sc(N)nc1-c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])c(Nc3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2)CC1
Yield: 46.7 %

Procedure:
To a mixture of 0.35 g (1.38 mmole) of 2-amino-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.2), 0.56 g (1.66 mmole) of 4-(3-fluoro-4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (IV.21a) and 10 mL of dimethylformamide was added 2.24 g (6.90 mmole) of cesium carbonate. The mixture was heated at 70 degrees for 5 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 0:100-40:60) to give 0.37 g of 4-{3-[5-carbamoyl-4-(3-chloro-phenyl)-thiazole-2-ylamino]-4-nitro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (VI.21).
Reaction SMILES: [CH3:1][NH:2][O:3][CH:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5]1.ClC([O:26][C:27](Cl)(Cl)Cl)=O.C.[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[F:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:27](=[O:26])[N:2]([CH3:1])[O:3][CH:4]2[CH2:5][CH2:6][N:7]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)(=[O:12])=[O:11])[CH2:8][CH2:9]2)=[CH:35][CH:34]=1
Reactant: CNOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(OC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
A solution of N-methyl-O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (130 mg, 0.384 mmol) in tetrahydrofuran (10 ml) was added to a suspension of trichloromethyl chloroformate (91.3 mg, 0.46 mmol) and activated charcoal (20 mg) in tetrahydrofuran (35 ml) at 0° C. over 30 minutes. After stirring at room temperature for 18 hours, the reaction mixture was filtered over silicagel and the filtrate was concentrated in vacuo. The residue was dissolved in tetrahydrofuran (15 ml), 4-fluoroaniline (65 mg, 1.13 mmol) and N,N-diisopropylethylamine (148 mg, 1.15 mmol) were added and the whole was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (50 ml), washed with H2O (20 ml×2), brine (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The residual solid was recrystallized from diethyl ether to give 3-(4-fluorophenyl)-1-methyl-1-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)urea (89.5 mg, 49%) as a white solid. LCMS: 476 [M+1]+. 1H NMR (DMSO-d6) δ: 1.79 (m, 2H), 1.98 (m, 2H), 2.59 (m, 2H), 3.0 (s, 3H), 3.62 (d, 2H), 3.89 (m, 1H), 7.11 (t, 2H), 7.50 (m, 2H), 7.94 (q, 2H), 8.12 (q, 2H), 8.70 (s, 1H).
Reaction SMILES: [N:1](OCCC(C)C)=O.[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([NH2:28])=[C:23]([CH3:29])[C:22]=1[CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].C([O-])(=O)C.[K+]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:9]([O:11][C:12](=[O:35])[C@@H:13]([CH2:20][C:21]1[C:22]([CH2:30][O:31][C:32](=[O:34])[CH3:33])=[C:23]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:28][N:1]=[CH:29]2)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10]
Reactant: CC(C)CCON=O
Reactant: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 80 %

Procedure:
Isoamyl nitrite (700 μL, 5.2 mmol), was added dropwise to an ice cold solution of 2-(S)-(2-Acetoxymethyl-4-amino-5-chloro-3-methyl-benzyl)-succinic acid diethyl ester (1.91 g, 4.8 mmol) in 5% acetic acid in toluene (81.2 mL). Mixture stirred at 0° C. for 45 minutes. Potassium acetate (1.50 g, 15.3 mmol) was added to the mixture. Reaction was stirred at room temperature for 14 hours. Mixture was quenched with water. Mixture was extracted with ethyl acetate (30 mL). Mixture was washed 2× saturated aqueous sodium bicarbonate. Organic was dried (magnesium sulfate) filtered and concentrated. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 80% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=8.23 (s, 1H), 7.26 (s, 1H), 5.45 (s, 2H), 4.09 (q, J=7.0, 4H), 3.20 (dd, J1=7.32, J2=13.2, 1H), 3.10 (m, 1H), 2.97 (dd, J1=7.0, J2=13.3, 1H), 2.73 (dd, J1=8.4, J2=16.8, 1H), 2.44 (dd, J1=5.5, J2=16.8, 1H), 2.08 (s, 3H), 1.18 (m, 6H). MS m/e (M+H)+=411.0.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)NC(=O)CO2
Reaction time: 8 h
Yield: 55.6 %

