Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.[CH:3]1([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]4[N:28]=[N:29][N:30]=[C:21]4[C:20]=3[N:19]=[C:18]2[CH2:31][O:32][N:33]2C(=O)C3[C:35](=CC=CC=3)[C:34]2=O)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:45]Cl>C(O)C>[CH:3]1([NH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[C:24]([CH3:26])=[C:23]([CH3:27])[N:22]4[N:28]=[N:29][N:30]=[C:21]4[C:20]=3[N:19]=[C:18]2[CH2:31][O:32][N:33]=[C:34]([CH3:45])[CH3:35])=[O:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: ClCCl
Reactant: Cc1c(C)n2nnnc2c2nc(CON3C(=O)c4ccccc4C3=O)n(CCCCNC(=O)NC3CCCCC3)c12
Agent: NN
Solvent: CCO
Product: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Anhydrous hydrazine (0.50 mL, 16.1 mmol) was added to a stirred suspension of N-cyclohexyl-N′-[4-(8-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butyl]urea (3.00 g, 5.36 mmol) in ethanol (36 mL). Over the next hour, dichloromethane (40 mL) and ethanol (20 mL) were added to prevent the reaction from solidifying. After one more hour, the solvent was removed under reduced pressure, then acetone (27 mL) and methanol (27 mL) were added. The mixture was stirred at room temperature for 2 hours, then a solid was isolated by filtration and washed with methanol. To the solid was added 1 M aqueous sodium hydroxide and the mixture was sonicated for 1 minute. The solid was isolated by filtration, washed with water, and dried under vacuum at 70° C. to provide 2.36 g of N-cyclohexyl-N′-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}urea.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH:21]([CH3:23])[CH3:22].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Br)cc(N(CC(C)C)C2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (1 g, 3.04 mmol) and isobutyraldehyde (1.09 g, 15.24 mmol) in methanol (15 mL), acetic acid (0.456 g, 7.6 mmol) was added. The reaction mixture was stirred at room temperature for 8 h. Sodium cyanoborohydride (0.522 g, 7.56 mmol) was then added at 0° C. and the reaction mixture stirred overnight at room temperature. The solvent was then removed under reduced pressure and crude product purified by column chromatography to afford methyl 5-bromo-3-(isobutyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (0.52 g, 54.33%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9]1[CH:14]=[C:13](F)[C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[CH2:7][NH:8][C:9]1[CH:14]=[C:13]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[C:12]([C:16](=[O:18])[CH3:17])=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)cc1F
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])c(NCC(=O)OC(C)(C)C)cc1-n1ccnc1
Yield: 87.1 %

Procedure:
By using 3.77 g (12.1 mmol) of N-(4-acetyl-5-fluoro-2-nitrophenyl)glycine tert-butyl ester, 3.28 g of imidazole and 15 ml of DMF, 3.80 g (87%) of N-[4-acetyl-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine tert-butyl ester was obtained.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[OH:24].O>CN(C)C=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH:16]=[C:15]1[CH:23]([C:25]1[CH:30]=[C:29]([Br:31])[CH:28]=[CH:27][C:26]=1[Cl:32])[O:24][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). This solution was cooled to −78° C., and a solution of 1.58 M hexane (10.5 ml) of n-butyllithium was added dropwise to the solution, and the mixture was stirred for 15 minutes at −78° C. Then, 5-chloro-2-bromobenzaldehyde (3.15 g) dissolved in tetrahydrofuran (50 ml) was added dropwise to the reaction mixture, and the mixture was stirred for two hours at room temperature. Aqueous solution of saturated ammonium chloride was added to the reaction mixture, and then the solvent was evaporated from the filtrate under reduced pressure to give the residue. Ethyl acetate and water were added to the residue obtained, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated from the filtrate under reduced pressure to give the residue, and the residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain 1-benzothien-2-yl(5-bromo-2-chlorophenyl) methanol (4.75 g). Imidazole (1.08 g) and tert-butyl dimethylchlorosilane (2.99 g) were added to a solution of 1-benzothien-2-yl(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml), and the mixture was stirred for three hours at 70° C. Water was added to the reaction mixture, and extracted with diethyl ether. The organic layer was dried over magnesium sulfate, the solvent was evaporated therefrom under reduced pressure to give the residue, and the resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-chloro phenyl)methoxy](tert-butyl) dimethylsilane (3.34 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1.Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[N:32]=[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46]C)[N:41]=2)[C:30]=1[CH3:48]>CN1C(=O)CCC1>[F:39][C:35]1[CH:34]=[C:33]2[C:38]([C:29]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:30]([CH3:48])[C:31]([C:40]3[N:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=3)=[N:32]2)=[CH:37][CH:36]=1
