Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=2[C:17](=[O:19])[CH3:18])=O)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[CH:1]1([C:4]2[NH:6][C:7]3[C:8]([C:17](=[O:19])[CH:18]=2)=[CH:9][C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=3)[CH2:3][CH2:2]1
Reactant: COc1cc(NC(=O)C2CC2)c(C(C)=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1cc2[nH]c(C3CC3)cc(=O)c2cc1OC
Yield: 62.3 %

Procedure:
2-Acetyl-4,5-dimethoxyaniline (2.0 g) was dissolved in tetrahydrofuran (50 ml), and to the mixture were added triethylamine (2.2 g) and dimethylaminopyridine (400 mg), and then a solution of cyclopropylcarbonyl chloride (1.7 g) in tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 3 hours. After the addition of a 10% aqueous solution of potassium hydroxide, the mixture was stirred and extraction was conducted with chloroform. The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 50 g). Elution with a mixed solvent of n-hexane (60 parts) and ethyl acetate (40 parts) gave N-cyclopropylcarbonyl-2-acetyl-4,5-dimethoxyaniline (2.5 g). This amide product (1.0 g) was suspended in t-butanol (50 ml), and potassium t-butoxide (2.1 g) was added to the suspension, and the mixture was heated under reflux for 15 hours. After the mixture was left to cool, extraction was conducted with a mixed solvent of chloroform (90 parts) and methanol (10 parts). The extract was washed with saturated saline and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wako Gel C-200, 30 g). Elution with a mixed solvent of chloroform (97 parts) and methanol (3 parts) gave 2-cyclopropyl-6,7dimethoxy-4(1H)-quinolone (compound 95, 580 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[OH-].[Na+].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COC(C)(C)C.O>[C:1]([CH2:3][C:4]([O:6][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: ClCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: N#CCC(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
A mixture of 1.7 g (0.02 mol) of cyanoacetic acid, 0.8 g (0.02 mol) of sodium hydroxide, 7.60 g (0.06 mol, 3 equivalents) of benzyl chloride and 0.64 g (2.0 mmol) of tetrabutylammonium bromide in 15 ml of tert-butyl methyl ether/water (v:v=2:1 ) was stirred at 100° C. (oil bath temperature 110° C.) for 3 h. The pH of the aqueous phase was then adjusted from 0.2 to 6.3 using 3.15 g of 1 M aqueous sodium hydroxide solution, the organic phase was separated off and the aqueous phase was extracted with tert-butyl methyl ether (2×5 ml). The combined organic phases was dried with sodium sulfate and analyzed by gas chromatography. 2.45 g (70 percent) of benzyl cyanoacetate was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1.[H][H]>C1COCC1.CO.[Pd]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:18][CH:17]=1)=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2
Reactant: Cc1ccc2ncc([N+](=O)[O-])c(Nc3ccc(C(C)(C)C#N)cc3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2ncc(N)c(Nc3ccc(C(C)(C)C#N)cc3)c2c1

Procedure:
2-(4-(6-Methyl-3-nitroquinolin-4-ylamino)phenyl)-2-methylpropanenitrile (Compound of Preparation 1,600 mg, 1.73 mmol) and 10% Pd—C (90 mg) were shaken in 15 mL of THF-MeOH (1:1) under 25 psi of hydrogen for 3 hours at RT. After completion of reaction, the catalyst was filtered-off and the filtrate was evaporated to dryness to obtain the title compound. Yield: 250 mg (46%); 1H NMR (DMSO-d6, 300 MHz): δ 8.507 (s, 1H), 7.819 (s, 1H), 7.698-7.726 (d, 1H, J=8.4 Hz), 7.641 (s, 1H), 7.211-7.239 (d, 2H, J=8.4 Hz), 7.164-7.198 (dd, 1H, J=8.4 Hz, 1.5 Hz), 6.503-6.532 (d, 2H, J=8.7 Hz), 5.178 (s, 2H), 2.358 (s, 3 Hs), 1.593 (s, 6H); MS: m/z 317 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[C:8](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:7][CH2:6]2
Reactant: CCOC(OCC)N(C)C
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Product: COc1cc2c(cc1OC)C(=O)C(=CN(C)C)CC2