Procedure:
Pd/C (10%) was added to a suspension of 6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (1.5 g) in MeOH (20 mL) and the reaction mixture was stirred under an atmosphere of hydrogen overnight. The mixture was filtered through Celite® and the filtrate was concentrated under vacuum to give the product (0.705 g, 56%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]C(OC(C)(C)C)=O)=[C:19]([CH3:31])[CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[ClH:33]>O1CCOCC1.C(OCC)C>[ClH:33].[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([CH3:31])[CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(N)c(C)c1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of N-(benzyloxycarbonyl)-4-[(1,1-dimethylethoxy)carbonyl]amino-3-methyl-L-phenylalanine methyl ester (4.52 mmol, 2 g) in dioxane (12 mL) was added 4N hydrochloric acid in dioxane (48 mmol, 2 mL) at room temperature and the solution was stirred for approximately 2 h as a white precipitate was formed. The solids were diluted with diethyl ether, the mother liquor was decanted and the residue was dried first on a rotary evaporator and then under high vacuum to afford 1.487 g (87% yield) of N-(benzyloxycarbonyl)-4-amino-3-methyl-L-phenylalanine methyl ester hydrochloride salt as an amorphous yellow solid. FAB-HRMS m/e calcd for C19H22N2O4 (M+H) 343.0142, found 343.0144.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]Br.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][P:14](=[O:18])([O:15][CH2:16][CH3:17])[O:13][CH2:11][CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cccc(F)c1CBr
Product: CCOP(=O)(Cc1c(F)cccc1F)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
2,6-difluorobenzyl bromide (3.0 g, 14.5 mmol) was combined with triethylphosphite (6.2 mL, 36.2 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 80° C. for 10 hours. The final product was a slightly yellow-tinted oil (3.30 g, 86% yield). 1H NMR (400.14 MHz, DMSO) δ 7.36 (m), 7.10 (m, 2H), 3.96 (m, 4H), 3.20 (d, J=21.08 Hz, 2H), 1.16 (t, J=7.05 Hz, 6H). 13C {1H} NMR (100.62 MHz, CDCl3) δ 161.0 (ddd, J=249.0, 7.3, 6.2 Hz, 2C), 128.4 (dt, J=10.2, 3.82 Hz), 111.0 (ddd, J=18.9, 6.0, 3.5 Hz, 2C), 108.5 (dt, J=19.8, 10.5 Hz), 62.1 (d, J=6.5 Hz, 2C), 20.6 (dt, J=142.1, 2.3 Hz), 16.0 (d, J=6.2 Hz, 2C). 31P {1H} NMR (161.97 MHz, DMSO): δ 24.68. Analysis calculated (found) %: C 50.01 (49.71), H 5.72 (5.78). MS (FAB, m/z): 265 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 265.08051 (265.08278).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:13])=[O:14])[CH:8]=[CH:7]2)=[O:21]
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Product: O=C(Nc1cccc2ccc(S(=O)(=O)O)cc12)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
8-Amino-2-naphthalenesulfonic acid (Aldrich, 1.00 g, 4.48 mmol) and 3,4-dichlorobenzoyl chloride (938 mg, 4.48 mmol) were dissolved in pyridine (10.0 mL), and the resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then concentrated in vacuo, and the residue was dissolved in 1N HCl. The solution was extracted with EtOAc (5×), and the combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound (1.70 g, 91%). 1H NMR (DMSO-d6) δ 11.30 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.83 (s, 1H), 8.65 (dd, J=8.0, 1.9 Hz, 1H), 8.58-8.50 (m, 1H), 8.50-8.43 (m, 2H), 8.34 (dd, J=8.6, 1.5 Hz, 1H), 8.19-8.14 (m, 2H), 6.14 (br s, 1H); MS(ESI−) m/z 394.2 (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]=1[CH2:17][S:18][C:19]1[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][N:20]=1.Cl[CH:27]([F:29])[F:28].O>CN(C)C=O>[Cl:7][C:8]1[N:12]([CH:27]([F:29])[F:28])[N:11]=[C:10]([C:13]([F:15])([F:14])[F:16])[C:9]=1[CH2:17][S:18][C:19]1[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][N:20]=1.[Cl:7][C:8]1[C:9]([CH2:17][S:18][C:19]2[CH2:23][C:22]([CH3:25])([CH3:24])[O:21][N:20]=2)=[C:10]([C:13]([F:15])([F:14])[F:16])[N:11]([CH:27]([F:29])[F:28])[N:12]=1
Reactant: CC1(C)CC(SCc2c(C(F)(F)F)n[nH]c2Cl)=NO1
Reactant: FC(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(SCc2c(C(F)(F)F)nn(C(F)F)c2Cl)=NO1
Product: CC1(C)CC(SCc2c(Cl)nn(C(F)F)c2C(F)(F)F)=NO1
Temperature: 135 °C
Reaction time: 3 h
Yield: 20.2 %
Yield: 25.8 %

