Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([Br:26])=[C:21]([CH3:27])[CH:20]=1)(=[O:17])[C:15]#[CH:16]>C1COCC1.[Cu]I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16]#[C:15][C:14]([O:18][C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([Br:26])=[C:23]([CH3:25])[CH:24]=2)=[O:17])[CH:3]=1
Reactant: Ic1cccnc1
Reactant: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)C#Cc2cccnc2)cc(C)c1Br
Temperature: 65 °C
Yield: 26.7 %

Procedure:
3-Iodopyridine (226 mg, 1.10 mmol) in THF (2 mL) was degassed under reduced pressure at −78° C., and then nitrogen gas was introduced. To the solution was added K2CO3 (276 mg, 2.00 mmol), CuI (15 mg, 0.079 mmol) and PdCl2(Ph3P)2 (7 mg, 0.01 mmol), and the mixture was stirred at 65° C. 4-bromo-3,5-dimethylphenyl propiolate (6-1) (253 mg, 1.00 mmol) in THF (2 mL) was added by syringe pump over a period of 5 h, and the mixture was stirred an additional 1 h after addition was complete. After being cooled to room temperature, the mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound 13-1 (88 mg, 27% yield) as a black oil.
Reaction SMILES: [C:1](=[N:9][OH:10])([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].Cl[C:14]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>CN(C)C=O>[CH3:19][O:18][C:16]([C:15]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:14]=1[O:10][N:9]=[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:2])=[O:17]
Reactant: CC(=NO)c1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1ON=C(C)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
A solution of 17.25 g of acetophenone oxime in 100 ml of dimethylformamide is added dropwise to a suspension of 5.92 g of 62.5% sodium hydride in 400 ml of dimethylformamide under ice-cooling. The mixture is stirred at the same temperature for 1.5 hours. A solution of 25.04 g of methyl 2-chloro-5-nitrobenzoate in 150 ml of dimethylformamide is added to the mixture, the mixture is stirred for 1 hour. The reaction mixture is poured into ice-water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from isopropanol to give 26.7 g of acetophenone O-(2-methoxycarbonyl-4-nitrophenyl)oxime as yellow needles.
Reaction SMILES: CS[C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1.[O-:27][CH2:28][CH3:29].[Na+].Cl>C(O)C>[CH2:28]([O:27][C:3]1[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10](=[O:13])[NH:9][C:7]=2[N:8]=1)[CH3:29]
Reactant: CSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
2-(Methylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (300 mg) was suspended in ethanol (9 ml), sodium ethoxide (20% ethanol solution, 1.33 g) was added thereto at room temperature, and the mixture was heated under reflux for 3 hr, and allowed to be cooled. The reaction mixture was poured into 0.5M hydrochloric acid (9 ml) under ice-cooling, and the brown precipitate was collected by filtration, washed with water, and dissolved in tetrahydrofuran (100 ml). The solution was diluted with ethyl acetate (150 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained brown residue was purified by silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (251 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5](F)=[CH:4][C:3]=1[CH2:10][OH:11].[Cl:12]C1C=CC(F)=CC=1C>>[Cl:12][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([F:1])=[C:3]([CH2:10][OH:11])[CH:4]=1
Reactant: Cc1cc(F)c(CO)cc1F
Reactant: Cc1cc(F)ccc1Cl
Product: Cc1cc(F)c(CO)cc1Cl

