Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[N:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1O)[C:12]([F:18])([F:17])[O:11][C:10]2([F:20])[F:19])=[O:5].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[F:20][C:10]1([F:19])[C:9]2[C:13](=[CH:14][C:15]3[O:5][C:4]([C:3]4[CH:21]=[CH:22][N:23]=[CH:24][C:2]=4[F:1])=[N:6][C:7]=3[CH:8]=2)[C:12]([F:17])([F:18])[O:11]1
Reactant: O=C(Nc1cc2c(cc1O)C(F)(F)OC2(F)F)c1ccncc1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1cnccc1-c1nc2cc3c(cc2o1)C(F)(F)OC3(F)F
Reaction time: 1 h
Yield: 78.8 %

Procedure:
To a mixture of 1.46 g of 3-fluoro-N-(1,1,3,3-tetrafluoro-6-hydroxy-1,3-dihydroisobenzofuran-5-yl)isonicotinamide, 10 ml of tetrahydrofuran and 2.02 g of triphenylphosphine, 0.90 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.09 g of 5,5,7,7-tetrafluoro-2-(3-fluoropyridin-4-yl)-5,7-dihydro-furo[3′,4′:4,5]benzo[1,2-d]oxazole (hereinafter, referred to as “active compound 87”).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=O)(=O)[N:4](C)[C:3]=1[C:15](=[O:23])[NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[O:19][N:18]=1.NC1C=C(C)ON=1.CC1ON=C(NC(=O)CN2C(=O)C3C=CC=CC=3S2(=O)=O)C=1>>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][NH:4][C:3]=1[C:15]1[O:23][N:18]=[C:17]([CH2:21][C:20](=[O:19])[CH3:22])[N:16]=1
Reactant: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Agent: Cc1cc(N)no1
Agent: Cc1cc(NC(=O)CN2C(=O)c3ccccc3S2(=O)=O)no1
Product: CC(=O)Cc1noc(C2=C(O)c3ccccc3SN2)n1