Procedure:
The 3,4-dihydro-6,7-dimethoxy-2-(dimethylaminomethylene)-1(2H)-naphthalenone starting material was prepared from 6,7-dimethoxy-1-tetralone (4.12 g, 20 mmol) and N,N-dimethyl formamide diethyl acetal (10.3 ml, 60 mmol) to give the product as red-brown crystals (3.26 g) m.p. 138-140°. MS (ES+) 284 (MNa+, 12%), 262 (MH+, 100%), 189 (28%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6](=O)[CH2:7][CH2:8][C:9](=O)[CH3:10]>C1(C)C=CC=CC=1>[OH:4][CH2:3][CH2:2][N:1]1[C:9]([CH3:10])=[CH:8][CH:7]=[C:6]1[CH3:5]
Reactant: NCCO
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1CCO
Yield: 87.1 %

Procedure:
A mixture of 20 g (0.33 mol) of 2-aminoethanol and 38 g (0.33 mol) of 2,5-hexanedione was stirred until the vigorous reaction subsided. 100 ml of toluene was added and the solution was refluxed to 15 hours in a Dean-Stark apparatus. The solvent was removed in vacuo and the resulting oil was kugelrohr distilled at 110° C./1.5 mm to yield 40 g (87%) of a white solid. NMR (CDCl3) δ 2.1 (1H, s), 2.2 (6H, s), 3.7 (4H, m), 5.6 (2H, s)
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:17](Cl)(=[O:19])=[O:18])=[C:14]([CH3:16])[N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C.O>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:17]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][C:14]=1[CH3:16])(=[O:18])=[O:19])([CH3:6])[CH3:5]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: CC(C)(N)CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(C)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.2 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (1.14 g, 13 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (2.95 g, 12 mmol) and triethylamine (1.78 ml, 13 mmol). The light yellow suspension was stirred at room temperature for 17 h, poured into water (100 ml) and extracted with dichloromethane (2×10 ml). The combined organic layers were washed with sat. NaHCO3 solution (2×70 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate/MeOH 9:1) and subsequent crystallization (ethyl acetate/MeOH/heptane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (1.15 g, 32%) as a light brown solid. MS (ISP) 306.1 [(M−H)−]; mp 194° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([O:26][C:27]([NH:29][CH2:30][CH2:31]OS(C)(=O)=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH2:19]([O:26][C:27](=[O:28])[NH:29][CH2:30][CH2:31][O:12][C:9]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)=[CH:7][CH:8]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)OCCNC(=O)OCc1ccccc1
Reactant: Oc1ccc(-c2cc[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCCOc1ccc(-c2cc[nH]n2)cc1)OCc1ccccc1
Temperature: 70 °C
Yield: 61 %

