Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:13]1[C:14](=[O:26])[C:15]2[C:20]([C:21](=[O:24])[C:22]=1[OH:23])=[C:19]([CH3:25])[CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:23][C:22]1[C:21](=[O:24])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[CH3:25])[C:14](=[O:26])[C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:29])[CH3:28]
Reactant: CCCCCCCCCCCCC1=C(O)C(=O)c2c(C)cccc2C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCC1=C(OC(C)=O)C(=O)c2c(C)cccc2C1=O

Procedure:
3.8 Parts of 2 -dodecyl-3-hydroxy-5-methyl-1,4-naphthoquinone, 8 parts of acetic anhydride and 32 parts of pyridine were stirred at room temperature for 16 hours. The resulting mixture was evaporated under reduced pressure to remove the pyridine. The residue was recrystallized from methanol to give 2.5 parts of 3-acetoxy-2-dodecyl-5-methyl-1,4-naphthoquinone, m.p. 69°-75° C.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([O:13]C1C(F)=C(F)C(F)=C(F)C=1F)=O)[CH2:3]2.[Br:25][C:26]1[CH:35]=[CH:34][C:29]2[CH:30]=[C:31]([NH2:33])[S:32][C:28]=2[CH:27]=1.C(=O)([O-])[O-].Cl>CN(C=O)C.C(#N)C>[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([CH2:10][C:11]([NH:33][C:31]1[S:32][C:28]3[CH:27]=[C:26]([Br:25])[CH:35]=[CH:34][C:29]=3[CH:30]=1)=[O:13])[CH2:3]2
Reactant: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Nc1cc2ccc(Br)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(CC1CN2CCC1CC2)Nc1cc2ccc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
89.2 mg (0.24 mmol) of pentafluorophenyl (1-azabicyclo[2.2.2]oct-3-yl)acetate hydrochloride are dissolved in 1 ml of DMF, mixed with 71.2 mg (0.31 mmol) of 6-bromo-1-benzothiophene-2-amine and stirred at room temperature overnight. 1 g of MP-carbonate (polymer-bound carbonate, capacity: 2.5-3.5 mmol/g; from Argonaut Technologies, USA) is added. After 3 h, the polystyrene resin is filtered off and washed with THF. The combined filtrates are concentrated in vacuo, and the crude product is purified by preparative HPLC. The hydrochloride is prepared by mixing the product with a mixture of 1 M hydrochloric acid and acetonitrile and again concentrating. Drying under high vacuum results in 14 mg (14% of theory) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:35]=[C:36]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:38][C:39]=1[Cl:40]>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:44]1[CH2:45][CH2:46][N:41]([C:36]2[CH:37]=[CH:38][C:39]([Cl:40])=[C:34]([Cl:33])[CH:35]=2)[CH2:42][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Yield: 7 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3,4-dichloro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.5 mg, 7.0%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([O:15]C(=O)C)[CH:12]=[CH:11][C:10]=2[O:19]C(=O)C)=[CH:5][CH:4]=1.O.O.O.C([O-])(=[O:29])C.[Na+].CO.Cl>O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=2[OH:19])=[CH:5][CH:4]=1)=[O:29]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(-c2ccc(C(Br)Br)cc2)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=Cc1ccc(-c2cc(O)ccc2O)cc1