Procedure:
A novel process for preparing 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (I), starting with 3-amino-5-methylisoxazole (II) is disclosed. Compound I exhibits anti-inflammatory properties and is useful for treating inflammation. In the process of the invention an intermediate obtained, 2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-actamide 1,1-dioxide (IV) undergoes rearrangement to provide 1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone, S,S-dioxide (V), which is methylated, according to conventional procedures. The methylated intermediate VI, upon further treatment, undergoes a second rearrangement to obtain the desired anti-inflammatory compound I.
Reaction SMILES: Br[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[O:10][C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:32])=[O:28]
Reactant: O=C(O)CC1(Br)OC2=CC=CC2=CC1c1ccccc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-bromo-3-phenyl-4-benzofuranacetic acid (12.1 g., 0.0365 mole) and cyclohexane (3.3 g., 0.04 mole) in 100 ml. of chloroform is treated with 5 g. of dinitrogen tetroxide in 20 ml. of chloroform dropwise. The mixture is stirred for 16 hours at about 25° C. then at 50°-55° C. for about 20 minutes. The mixture is washed with water, and the organic layer is treated with an aqueous base. The aqueous layer is acidified, then extracted with dichloromethane. The organic layer is washed thrice with water, dried and evaporated. Two recrystallizations from benzene give light yellow solid 2-nitro-3-phenyl-4-benzofuranacetic acid, m.p. 187.5°-189.5° C.
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:24]3[N:23]=[CH:22][N:21]=[C:16]([NH:17][CH2:18][CH2:19][NH2:20])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:25])[C@@H:8]1[OH:26])([OH:4])([OH:3])=[O:2].C(=O)(O)[O-].[Na+].F[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[N+:42]([O-:44])=[O:43].Cl.[OH-].[Na+]>O.C(O)C>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[C:24]3[N:23]=[CH:22][N:21]=[C:16]([NH:17][CH2:18][CH2:19][NH:20][C:37]4[CH:38]=[CH:33][C:34]([N+:42]([O-:44])=[O:43])=[CH:35][C:36]=4[N+:39]([O-:41])=[O:40])[C:15]=3[N:14]=[CH:13]2)[C@H:9]([OH:25])[C@@H:8]1[OH:26])([OH:4])([OH:3])=[O:2]
Reactant: NCCNc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NCCNc2ncnc3c2ncn3[C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
Two hundred fifty mg N6 -(2-aminoethyl)adenosine-5'-monophosphate (0.65 mmol) from Part A of this Example was dissolved in 20 ml water at pH 8. Then 168 mg sodium bicarbonate was added, followed by 0.2 ml 1-fluoro-2,4-dinitrobenzene (1.58 mmol dissolved in 2 ml ethanol). The reaction mixture was stirred in the dark at room temperature for 4 hr and then an additional 0.1 ml 1-fluoro-2,4-dinitrobenzene in 1 ml ethanol was added. After the reaction mixture had stirred overnight, it was adjusted to pH 2.0 with hydrochloric acid and was poured into 200 ml ethanol. The precipitate which formed was dissolved in 200 ml water and this solution was adjusted to pH 8.0 with sodium hydroxide and chromatographed on a 2.5×30 cm column of DEAE-cellulose in the bicarbonate form (available from Reeve Angel, Clifton, N.J.). The chromatogram was developed with a linear gradient generated with 1.5 liters water and 1.5 liters 0.7 M ammonium bicarbonate. A major peak of yellow material which absorbed uv light was eluted between 1200 and 1500 ml of the gradient. Ammonium bicarbonate was removed by repeated evaporation to dryness to give 40 percent yield of the desired product. This product migrated as one yellow spot on thin-layer chromatograms developed with the same two solvents mentioned in Part A of this Example and on epichlorohydrintriethanolamine anion-exchange paper developed with 0.25M sodium acetate-acetic acid buffer, pH 5.0. In 0.02N hydrochloric acid the product had optical absorption maxima of 264 nm and 363 nm with millimolar extinction coefficients of 21.8 and 14.2, respectively.
Reaction SMILES: [I:1][C:2]1[N:9]2[C:5]([S:6][C:7](S(C)=O)=[N:8]2)=[N:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH2:13]([NH:20][C:7]1[S:6][C:5]2=[N:4][CH:3]=[C:2]([I:1])[N:9]2[N:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)c1nn2c(I)cnc2s1
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: Ic1cnc2sc(NCc3ccccc3)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
5-Iodo-2-methanesulfinyl-imidazo[2,1-b][1,3,4]thiadiazole (500.00 mg; 1.60 mmol; 1.00 eq.) was dissolved in dichloromethane (1.60 ml) and benzylamine (622.18 μl; 4.79 mmol; 3.00 eq.) was added. Then, the reaction was refluxed overnight. The reaction was concentrated in vacuo. Then, 5 ml of isopropanol were added and the suspended solution was heated under reflux for 15 min. The mixture was allowed to cool to room temperature and then cooled to 0° C. After 15 min at 0° C., the solid was filtered and washed with isopropanol to give a white solid. The solid was dried at 60° C. for 1 h to give 460.2 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][S:5][C:6]1[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:8]([OH:11])=[N:9][N:10]=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30]Br.C[O-].[Na+].Cl>CN(C=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30][O:11][C:8]1[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:6]([S:5][CH2:4][C:3]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=2[Cl:1])=[N:10][N:9]=1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Oc1nnc(SCc2c(F)cccc2Cl)n1-c1ccccc1C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1COc1nnc(SCc2c(F)cccc2Cl)n1-c1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-((2-chloro-6-fluorobenzyl)thio)-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-ol (50 mg, 0.124 mmol), 2-chloro-6-fluorobenzyl bromide (39 mg, 0.175 mg), and sodium methoxide (18 mg, 0.33 mmol) in anhydrous DMF was stirred at 80° C. for 8 h. The reaction mixture was cooled to room temperature and neutralized to pH 5 with 5N HCl. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC to afford 3-((2-Chloro-6-fluorobenzyl)oxy)-5-((2-chloro-6-fluorobenzyl)thio)-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazole (598). 1H NMR (400 MHz, CDCl3) δ: 7.81-7.79 (m, 1H), 7.63-7.60 (m, 2H), 7.33-7.24 (m, 2H), 7.19-7.14 (m, 2H), 7.10-7.04 (m, 2H), 6.90-6.85 (m, 2H), 5.20 (s, 2H), 4.23 (dd, J=13.0, 1.6, 1H), 4.15 (dd, J=13.0, 1.6, 1H). LC-MS ESI m/z; found 546.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH2:23])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:46]([O:48][C:49]1[CH:57]=[CH:56][CH:55]=[CH:54][C:50]=1[C:51](O)=[O:52])[CH3:47]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]2[O:18][CH:19]=[C:20]([CH2:22][NH:23][C:51](=[O:52])[C:50]3[CH:54]=[CH:55][CH:56]=[CH:57][C:49]=3[O:48][CH2:46][CH3:47])[N:21]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(CN)co2)cc1OCc1ccccc1
Reactant: CCOc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(C)=O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OCc3ccccc3)c2)n1