Procedure:
A round-bottomed flask was charged with 4-pyrazol-3-yl-phenol (840 mg, 5.25 mmol), potassium carbonate (2.17 g, 15.7 mmol), and methanesulfonic acid 2-benzyloxycarbonylamino-ethyl ester (C. A. Townsend, et al., Tetrahedron, 47, 2591 (1991)) (2.86 g, 10.5 mmol) in 10.5 ml of dry dimethylsulfoxide. The resulting solution was heated to about 70° C. for about four days. The reaction mixture was then poured into 1 N HCL, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (methylene chloride to 2% methanol/methylene chloride) to afford 1.09 g (61% yield) of desired product. LRMS ([M+H+])=338.1.
Reaction SMILES: [Cl-].[NH4+].O.[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][C@@H:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:15]([CH3:26])[CH2:14]2)=[C:9]([C:27]#[N:28])[CH:8]=1)([O-])=O>[Fe].C(O)C>[NH2:4][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][C@@H:17]([CH3:19])[N:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@@H:15]([CH3:26])[CH2:14]2)=[C:9]([C:27]#[N:28])[CH:8]=1
Reactant: CCOC(=O)CN1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@@H]1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CN1[C@H](C)CN(c2ccc(N)cc2C#N)C[C@@H]1C
Temperature: 65 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Ammonium chloride (1.2 g) and iron powder (6.1 g) were added to a mixed solvent of water (90 ml) and ethanol (270 ml), and the mixture was heated to 65° C. Then, ethanol solution (20 ml) containing ethyl cis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g) was dropwise added in parts over 20 min and the mixture was stirred at a refluxing temperature for 1 h. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of diisopropyl ether-n-hexane to give the title compound (9.5 g), melting point: 45° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[C:22]([N:26]([CH2:37][CH3:38])[S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=1)=O>C(O)(=O)C>[CH2:37]([N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[N:3]3[N:4]=[CH:5][C:6]([C:7]([C:9]4[O:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)[CH:21]=1)[S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH3:38]
Reactant: Nc1n[nH]cc1C(=O)c1ccco1
Reactant: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccc(C)cc1
Solvent: CC(=O)O
Product: CCN(c1cccc(-c2ccnc3c(C(=O)c4ccco4)cnn23)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
A mixture of 5.9 g of (3-amino-1H-pyrazol-4-yl)-2-furanylmethanone, 12.4 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-4-methylbenzenesulfonamide and 200 ml of glacial acetic acid was refluxed for 18 hours, then cooled to room temperature and evaporated to dryness. The residue was partitioned between 200 ml of dichloromethane and 100 ml of saturated aqueous sodium bicarbonate. The dichloromethane layer was dried, then filtered through hydrous magnesium silicate and washed with 200 ml of dichloromethane. The filtrate and wash were combined with 200 ml of hexane, concentrated to 250 ml, diluted with 100 ml of hexane and concentrated to turbidity. A heavy oil formed which was separated and cooled to -10° C. producing a solid. This solid was washed with hexane and then dried in vacuo at 60° C. giving N-ethyl-N-[3-[3-(2-furanylcarbonyl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]-4-methylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[C:25]([F:26])=[CH:24][C:6]([O:7][C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:23])=[C:5]([O:27]C)[CH:4]=1)[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:1]([C:3]1[C:25]([F:26])=[CH:24][C:6]([O:7][C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]3)=[O:13])=[CH:10][C:9]=2[F:23])=[C:5]([OH:27])[CH:4]=1)[CH3:2]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCNC(=O)C3)cc2F)cc1F
Reaction time: 20 h

Procedure:
To a solution of 4-[4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoyl]piperazin-2-one (38 mg, 0.10 mmol; which may be prepared as described in D3) in dichloromethane (300 μL) under Argon cooled at −30° C. was added dropwise boron tribromide (1M in dichloromethane, 273 μL, 0.27 mmol). The mixture was allowed to come to room temperature and after stirring 20 h, was diluted with dichloromethane. The mixture was quenched carefully at 0° C. with an aqueous saturated solution of ammonium chloride and then diluted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, using dichloromethane/methanol (95:5) as eluent. The title product was obtained as a white solid (32 mg, 86%).
Reaction SMILES: C([Mg]Cl)CCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1.CN(C)[CH:22]=[O:23]>O1CCCC1.CCCCCC.C(O)(=O)C.C1(C)C=CC=CC=1>[Br:19][C:16]1[CH:17]=[C:18]([CH:22]=[O:23])[CH:13]=[N:14][CH:15]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: O=Cc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.1 %