Procedure:
A mixture of about 4.4 g. (0.01 mole) of 4'-dibromomethyl-2,5-diacetoxy-1,1'-biphenyl, prepared as described in Example 2, and about 4.4 g. (0.03 mole) of sodium acetate trihydrate in a mixture of 50 ml. of methanol and 25 ml. of water was heated at reflux under nitrogen for about 4 hours. 5 ml. of concentrated hydrochloric acid were added and refluxing continued for an additional 11/2 hours. Most of the methanol was removed by evaporation on a steam bath under nitrogen resulting in precipitation of a light cream colored solid. The mixture was diluted with 50 ml. of water, cooled in an ice bath, and the resultant solid filtered, washed with water, and dried in a vacuum oven. Yield of about 2.0 g. of 4'-formyl-2,5-dihydroxy-1,1'-biphenyl, m.p. 203°-205° C. Thin layer chromatography indicated one component. Proton nuclear magnetic resonance and infrared spectra confirmed the structure and were essentially identical to the spectra obtained from the product of Example 3. The product gave a positive test with 2,4-dinitrophenylhydrazine spray reagent.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[CH:14]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>O1CCOCC1>[C:21]1([CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=3)[CH2:31][CH2:32]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)Cc1ccc(CBr)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
A 200 ml eggplant-shaped flask was charged with 5.38 g of methyl 4-bromomethylphenylacetate, 6.06 g of 1-benzhydrylpiperazine, 6.1 ml of triethylamine, and 100 ml of dioxane and the mixture was stirred at room temperature for 5 hours. The solvent was then distilled off and the residue was extracted with ethyl acetate. The extract was washed with water, the solvent was distilled off, and the residue was recrystallized from methanol to provide 8.33 g of methyl 4-[(4-diphenylmethyl-1-piperazinyl)methyl]phenylacetate melting at 124° C.-125° C.
Reaction SMILES: C12BC(CCC1)CCC2.[Cl:10][C:11]1[C:12]([C:26]2[N:30]([CH2:31][CH:32]=[CH2:33])[N:29]=[N:28][N:27]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[Cl:21])[N:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[N:14]2.C[N+]([O-:38])(C)C>O1CCCC1>[Cl:10][C:11]1[C:12]([C:26]2[N:30]([CH2:31][CH2:32][CH2:33][OH:38])[N:29]=[N:28][N:27]=2)=[C:13]2[C:18](=[CH:19][C:20]=1[Cl:21])[N:17]=[C:16]([O:22][CH3:23])[C:15]([O:24][CH3:25])=[N:14]2
Reactant: C[N+](C)(C)[O-]
Reactant: C=CCn1nnnc1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)c(Cl)c(-c3nnnn3CCCO)c2nc1OC
Yield: 72.7 %

Procedure:
9-Borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 9.1 mL, 4.55 mmol) was added dropwise to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-(1-allyl-1H-tetrazol-5-yl)quinoxaline (Preparation 19, 0.67 g, 1.82 mmol) in dry tetrahydrofuran (15 mL) at room temperature under nitrogen. The reaction mixture was heated under reflux for 18 hours, trimethylamine-N-oxide (1.03 g, 13.7 mmol) was added portionwise to the cooled reaction mixture and the mixture was heated under reflux for 2 hours then concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (100:0 changing to 99.5:0.5, by volume) to give the title compound (0.510 g, 73%) as a white solid, mp 188-189° C.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[S:8][C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]1=2)[CH:2]=[CH2:3].ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[CH2:1]([O:4][C@@H:5]1[C@H:9]([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[S:8](=[O:26])[C:7]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:6]1=2)[CH:2]=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCO[C@H]1c2ccc(Cl)cc2S[C@H]1Cn1ccnc1
Solvent: ClCCl
Product: C=CCO[C@H]1c2ccc(Cl)cc2S(=O)[C@H]1Cn1ccnc1
Reaction time: 1 h

Procedure:
Dissolve 21.7 g. (70.7 mmole) of (±)-cis-3-allyloxy-6-chloro-2,3-dihydro-2-(1H-1-imidazolylmethyl) benzo[b]thiophene in 500 mL of CH2Cl2 and cool the solution to 0°-5°. Added 14.6 g (70.7 mmole) of m-chloroperoxybenzoic acid (tech. 80-85%) and stir the reaction mixture at 0°-5° for 1 hour. Extract the reaction mixture with 500 mL of 5% aqueous NaHCO3 followed by 500 mL of H2O. Dried the CH2Cl2 layer over anhydrous MgSO4 and concentrate it to give (±)-cis-3-allyloxy-6-chloro-2,3-dihydro-2-(1H-1-imidazolylmethyl)benzo[b]thiophene-1-oxide, a gum, m/e 322.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[O:11]=[S:8]1(=[O:12])[CH2:9][CH2:10][CH:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:6][CH2:7]1
Reactant: O=S1(=O)CCC(Oc2ccccc2Br)CC1
Reactant: C1CNCCN1
Product: O=S1(=O)CCC(Oc2ccccc2N2CCNCC2)CC1