Procedure:
3.1 g (22.5 mmoles) of anhydrous potassium carbonate was added to a solution of 2.3 g (7.3 mmoles) of 3-(5-chloro-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline dissolved in 50 ml of N,N-dimethylformamide. Thereinto was blown chlorodifluoromethane. The resulting mixture was stirred at 130 to 140° C. for 3 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was pored into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.69 g (yield: 25.8%) of 3-(5-chloro-1-difluoromethyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as light yellow crystals (melting point: 41.0 to 42.0° C.) and 0.54 g (yield: 20.2%) of 3-(3-chloro-1-difluoromethyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a white powder (melting point: 89.0 to 90.0° C.).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:65])([F:64])[O:54][C:55]1[CH:56]=[C:57]([CH:61]([NH2:63])[CH3:62])[CH:58]=[CH:59][CH:60]=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:52][C:53]([F:64])([F:65])[O:54][C:55]1[CH:56]=[C:57]([CH:61]([NH:63][C:16]([C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])[CH3:62])[CH:58]=[CH:59][CH:60]=1
Reactant: O=C(O)c1sc(-c2ccccc2)nc1C(F)(F)F
Reactant: CC(N)c1cccc(OC(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(NC(=O)c1sc(-c2ccccc2)nc1C(F)(F)F)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.3 %

Procedure:
To a solution of 2-phenyl-4-trifluoromethyl-thiazole-5-carboxylic acid (35 mg, 0.128 mmol) in DMF (1 mL) was added PyBOP (73 mg, 0.141 mmol) and DMAP (16 mg, 0.128 mmol). A solution of 1-(3-trifluoromethoxyphenyl)-ethylamine (27 mg, 0.128 mmol) in DMF (0.5 mL) was then added, followed by Et3N (36 μL, 0.256 mmol). This mixture was stirred at 25° C. for 18 h. The reaction mixture was applied directly to a preparatory HPLC column for purification (C18, 10-100% methanol/water/0.1% trifluoroacetic acid) which gave the amide as a white solid (24.9 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Cl>>[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[CH2:24][N:8]1[C:7](=[O:20])[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[N:9]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(Cc2ccc(Cl)cc2Cl)c1=O
Yield: 88.3 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and 2,4-dichlorobenzyl chloride as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 88.3%.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5](Cl)[C:4]=1[C:19]([O:21][CH3:22])=[O:20].C(N(CC)CC)C.[CH3:31][NH:32][CH:33]1[CH2:35][CH2:34]1.O>CN(C=O)C>[F:1][CH:2]([F:23])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:32]([CH:33]2[CH2:35][CH2:34]2)[CH3:31])[C:4]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: CNC1CC1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(C)C1CC1
Yield: 50.5 %

Procedure:
A solution of 5.0 g (0.008 mol) of product from Example 103, 0.83 g (0.0082 mol) of triethylamine and 0.875 g (0.012 mol) of N-methylcyclopropylamine in 100 ml of DMF was stirred at room temperature for 12 hours. The reaction mixture was poured into H2O and extracted with diethyl ether. The ether phase was washed with H2O and dried (MgSO4). The dry ether phase was concentrated in vacuo to 2.4 g of a yellow oil. The crude product was purified by HPLC in 10% ethyl acetate/cyclohexane followed by kugelrohr distillation at 67 Pa and 125° C. pot temperature, affording 1.6 g (49%) of product as a yellow solid; mp 37°-40° C.