Procedure:
n-Butylmagnesium chloride (4.00 mmol) in 2.00M tetrahydrofuran solution (2.00 mL) was added to ice-cooled n-butyllithium (8.06 mmol) in 1.55M hexane (5.20 mL). The mixture was stirred at 0° C. for 15 minutes to give a suspension. The suspension was added to a mixture of toluene (15 mL) and tetrahydrofuran (10 mL) containing 2,5-dibromo-pyridine (2.37 g, 10.0 mmol) over a period of 10 minutes or more while keeping the temperature below 5° C. to give an orange solution. The solution was stirred at 0° C. for one hour, and N,N-dimethylformamide (1.0 mL, 13 mmol) was added thereto. The resultant suspension was stirred at room temperature for 30 minutes, and tetrahydrofuran (10 mL) was added, followed by further stirring at room temperature for 30 minutes. After addition of 1M aqueous acetic acid (20 mL) to the suspension, the organic phase was separated, and the aqueous phase was extracted with toluene (20 mL). The organic phase and the toluene extract were combined, washed with an aqueous sodium chloride saturated solution (15 mL), dried over magnesium sulfate and concentrated under reduced pressure to remove the solvent. The resultant residue was purified by flash column chromatography on silica gel in a developing solvent system of hexane-ethyl acetate (10:1, v/v) to give the title compound (1.062 g, 57% yield) as a colorless solid.
Reaction SMILES: Cl.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:43])=[C:9]([F:42])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[C:21]([CH3:24])[C:20]([F:25])=[C:19]([NH:26]CC3C=CC(OC)=CC=3)[N:18]=1)[CH:14]=[C:13]([C:36]([O:38]CC)=[O:37])[C:12]2=[O:41]>O>[NH2:26][C:19]1[N:18]=[C:17]([N:15]2[C:16]3[C:11](=[CH:10][C:9]([F:42])=[C:8]([F:43])[C:7]=3[Cl:6])[C:12](=[O:41])[C:13]([C:36]([OH:38])=[O:37])=[CH:14]2)[C:22]([F:23])=[C:21]([CH3:24])[C:20]=1[F:25]
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)c(C)c2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)c(N)nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c1F
Reaction time: 3 h

Procedure:
To a mixed solution of 2.5 ml of 4N hydrochloric acid and 2.5 ml of acetic acid was added all amount of the above described ethyl 8-chloro-1-[3,5-difluoro-6-(p-methoxybenzylamino)-4-methylpyridine-2-yl]-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 3 hours and allowed to cool and stand. To the residue was added 10 ml of distilled water, and the solution was concentrated under reduced pressure. The procedure of adding 10 ml of ethanol and concentrating the solution under reduced pressure was repeated three times, and 6 ml of chloroform was added to the residue, and the mixture was heated under reflux with stirring for 1 hour and allowed to cool. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 128 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]=1[CH2:15][CH2:16][CH3:17].[F:18][C:19]1[N:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][CH:20]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[C:25]([C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[N:24]=2)=[O:26])[C:3]=1[CH2:15][CH2:16][CH3:17]
Reactant: O=C(O)c1cccc(F)n1
Reactant: CCCc1c(Cl)ncnc1CNCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCc1c(Cl)ncnc1CN(CCC(C)C)C(=O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (6-chloro-5-propyl-pyrimidin-4-ylmethyl)-(3-methyl-butyl)-amine (0.715 g, 2.8 mmol) and 6-fluoro-pyridine-2-carboxylic acid (0.47 g, 3.34 mmol) in DCM (10 ml) is added EDCI (0.61 g) and DMAP (0.153 g). The mixture is stirred at room temperature overnight. DCM (10 ml) is added to dilute the mixture. The mixture is washed with water (5 mL), dried (Na2SO4) and solvent evaporated. Preparative TLC purification of the residue (2:1 of hexane: ethyl acetate) provides the title product. H1 NMR δ (CDCl3) 8.69 and 8.75 (s, 1H), 7.71-7.97 (m,1H), 7.58-60 (m, 1H), 4.79 and 5.07 (s, 2H), 3.50-3.64 (m, 21), 2.59-2.87 (m, 2H), 1.45-1.72 (m,5H), 0.92-1.09 (m, 4H), 0.81 (d, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH:12]=2)=[N:8][CH:9]=1)[CH3:2].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=O)[O:32]C2C=CC=CC=2)[N:25]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[CH:17]=[C:18]2[CH2:23][CH2:22][N:21]([C:31]([NH:30][C:26]3[N:25]=[N:24][CH:29]=[CH:28][CH:27]=3)=[O:32])[CH2:20][CH2:19]2)=[N:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnn1)Oc1ccccc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccc(Oc2cccc(C=C3CCN(C(=O)Nc4cccnn4)CC3)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
To a solution of 5-ethoxy-2-(3-(piperidin-4-ylidenemethyl)phenoxy)pyridine (0.22 g, 0.708 mmol) in DMSO (4 mL) was added phenyl pyridazin-3-ylcarbamate (0.152 g, 0.708 mmol) followed by triethylamine (0.265 mL, 2.12 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (38% acetone, 62% hexane) to give the title compound (0.225 g, 73% yield). 1H NMR (500 MHz, CDCl3): δ 8.80 (s, 1H), 8.29 (s, 1H), 7.87 (d, J=3.0 Hz, 1H), 7.41 (d, J=4.0 Hz, 1H), 7.34-7.23 (m, 1H), 6.99-6.93 (m, 3H), 6.86 (d, J=9.0 Hz, 1H), 6.39 (s, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.67 (s, 2H), 3.57 (s, 2H), 2.6-2.5 (m, 2H), 2.47 (m, 2H), 1.40 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 157.32, 156.79, 155.24, 151.82, 147.4, 138.74, 137.55, 133.57, 129.40, 127.97, 126.82, 124.89, 124.56, 120.55, 118.91, 112.52, 64.61, 45.66, 44.66, 35.78, 29.14, 14.82; m/z (432.1, M+ H+); HPLC: 98.76%.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:26](=[O:31])[C@@H:27]([CH2:29][OH:30])[NH2:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:40]1([CH3:50])[CH:45]=[CH:44][C:43]([S:46]([OH:49])(=[O:48])=[O:47])=[CH:42][CH:41]=1>CO>[C:40]1([CH3:50])[CH:41]=[CH:42][C:43]([S:46]([OH:49])(=[O:47])=[O:48])=[CH:44][CH:45]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:26](=[O:31])[C@@H:27]([CH2:29][OH:30])[NH2:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)CO)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)CO)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
A solution of 0.175 g (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(D-seryl)valerohydrazide in 2 ml of methanol was treated with 0.073 g of p-toluenesulphonic acid. The mixture was stirred for 3 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.160 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(D-seryl)valerohydrazide p-toluenesulphonate in the form of a white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2.[OH:16]O.[OH-].[NH4+]>C(O)(=O)C>[F:15][C:2]([F:1])([F:14])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-:16])=[CH:9][CH:8]=[CH:7]2
Reactant: FC(F)(F)Oc1ccc2ncccc2c1
Reactant: OO
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Product: [O-][n+]1cccc2cc(OC(F)(F)F)ccc21
Temperature: 82 °C