Reactant: c1cc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: COc1cccc(-c2nc3cc(F)ccc3c(Cl)c2C)n1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2cccc(O)n2)nc2cc(F)ccc2c1N1CC2(CCOCC2)c2ccc(N3CCOCC3)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-morpholino-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran] (87 mg, 0.32 mmol) (described herein), 4.0M hydrochloric acid in 1,4-dioxane (66 μL, 0.25 mmol), 4-chloro-7-fluoro-2-(6-methoxypyridin-2-yl)-3-methylquinoline (80 mg, 0.25 mmol) (described herein), and NMP (440 μL), and heating in a microwave at 150° C. for 180 min. Purification afforded 6-(7-fluoro-3-methyl-4-(6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)-2-quinolinyl)-2-pyridinol as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.65-7.85 (2H, m), 7.48-7.61 (1H, m), 7.27-7.32 (1H, m), 7.15 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=6.7 Hz), 6.73 (1H, d, J=9.4 Hz), 6.37 (1H, dd, J=8.2, 2.3 Hz), 5.56 (1H, d, J=2.3 Hz), 3.98-4.09 (2H, m), 3.88-3.98 (2H, m), 3.62-3.78 (4H, m), 3.47-3.61 (2H, m), 2.84-3.03 (4H, m), 2.51 (3H, s), 2.09-2.24 (2H, m), 1.83-1.93 (1H, m), 1.71-1.83 (1H, m). Mass Spectrum (ESI) m/e=527 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]1([C:18]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][C:25]3[NH:24][N:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C.O.[OH-].[Na+]>[C:30]1([C:18]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:26][C:25]3[N:24]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[N:23]=[C:22]([C:27]([OH:29])=[O:28])[C:21]=3[CH:20]=[CH:19]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2nc(C(=O)O)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Temperature: 20 °C
Yield: 63.2 %

Procedure:
A solution of 1 g of p-toluenesulphonyl chloride in 10 cm3 of diethyl ether is added, at a temperature in the region of 20° C., to a solution of 1 g of 6,6-diphenyl-6,7-dihydro-1H-indazol-3-carboxylic acid in 10 cm3 of water and 10 cm3 of a normal aqueous sodium hydroxide solution. The reaction mixture, which sets to a solid after about ten minutes of vigorous stirring, is diluted with 10 cm3 of water. After stirring for about eighteen hours at a temperature in the region of 20° C., the reaction mixture is filtered. The solid is washed with three times 20 cm3 of water and then suspended in 20 cm3 of water. 10 cm3 of a normal aqueous hydrochloric acid solution are added. The mixture is extracted with three times 50 cm3 of ethyl acetate. The combined organic phases are successively washed with three times 70 cm3 of water and once 70 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)]. 0.94 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-carboxylic acid is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11])#[N:2].[H-].[Na+].Br[C:15]([CH3:19])([CH3:18])[CH:16]=[O:17].O>CN1C(=O)N(C)CCC1>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])#[N:2]
Reactant: CC(C)(Br)C=O
Reactant: CCc1ccc(O)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCc1ccc(OC(C)(C)C=O)c(C#N)c1
Temperature: 4 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2-Cyano-4-ethylphenol (1.47 g) was added portionwise to a stirred, ice-cooled suspension of sodium hydride (60% w/w dispersion in mineral oil, 420 mg) in DMPU (10 ml) under argon. Stirring was continued for 1 hour at ambient temperature, the mixture cooled to 4° C. and 2-bromo-2-methylpropanal (2.26 g) in DMPU (2 ml) added. Stirring was continued for 18 hours at ambient temperature. Water (50 ml) was added and the resulting mixture extracted with ether (3×50 ml). The combined extracts were washed with water (2×30 ml) and saturated brine (2×30 ml), then dried (MgSO4). Evaporation of the solvent and purification of the residual oil by flash chromatography, eluting with 20% v/v ethyl acetate in hexane, gave 2-(2-cyano-4-ethylphenoxy)-2-methylpropanal (2.04 g), as a colourless oil;