Procedure:
(5-Chloro-2-fluoro-4-methyl-phenyl)-methanol was prepared in analogous fashion to (2,5-difluoro-4-methyl-phenyl)-methanol using 2-chloro-5-fluorotoluene as starting material. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, 1H, J=6.8 Hz), 6.92 (d, 1H, J=10 Hz), 4.69 (s, 2H), 2.34 (s, 3H) ppm.
Reaction SMILES: [C:1](=[S:3])=S.[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1)[CH3:5]>O1CCCC1>[CH2:4]([O:6][CH2:7][CH2:8][N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=[C:10]1[CH2:18][N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][N:27]=[C:1]=[S:3])[CH2:23][CH2:24]1)[CH3:5]
Reactant: S=C=S
Reactant: CCOCCn1c(CN2CCN(CCN)CC2)nc2cccnc21
Solvent: C1CCOC1
Product: CCOCCn1c(CN2CCN(CCN=C=S)CC2)nc2cccnc21
Yield: 100 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 18 parts of carbon disulfide, 7.22 parts of N,N'-methanetetraylbis[cyclohexanamine] and 135 parts of tetrahydrofuran was added dropwise a solution of 12.9 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperazineethanamine in tetrahydrofuran. Upon complete addition, the temperature was allowed to reach room temperature. After stirring for 1 hour at room temperature, the mixture was evaporated, yielding 13.1 parts (100%) of 3-(2-ethoxyethyl)-2-[[4-(2-isothiocyanatoethyl) -1-piperazinyl]methyl]-3H-imidazo[4,5-b]pyridine as a residue (compound 121)
Reaction SMILES: [OH:1][C:2]1[C:12]2=[C:13]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:10][C:11]2=[O:14])=[CH:4][CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:15][O:1][C:2]1[C:12]2=[C:13]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[CH2:10][C:11]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1Cc2cccc3ccc(O)c1c23
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2cccc3c2c1C(=O)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.7 %

Procedure:
A known compound, 8-hydroxyacenaphthen-1-one (7.0 g) (J. Chem. Soc., 1954, p. 4299), was dissolved in N,N-dimethylformamide (70 ml), potassium carbonate (7.9 g) and methyl iodide (6.8 g) were added, and the mixture was stirred at room temperature for 5 hr. After completion of the reaction, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give 8-methoxyacenaphthen-1-one (5.7 g). The obtained methoxy form was dissolved in methanol (25 ml), sodium borohydride (220 mg) was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was gradually added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 8-methoxy-1-acenaphthenol (5.6 g). The title compound (2.28 g) was obtained according to the method of Example 125 and using the obtained alcohol form.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)=[O:12]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16]2[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=2)=[CH:4][C:3]=1[F:9]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: Nc1ccc(O)cc1F
Product: CC(=O)c1ccc(Oc2ccc(N)c(F)c2)cc1

Procedure:
This compound is prepared according to a method analogous to that described in Example 1.1 using 4-amino-3-fluorophenol (7.68 g, 0.06 mol) and 4-fluoroacetophenone (8.34 g, 0.06 mol) as starting compounds. After treatment, a white-coloured powder is obtained.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][C:17]2[N:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1>O1CCOCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[C:17]3[N:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19](=[O:21])[O:20][C:2]2=[O:3])=[CH:26][CH:27]=1
Reactant: COc1ccc(CNc2ncccc2C(=O)O)cc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Cn2c(=O)oc(=O)c3cccnc32)cc1
Yield: 67.7 %