Procedure:
To a solution of the crude 6-trifluoromethoxy-quinoline of Step A (obtained from 50 mmol of 4-trifluoromethoxy aniline) in glacial acetic acid (54 mL) is added dropwise 30% hydrogen peroxide (8 mL). The mixture is heated at 82° C. under nitrogen for 16 hours, cooled, carefully basified with concentrated ammonium hydroxide and extracted with ethyl acetate. The extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is twice azeotroped with benzene, and then flash chromatographed on silica gel Merck-60 using dichloromethane followed by a gradient of methanol (0.5–2%) in dichloromethane to provide the title compound as a pale brown oil that solidifies upon standing. The pale brown crystals (4.8 g) melt at 68–70° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6](=[O:14])[N:5]([CH3:15])[C:4](=[O:16])[C:3]=1[NH:17][C:18]([C:20]1([CH3:34])[CH2:29][CH2:28][C:27]2[C:22](=[C:23]([CH3:33])[C:24]([CH3:32])=[C:25]([OH:31])[C:26]=2[CH3:30])[O:21]1)=[O:19].N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>ClCCl>[C:41]([O:31][C:25]1[C:26]([CH3:30])=[C:27]2[C:22](=[C:23]([CH3:33])[C:24]=1[CH3:32])[O:21][C:20]([CH3:34])([C:18]([NH:17][C:3]1[C:4](=[O:16])[N:5]([CH3:15])[C:6](=[O:14])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=1[NH2:1])=[O:19])[CH2:29][CH2:28]2)(=[O:43])[CH3:42]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
The compound of Example 1 (1.77 g, 3.80 mmol) and pyridine (0.154 mL, 1.90 mmol) were dissolved in dichloromethane (30 mL). To the resultant solution was added dropwise acetic anhydride (0.714 mL, 7.60 mmol) under ice cooling. The resultant reaction mixture was stirred overnight at room temperature, washed with 1N hydrochloric acid and 10% aqueous solution of sodium chloride successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethyl acetate and filtered to give the title compound (yield 87%).