Procedure:
Ortho-fluoro bromobenzene was reacted with tetrahydro-thiopyran-3-ol to give 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran in a manner similar to preparation 24A. 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran (1.94 g, 7.10 mmol) is placed in DCM (70 mL) and calcium carbonate (2.84 g, 28.41 mmol) was added. To this mixture cooled to 0° C. in an ice bath was added meta-chloro peroxy-benzoic acid (6.13 g, 17.75 mmol 50%) in portions while monitoring the temperature. The mixture was allowed to warm to r.t and stirred for about 15 minutes. The mixture was filtered over celite, and washed with sodium bisulfite solution (2×250 mL) and sodium bicarbonate (2×250 mL). The mixture was then concentrated to an oil. Chromatography (EtOAc/hexanes) provided 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran 1,1-dioxide (2.2 g, quant.) as a yellow solid. 4-(2-Bromo-phenoxy)-tetrahydro-thiopyran 1,1-dioxide was coupled to piperazine using the Buchwald chemistry described in preparation 1A to afford the title compound. LRMS (ESI+): 311.1 (M+1)
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][N:39]3C(=O)C4C(=CC=CC=4)C3=O)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CCO>[NH2:39][CH2:38][CH2:37][CH2:36][O:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:23][CH:24]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN3C(=O)c4ccccc4C3=O)c2)cc1
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCN)c2)cc1
Yield: 61.2 %

Procedure:
The product from Example 70B (0.323 g, 0.479 mmoles) in EtOH (5 mL) was treated with hydrazine hydrate (0.15 mL, 4.79 mmoles). The reaction was heated overnight at 60 C. Reaction mixture concentrated under reduced pressure, and residue dissolved in ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% to 20% MeOH:CHCl3) to provide the title compound (0.160 g, 61%). MS (ESI+) m/z 546 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:12]([O-])(=[O:14])[CH3:13].[Na+].O>C(O)(=O)C>[C:12]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:14])[CH3:13]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc(C(=O)O)cc1
Yield: 72.5 %

Procedure:
A mixture of 4-aminomethylbenzoic acid (Aldrich, 1.51 g, 0.01 mol) and anhydrous sodium acetate (1.5 g, 0.018 mol) in glacial acetic acid (5 mL) was heated at reflux for 18 h. On cooling, the mixture was poured into cold water (50 mL). The precipitate was separated by filtration and washed several times with cold water. The cake was recrystallized from water to give 1.4 g (72.5%) of the title compound as a white powder, mp 195° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N+:7]([O-:16])=[CH:6][C:5]=2[N:10]=1
Reactant: Cc1nc2cnccc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c[n+]([O-])ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methyl-thiazolo[4,5-c]pyridine (2.3 g, 15.3 mmol) was dissolved in 150 ml chloroform and 3-chloroperoxybenzoic acid (4.15 g, 16.8 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then evaporated. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0->90:10 gradient). The desired product was obtained as a white solid (2.1 g, 83%), MS: m/e=167.2 (M+H+).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][C:15]1[C:20]([CH2:21][OH:22])=[CH:19][CH:18]=[C:17]([C:23]([F:26])([F:25])[F:24])[N:16]=1.[CH3:27][O:28][C:29](=[O:43])[CH2:30][C:31]1[C:35]2[C:36]([CH3:42])=[CH:37][C:38](O)=[C:39]([CH3:40])[C:34]=2[S:33][CH:32]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:27][O:28][C:29](=[O:43])[CH2:30][C:31]1[C:35]2[C:36]([CH3:42])=[CH:37][C:38]([O:22][CH2:21][C:20]3[C:15]([CH3:14])=[N:16][C:17]([C:23]([F:24])([F:26])[F:25])=[CH:18][CH:19]=3)=[C:39]([CH3:40])[C:34]=2[S:33][CH:32]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2c(C)c(O)cc(C)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(C)c(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a mixture of tri-n-butylphosphine (0.196 mL), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (105 mg), methyl(6-hydroxy-4,7-dimethyl-1-benzothiophen-3-yl)acetate (130.9 mg) and THF (5.0 mL) was added ADDP (198 mg) at room temperature. The mixture was stirred at room temperature overnight under nitrogen atmosphere. The mixture was concentrated in vacuo. To the residue was added IPE, and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (159 mg) as solid. The solid was crystallized from EtOAc-hexane.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:10])([CH2:8][OH:9])[CH3:7])(=[O:3])[OH:2].[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1>C(O)CCCCC>[C:1](=[O:2])([O:4][CH2:5][C:6]([CH3:10])([CH3:7])[CH2:8][OH:9])[O:3][CH2:15][CH2:16][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(CO)COC(=O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)OCC(C)(C)CO
Temperature: 100 °C