Procedure:
A 3.5 g quantity of the [2-(3-benzyloxy-4-methoxy phenyl)oxazol-4-yl]methylamine obtained in Reference Example 7 was suspended in 70 ml of acetone. To the obtained suspension were added 2.3 g of 1-hydroxybenzotriazole, 3.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 3.8 g of 2-ethoxybenzoic acid, and the mixture was heated and refluxed for one hour. The reaction mixture was cooled, and acetone was distilled off under reduced pressure. Water was added to the residue, and extraction was then performed with ethyl acetate. The organic layer was washed with water twice, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give 4.6 g of white powdery N-[2-(3-benzyloxy-4-methoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(Br)c(C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-3-methyl-2-nitrophenol (2.200 g, 9.48 mmol) in acetone (35 mL) was added potassium carbonate (3.276 g, 23.70 mmol) and methyl iodide (1.47 mL, 23.70 mmol) and the.mixture was heated to reflux for 4 h. The reaction was cooled to rt, filtered and the filtrate was evaporated under reduced pressure to afford the crude product. Purification of the crude product by column chromatography over silica gel eluting with EtOAc/hexane afforded pure 1-bromo-4-methoxy-2-methyl-3-nitrobenzene as pale yellow solid. 1H NMR (400 MHz, CDCl3) δ=2.33 (s, 2H), 3.87 (s, 3H), 6.78 (d, J=8.84 Hz, 1H) and 7.58 (d, J=8.84 Hz, 1H); MS (ES+): m/z 247.26 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[C:19]([O:28][CH3:29])[CH:18]=2)=[O:15])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N1CCOCC1)C>ClCCl>[C:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:12][C:13](=[O:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:27][CH:26]=[N:25][CH:24]=3)=[C:19]([O:28][CH3:29])[CH:18]=2)=[O:15])([CH3:10])[CH3:11])=[CH:4][CH:3]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccccc1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(N)cc2)ccc1-c1cnco1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)Cc2ccc(NC(=O)c3ccccc3)cc2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.7 %

Procedure:
A mixture of 30 mg (0.074 mmol) of N-[2-(4-aminophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide, 10 mg (0.082 mmol) of benzoic acid, 14 mg (0.092 mmol) of 1-hydroxybenzotriazole hydrate, 21 mg (0.11 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 18 mg (0.16 mmol) of N-ethylmorpholine in 2 ml of dichloromethane was stirred at room temperature for 18 hours then diluted with dichloromethane and washed with 2M hydrochloric acid and saturated sodium bicarbonate. The organic phase was dried over magnesium sulphate, evaporated to dryness and the residue chromatographed on silica gel using ethyl acetate/petrol (2:1) for the elution. There was obtained 9 mg of N-[2-(4-benzamidophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a white solid. MS: m/e 513 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([N:23]([CH3:31])[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])=[CH:17][CH:16]=3)[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:32])[C:6]=2[CH:33]=1.[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:34][O:35][C:36]1[N:41]=[CH:40][C:39]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([C:21]([N:23]([CH3:31])[CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:22])=[CH:19][CH:20]=4)[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:32])[C:6]=3[CH:33]=2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(Br)cc3c2C)C(C)C)cc1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(-c4ccc(OC)nc4)cc3c2C)C(C)C)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 17.2 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[1-(5-bromo-3-methyl-1-benzofuran-2-yl)-2-methylpropyl]amino}phenyl)carbonyl](methyl)amino}propanoate (0.55 g) synthesized in the above-mentioned (2) in N,N-dimethylacetamide were added (6-methoxypyridin-3-yl)boronic acid (0.33 g), potassium carbonate (0.29 g) and tetrakistriphenylphosphine palladium (0.12 g), and the mixture was stirred at 70° C. for 24 hr under argon atmosphere. The reaction mixture was cooled to room temperature, and filtered through celite, and the residue was washed with diethyl ether. Water was added to the filtrate, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1, volume ratio) to give ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (0.10 g) as a pale-yellow oil. The obtained oil was dissolved in ethanol (1 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.06 g, 10%) as a colorless solid.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.25 mL, 3.12 mmol) was added dropwise by syringe to a solution of 1-methyl-1H-1,2,3-triazole (268 mg, 3.22 mmol) in dry THF (32 mL) in a dry ice-methanol bath. The suspension was stirred for 30 minutes, slowly allowing the reaction mixture to warm to −10° C. (4-Chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.500 g, 1.05 mmol, Intermediate 45: step f) in dry THF (5 mL) was added to the mixture via syringe and the resulting mixture was allowed to warm to ambient temperature overnight. The reaction was quenched with water. Brine was added and the aqueous mixture was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-8% MeOH-DCM) to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=1.7 Hz, 1H), 8.24 (d, J=1.9 Hz, 1H), 8.22 (s, 1H), 7.79-7.76 (m, 1H), 7.75 (d, J=8.7 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.42 (dd, J=8.7, 2.0 Hz, 1H), 6.97 (s, 1H), 5.95 (s, 1H), 4.30 (s, 2H), 4.08 (s, 3H), 3.88 (s, 3H), 3.33 (s, 3H), 2.12 (s, 3H); MS m/e 557.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH2:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(=O)OCc1ccccc1)(NC(=O)OCc1ccccc1)C(=O)OCC
Yield: 98.9 %