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>CC(O)C.CCCCCC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Solvent: CCCCCC
Solvent: CC(C)O
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
Ethyl 3-[{[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (12.0 g) which is a synthetic intermediate in Example 149 was dissolved in 2-propanol-hexane (8:2, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mmL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with 2-propanol-hexane (8:2, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 23.7 min were collected, and concentrated. The obtained amorphous compound (5.58 g) was dissolved in ethanol (20 mL) and tetrahydrofuran (20 mL), 1N lithium hydroxide (20 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (30 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (5.2 g, 99%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:22]1[N:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=1>CS(C)=O>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:22]4[N:27]=[CH:26][C:25]([C:28]([NH:30][CH3:31])=[O:29])=[CH:24][CH:23]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CNC(=O)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.6 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (40 mg, 0.158 mmol) in DMSO (2 ml) was added NaH (14 mg, 0.316 mmol, 60 in mineral oil) at RT in one portion. The suspension was stirred for 2 h at RT then 6-chloro-N-methylpyridine-3-carboxamide (54 mg, 0.316 mmol) was added in one portion. The mixture was heated at 80-100° C. in a sealed tube over night. After cooling to RT, the solution was partitioned between brine/water (1:1 mixture, 15 ml) and DCM (20 ml). The organic layer was separated, washed with brine (2×20 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC to provide the title compound as white solid (83 mg, 56% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[NH:7]C(OC(C)(C)C)=O)(=[O:3])[NH2:2].[ClH:23].C(=O)([O-])[O-].[K+].[K+].CCOCC>C1COCC1>[ClH:23].[C:1]([O:4][CH2:5][C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[NH2:7])(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N[C@H](COC(N)=O)Cc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)OC[C@@H](N)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
In a 100 mL flask equipped with magnetic stirrer, O-carbamoyl-N-(t-butyloxycarbonyl)-o-fluorophenylalaninol obtained in Example 1 was dissolved in 40 ml of THF and was added with 20 ml of 6N aqueous hydrochloric acid solution. The reaction mixture was stirred at room temperature for 8 hours, followed by the neutralization with saturated aqueous potassium carbonate solution. Thereafter, the organic layer was extracted 3 times with dichloromethane, dried over magnesium sulfate and distilled in vacuo, to give a yellowish liquid. This was dissolved in 30 ml of THF and added with anhydrous hydrochloric acid at 0° C., to obtain desirable white precipitates. To this was added 30 ml of anhydrous ether, with the aim of maximizing the precipitation. As a result, 1.22 g of the title compound was obtained: Yield 73%.
Reaction SMILES: [Cl:1][CH:2]=[CH:3][Cl:4].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1>>[Cl:1][CH:2]1[CH:3]([Cl:4])[CH:7]2[CH2:8][CH:9]1[CH:5]=[CH:6]2
Reactant: ClC=CCl
Reactant: C1=CCC=C1
Product: ClC1C2C=CC(C2)C1Cl

Procedure:
1,2-Dichloroethylene was reacted with cyclopentadiene at 175° C. in the same manner as Examples 1-7 to produce 5,6-dichloronorbornene (called "DCN" hereinafter).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH:19]([NH:37][OH:38])[CH2:20][S:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:16][C:11]=2[O:10][CH2:9]1>C1COCC1.C(O)=O>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]#[C:18][CH:19]([N:37]([OH:38])[CH:1]=[O:3])[CH2:20][S:21]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)(=[O:23])=[O:22])=[CH:16][C:11]=2[O:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(CC(C#Cc1ccc2c(c1)OCO2)NO)N1CCN(c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CN(O)C(C#Cc1ccc2c(c1)OCO2)CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