Procedure:
3.9 g of neopentyl glycol carbonate was dissolved in 5.0 g of n-hexanol and 0.075 g of p-toluenesulfonic acid was added to the solution. The mixture was heated at 100° C. for 20 minutes. After the reaction, the mixture was evaporated in vacuo to remove unreacted n-hexanol and then filtered to remove unreacted neopentyl glycol carbonate. n-Hexyl 2,2-dimethyl- 3-hydroxypropyl carbonate was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][C:14]1=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C:14]2=[O:19])=[CH:9][C:6]=1[C:7]#[N:8])([O-:12])=[O:11]
Reactant: O=C1COCCN1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1cc(N2CCOCC2=O)ccc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 54.2 %

Procedure:
A suspension of 5-chloro-2-nitrobenzonitrile (2.41 g), morpholin-3-one (2 g), cesium carbonate (6.45 g), tris(dibenzylideneacetone)dipalladium (120 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (230 mg) in 30 ml dioxane was heated for 24 h at 120° C. The reaction mixture was cooled to 25° C., diluted with CH2Cl2 and filtered through decalite. The organic layer was washed with water and brine and purified by chromatography (silica gel, AcOEt) to yield 2-nitro-5-(3-oxo-morpholin-4-yl)-benzonitrile as a yellow solid (1.77 g). MH+=248.3
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(Br)(Br)Br.[NH2:23][OH:24]>>[C:1]([NH:4][CH:5]([NH:23][OH:24])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: NO
Agent: BrB(Br)Br
Product: CC(=O)NC(NO)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BBr3 (1M in CH2Cl2, 8.8 mL, 8.8 mmol), and anhydrous NH2OH (5-6 equiv) gave an oily residue. The residue was separated into three components by flash chromatography on SiO2 gel (7.5% MeOH/CHCl3).
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[C:3]=1[NH2:4].[Cl:23][C:24]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[Cl:23][C:24]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:4][C:3]1[C:5]([C:19]([F:20])([F:21])[F:22])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:2]=1[I:1])=[O:27]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1Cl

Procedure:
According to the method of 3-2 of Example 3, a target compound was prepared from 2-iodo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)aniline and 2-chloro-3-nitrobenzoyl chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.P([O-])([O-])([O-])=[O:15].[K+].[K+].[K+]>CS(C)=O>[CH2:3]1[C:4]2[C:9](=[CH:8][C:7]([C:6]([CH:5]=2)=[O:15])=[O:10])[NH:1][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: O=P([O-])([O-])[O-]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1C=C2CC(C(=O)O)NC2=CC1=O