Procedure:
Trichloromethyl chloroformate (3.36 mL, 27.8 mmol) was added slowly to a suspension of 2-(4-methoxy-benzylamino)-nicotinic acid (11) (6 g, 23.23 mmol) in dioxane and refluxed for 18 h under nitrogen atmosphere. The solution was cooled and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and washed by saturated NaHCO3 solution. The organic phase was dried over Na2SO4 and evaporated to yield a residue. The residue was recrystallized by ether to yield 4.47 g (67%) of 1-(4-methoxy-benzyl)-1H-pyrido[2,3-d][1,3]oxazine-2,4-dione (12) as white solids. MP: 160° C.; 1H-NMR (DMSO-d6): δ 3.71 (s, 1H), 5.27 (s, 2H), 6.85 (d, J=7.0 Hz, 2H), 7.33 (m, 3H), 8.40 (dd, J=1.5, 7.5 Hz, 1H), 8.75 (dd, J=1.5, 7.5 Hz, 1H); EIMS: 286 (M+23).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:37]([NH:41][C:42]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:47]2[CH:48]=[CH:49][C:44]([C:42]([NH:41][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:43])=[CH:45][CH:46]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)NC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 56.9 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (522 mg, 1 mmol), [4-(tert-butylaminocarbonyl)phenyl]boronic acid (442 mg, 2 mmol), and dichlorobis(triphenylphosphine)palladium (II) (70.2 mg, 0.1 mmol) in dioxane (5 mL) was added an aqueous sodium carbonate solution (2 M, 1.25 mL, 2.5 mmol). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (250 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 20% ethyl acetate/hexanes) to afford 4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-N-tert-butyl-benzamide (300 mg, 56.9%) as a light yellow solid: LC/MS m/e calcd for C31H33N3O3S [M+H]+ 528.69, observed 528.0.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[N:16][C:15]=3[CH3:29])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[H-].[Na+]>>[C:35]([O:34][C:32](=[O:33])[CH2:31][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)=[N:16][C:15]=3[CH3:29])[CH:6]=2)[C:2]([CH3:1])=[CH:3]1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2c(C)cn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 a], 3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-1H-indole was reacted with tert-butyl bromoacetate in the presence of sodium hydride to obtain (3-methyl-6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28]C(=O)C)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])(=[O:6])=[O:5].[OH-].[Na+].O>O1CCCC1>[CH:3]([S:4]([CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:6])=[O:5])=[CH2:2]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)S(=O)(=O)CCCl)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CS(=O)(=O)C(CCCCCCC(=O)O)CCCC(O)CCCCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 8-(2-chloroethylsulfonyl)-12-acetoxyheptadecanoate (43.5 g., 0.09 mole), sodium hydroxide (14.4 g., 0.36 mole), water (150 ml.) and tetrahydrofuran (600 ml.) is stirred at 25° C. for 24 hours. Most of the tetrahydrofuran is removed by evaporation in vacuo keeping the temperature of the evaporating solution at 30° C. or below. The residue is diluted with water (300 ml.) and extracted with ether. The aqueous solution is acidified with dilute hydrochloric acid. The oily product is taken up in ether, washed with water and dried over sodium sulfate. The ether is evaporated to leave the product as a yellowish, very viscous oil. Purification is effected by column chromatography on silica gel with benzene-dioxane as eluting solvent mixture. The title compound is obtained as a colorless viscous oil.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)=[O:23])=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([F:7])[CH2:26][CH2:25]1)=[O:23])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC(O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N1CCC(F)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.4 %

Procedure:
DAST (1.2 mL, 9 mmol) was added to a solution of (R)-2-(4-hydroxy-piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.6 g, 8.7 mmol) in DCM at −78° C. The mixture was stirred at rt for 20 hours. The reaction was cooled to 0° C., quenched with sodium bicarbonate and extracted with DCM. The organic layer was concentrated and purified on a silica gel column to give 1.5 g of (R)-2-(4-fluoro-piperidine-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C@H:9]([C:14]([NH:16][CH2:17][C:18]#[N:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][O:5][C:6]=1[CH3:7].C(OC([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=O)(C)(C)C>>[C:18]([CH2:17][NH:16][C:14](=[O:15])[C@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[NH:8][C:3]1[C:2]([C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][NH:27][CH2:32][CH2:31]3)=[CH:38][CH:37]=2)=[C:6]([CH3:7])[O:5][N:4]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: Cc1onc(N[C@@H](CC(C)C)C(=O)NCC#N)c1Br
Product: Cc1onc(N[C@@H](CC(C)C)C(=O)NCC#N)c1-c1ccc(N2CCNCC2)cc1