Acetic anhydride (1.00 mL; 10.59 mmol) was added dropwise to formic acid (5 mL) at 0° C. and the mixture was stirred for 30 min. 1 mL of this solution was then added to a solution of N-[3-(1,3-benzodioxol-5-yl)-1-({[4-(4-fluorophenyl)-1-piperazinyl]sulfonyl}methyl)-2-propynyl]hydroxylamine (150.0 mg; 0.34 mmol) in THF (3 mL) and formic acid (0.7 mL) and the mixture was stirred overnight. The reaction mixture was then evaporated to dryness, the residue dissolved in MeOH and heated at 60° C. for 3 h. The solution was allowed to cool down to rt and the precipitate obtained was filtered. It was redissolved in EtOAc and precipitated again in pentane, filtered and dried under reduced pressure to give the title compound (1) (80 mg, 50% yield) as a white solid. HPLC, Rt: 3.58 min (purity: 96.9%). LC/MS, M+(ESI): 476.3, M−(ESI): 474.3. 1H NMR (CDCl3) δ: 9.55 (s, 0.5H), 9.12 (s, 0.5H), 8.1 (m, 1H), 6.90-7.09 (m, 7H), 6.05 (s, 2H), 4.81 (s, 0.5H), 4.61 (s, 0.5H), 3.62 (m, 2H), 3.31 (m, 4H), 3.14 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[O:16][C:15](=[O:17])[C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(c2ccc(F)cc2)=NC12CCCCC2
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
After a suspension of 13.3 g (50 mmol) of 1-[(4-fluorobenzoyl)amino]cyclohexanecarboxylic acid in 30 ml of acetic anhydride was stirred at 100° C. for 30 minutes, the reaction solution was concentrated under reduced pressure. Toluene was added to the residue, and the mixture was washed with water, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine. After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 8.5 g (69%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:19])[C:11](=[O:18])[CH:12]=[CH:13][C:14]=2[C:15]([OH:17])=O)=[C:4]([F:20])[CH:3]=1.[CH:21]([O:23][CH2:24][CH2:25][O:26][NH2:27])=[CH2:22]>>[CH:21]([O:23][CH2:24][CH2:25][O:26][NH:27][C:15]([C:14]1[CH:13]=[CH:12][C:11](=[O:18])[N:10]([CH3:19])[C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:20])=[O:17])=[CH2:22]
Reactant: C=COCCON
Reactant: Cn1c(Nc2ccc(Br)cc2F)c(C(=O)O)ccc1=O
Product: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Yield: 60 %

Procedure:
2-(4-Bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.020 g, 0.059 mmol) was coupled as described previously in Example 154 using O-(2-vinyloxy-ethyl)-hydroxylamine to yield 0.015 g (60%) pure desired product as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]1>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]2)[N:3]=1
Reactant: OCCC1CCNCC1
Reactant: Clc1cc2ccccc2cn1
Product: OCCC1CCN(c2cc3ccccc3cn2)CC1
Yield: 21.7 %

Procedure:
The process is performed as described in Example 4 (step 4.1). Starting with 1 g (6.11 mmol) of 3-chloroisoquinoline and 0.869 g (6.72 mmol) of 2-(4-piperidyl)ethanol, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.34 g of pure product is obtained in the form of an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:9]([CH:11]([OH:14])[CH2:12][CH3:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O>CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:9]([C:11](=[O:14])[CH2:12][CH3:13])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(O)c1cc(C(C)(C)C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Solvent: CS(C)=O
Solvent: O
Product: CCC(=O)c1cc(C(C)(C)C)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19 %

Procedure:
1-{5-(Tert-butyl)-2-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-1-propanol was dissolved in anhydrous dimethylsulfoxide (1 ml) to prepare a solution. A sulfur trioxide trimethylamine complex (70 mg) was added to the solution at 0° C., and the mixture was stirred at room temperature for 18 hr. Water (1 ml) was added dropwise to the reaction solution to stop the reaction. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give the title compound (37 mg, yield 19%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[C:17]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[N:18][O:19][C:20]=2[CH:21]2[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:21]1([C:20]2[O:19][N:18]=[C:17]([C:24]3[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=3[Cl:30])[C:16]=2[CH2:15][O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1COC1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
In a cooled (ice bath) 500 mL flask under nitrogen, is added a solution of 4-[5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (16 g, 34.3 mmol) in dichloromethane (80 mL). This is followed by dropwise addition of trifluoroacetic acid (80 mL) (added over 30 minutes). The reaction is stirred at room temperature for 90 min. The solvent is removed under vacuum, EtOAc is added (400 mL), and the mixture is washed with 2 N NaOH (2×250 mL) and brine. The organic layer is dried over MgSO4, filtered and evaporated to obtain the title compound as a brown oil (11.78 g, 93%). MS (m/e): 367 (M+1)