Procedure:
The concentration of enzyme, substrate and inhibitor was denoted as [E], [S] and [I], respectively. 80 microliters of 0.067 M potassium phosphate buffer (pH 6.8), 40 microliters of L-tyrosine in 0.067 M potassium phosphate buffer (pH 6.8), 40 microliters of inhibitor in 5% DMSO solution, and 40 microliters of mushroom tyrosinase solution were added to a 96-well microplate, to make the final concentration of each reagent to be: 0.2 mg/ml [S], and 96 units/ml [E], with varying [I]. 5% DMSO solution instead of an inhibitor solution was added to a blank solution and adjusted to the total volume of 200 microliters as control. The assay mixture was incubated at 37° C. The amount of dopachrome produced in the reaction mixture was measured at 475 nm in a microplate reader at different time periods. The percentage of inhibition of tyrosinase activity was calculated as follows: Inhibition (%)=[(A−B)−(C−D)]/(A−B)×100
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([NH2:19])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[C:22]([C:31]([F:34])([F:33])[F:32])=[N:23][N:24]([CH2:27][C:28](O)=[O:29])[C:25]=1[CH3:26].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Cl:20][C:21]1[C:22]([C:31]([F:33])([F:32])[F:34])=[N:23][N:24]([CH2:27][C:28]([NH:19][C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:29])[C:25]=1[CH3:26]
Reactant: Nc1cnn(-c2ccc(F)cc2)c1-c1ccccc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)Nc1cnn(-c2ccc(F)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-phenylpyrazol-4-amine (0.03 g, 0.12 mmol) in DMF (1.0 mL) was added 2-[4-chloro-5-methyl-3-(trifluoromethyl)pyrazol-1-yl]acetic acid (0.024 g, 0.12 mmol), followed by diisopropylethylamine (0.031 g, 0.24 mmol) and HATU (0.055 g, 0.14 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.020 g, 0.045 mmol, 28%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.55 (s, 1H), 7.44-7.34 (m, 3H), 7.22-7.14 (m, 2H), 7.07-6.93 (m, 4H), 4.86 (s, 2H), 2.29 (s, 3H); MS: (ES) m/z calculated for C22H16ClF4N5O [M+H]+ 478.1, found 477.8.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[C@@H:5]([CH3:7])[OH:6].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>>[OH:6][C@H:5]([CH3:7])[C@H:4]([NH:3][C:18]([O:20][CH3:21])=[O:19])[C:8]([OH:10])=[O:9]
Reactant: C[C@@H](O)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@H](C(=O)O)[C@@H](C)O
Temperature: 0 °C
Reaction time: 15 h
Yield: 538.6 %

Procedure:
An aqueous NaOH (1 M, 167 mL) solution is added, while stirring, to L-Threonine (20 g, 30.5 mmol) in a round bottom flask (1 L). To this solution was added sodium carbonate (9.8 g, 92.3 mmol). The flask is cooled to 0° C. in an ice-water bath. Methyl chloroformate (14.3 mL, 184.7 mmol) is added drop wise and the reaction mixture is allowed to stir for 15 hours and reach room temperature. The reaction mixture is washed with CH2Cl2 (3×50 mL), and the aqueous layer is contained in a round bottom flask and cooled over an ice-water bath. Concentrated HCl (aq) is added drop wise until pH 2. The aqueous solution is brought to room temperature and the water is removed in vacuum. The residue was taken up in a 2:1 mixture of MeOH/CH2Cl2 (150 mL, filtered and washed with 2:1 mixture of MeOH/CH2Cl2 (50 mL). The filtrate was concentrated and dried in vacuum at 40° C., resulting in white foam (29.1 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([F:38])=[CH:11][C:12]([F:37])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([O:29][CH3:30])=[C:22]([N+:26]([O-])=O)[C:23]=3[CH3:25])[C:18](=[O:31])[C:17]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:16]2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Fe].C(O)(=O)C>[NH2:26][C:22]1[C:23]([CH3:25])=[C:24]2[C:19]([C:18](=[O:31])[C:17]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[C:10]([F:38])=[CH:11][C:12]=2[F:37])=[CH:20][C:21]=1[O:29][CH3:30]
Reactant: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c([N+](=O)[O-])c(OC)cc2c1=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(-c2cc(NC(=O)OC(C)(C)C)c(F)cc2F)c2c(C)c(N)c(OC)cc2c1=O
Temperature: 80 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
Acetic acid (2 ml) and iron powder (150 mg) were added to ethyl 1-(5-tert-butoxycarbonylamino-2,4-difluorophenyl)-6-methoxy-8-methyl-7-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylate (200 mg), and the mixture was stirred at 80° C. for 40 minutes. The catalyst was removed by filtration through Celite, and the solvent and the like in the filtrate were distilled off. The residue was subjected to column chromatography on silica gel to conduct elution with chloroform, thereby obtaining the title compound (140 mg) as an amorphous substance.