Procedure:
A solution of diethyl 2-benzyloxycarbonylaminomalonate (30 g) in anhydrous DMF (100 mL) was added portionwise with sodium hydride (60%, 4.27 g) with ice cooling and stirring, then the mixture was stirred at room temperature for 30 minutes, and then added with benzyl 2-bromoacetate (28.9 g), and the mixture was stirred overnight. The reaction mixture was poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, and then purification was performed with n-hexane/ethyl acetate (4:1), to obtain the title compound (43.9 g, yield: 99%) as colorless oil.
Reaction SMILES: [C:1](=[N:15]O)([C:3]1([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH2:6][CH2:5][CH2:4]1)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].[OH-].[Na+]>CCOCC.O>[Cl:14][C:9]1[CH:8]=[C:7]([C:3]2([CH:1]([NH2:15])[CH3:2])[CH2:6][CH2:5][CH2:4]2)[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: CC(=NO)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CC(N)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reaction time: 1 h

Procedure:
A solution of the oxime prepared above (4.0 g) in ether (50 ml) was added slowly to a stirred suspension of lithium aluminium hydride (0.9 g) in ether (50 ml) under nitrogen. The mixture was heated under reflux for one hour and, after cooling, water and then a 20% aqueous solution of Rochelle's salt (potassium sodium tartrate tetrahydrate) (27 ml) and a 10% aqueous solution of sodium hydroxide (6 ml) added. The reaction mixture was stirred for one hour and then continuously extracted with ether during eighteen hours. The ether extract was dried and the ether removed to leave a solid from which 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine was separated by high pressure liquid chromatography. The product was identified by standard analytical techniques as the compound of Example 1 in the form of its free base.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:13]=1)=[O:10].Br[CH2:26][CH2:27][CH2:28][C:29]1[CH:33]=[CH:32][NH:31][CH:30]=1>>[CH3:7][CH:8]([CH3:24])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:27][CH2:28][C:29]3[CH:33]=[CH:32][NH:31][CH:30]=3)[CH2:20][CH2:19]2)[CH:13]=1)=[O:10]
Reactant: BrCCCc1cc[nH]c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3cc[nH]c3)CC2)c1

Procedure:
Prepared by Procedure K (KI) and Scheme E (K2CO3) using 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide and 3-(3-bromopropyl)-1H-pyrrole: ESMS m/e: 354.2 (M+H)+.
Reaction SMILES: [CH:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[N+:16]([O-])=O)([CH2:3][CH3:4])[CH3:2]>[Pd].C(O)C>[CH:1]([NH:5][C:6]1[C:7]([NH2:16])=[CH:8][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCC(C)Nc1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 74 %

Procedure:
A mixture of 1.16 g of N-(sec-butyl)-2-nitro-4-trifluoromethylaniline, 9 ml of ethanol and 0.12 g of 5% palladium charcoal was stirred for 5.5 hours at room temperature under a hydrogen atmosphere of about 1 atm. The reaction mixture was filtrated through Celite (registered trademark), and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of N1-sec-butyl-4-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C1(C=CC(O)=CC=1)O.C1C(=O)N([Cl:33])C(=O)C1>C(Cl)(Cl)Cl.CC(O)=O.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([Cl:33])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3cc(C)sc3C2C1
Reactant: O=C1CCC(=O)N1Cl
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2Cc3c(sc(C)c3Cl)C2C1
Temperature: 40 °C

Procedure:
The product of step c) (74.2 mg, 0.30 mmol) was placed in a vial and diluted with CHCl3 (740 μl) and AcOH (740 μl). Next, hydroquinone (−5 mg) was added followed by NCS (41.3 mg, 0.31 mmol) and the contents were heated to 40° C. for 6 hours. The crude reaction mixture was diluted with water (2 ml) and extracted with EtOAc (3×3 ml). The organic layer was dried (MgSO4) and purified by preparative TLC using hexanes/EtOAc 50:50 providing subtitled product. MS calculated for C13H16ClNO2S+H 286, observed 286.