Procedure:
N2-(4-bromo-5-methylisoxazol-3-yl)-N1-(cyanomethyl)leucinamide was treated with 4-[4-(tert-butoxycarbonyl)-1-piperazinyl]phenylboronic acid (prepared as described in Example 1) as described in Example 1 to afford, after BOC removal with methanesulfonic acid as described in Example 1, N1-(cyanomethyl)-N2-[5-methyl-4-(4-piperazin-1-ylphenyl)isoxazol-3-yl]leucinamide. MS (+APCI): 411.4 [M+1]+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:9][OH:10])[CH2:7][CH3:8].[Li+].CC([N-]C(C)C)C.[C:19]([O:26][CH2:27][CH3:28])(=[O:25])[C:20]([O:22]CC)=O>C1COCC1>[OH:10][N:9]=[C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:7]([CH3:8])[C:20](=[O:22])[C:19]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=NO)c1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(C)C(=NO)c1cccs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
1-(Thiophen-2-yl)propan-1-one oxime (6.3 g, 40.6 mmol) was dissolved in 100 mL of THF and cooled to 0° C. LDA solution (46.7 mL, 93.5 mmol, 2M in heptane/THF/ethyl benzene) was added dropwise, and the reaction mixture was stirred at 0° C. for 1 hour and then warmed to room temperature. The mixture was then transferred to an addition funnel and added dropwise to a flask containing a pre-cooled mixture of diethyl oxalate (27.6 mL, 203 mmol) and THF (100 mL) at 0° C. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The mixture was cooled in an ice bath and quenched with 150 mL of 10% hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The aqueous layer was then neutralized with solid sodium bicarbonate and extracted further with CH2Cl2. The organic layers were combined, dried over MgSO4 and concentrated. The crude oil was purified by chromatography (0-20% EtOAc/hexanes) to give 7.7 g of the title compound. MS: (+) m/z 256.33 (M+1).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[C:8]([O:17][CH3:18])[C:7]=1[OH:19])[CH:2]=[C:3]([CH3:5])[CH3:4].C1C=CC=CC=1>CCCCCC>[CH2:13]([O:12][C:9]1[C:8]([O:17][CH3:18])=[C:7]2[C:6]([CH:1]=[CH:2][C:3]([CH3:4])([CH3:5])[O:19]2)=[CH:11][CH:10]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: COc1c(OCC(C)C)ccc(CC=C(C)C)c1O
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COc1c(OCC(C)C)ccc2c1OC(C)(C)C=C2
Yield: 79.7 %

Procedure:
A mixture of 5.8 g (22 millimoles) of 2-prenyl-5-isobutoxy-6-methoxy-phenol, a molar equivalent amount of methyl-trialkyl (C8 -C10)-ammonium dichromane and 100 ml of benzene is refluxed for 10 hours. The reaction mixture is diluted with hexane, washed with 20% sodium thiosulfate, the organic phase is dried, evaporated and the residue is purified by column chromatography (see Example 3). Thus 4.6 g of the desired compound are obtained in the form of a colorless oil, yield 80%.
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@@H:14]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+].[C:31](Cl)(=[O:35])[O:32][CH2:33][CH3:34]>ClCCl>[C:16]([NH:15][C@H:14]1[CH2:13][CH2:12][N:11]([C:31]([O:32][CH2:33][CH3:34])=[O:35])[CH2:10][C@H:9]1[O:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(N[C@H]1CCNC[C@H]1OCc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)N1CC[C@H](NC(=O)c2ccccc2)[C@H](OCc2ccccc2)C1
Reaction time: 3 h

Procedure:
To a stirred solution of 40 parts of cis-N-[3-(phenylmethoxy)-4-piperidinyl]benzamide in 153 parts of tetrahydrofuran were added 323 parts of a sodium hydroxide solution 1N. Then there was added dropwise a solution of 15.4 parts of ethyl carbonochloridate in 58 parts of tetrahydrofuran at a temperature below 5° C. Upon completion, stirring was continued for 3 hours while cooling in an ice-bath (temp. below 5° C.). Dichloromethane was added and the layers were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were washed with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and crystallized from acetonitrile. A first fraction was filtered off, yielding 30.2 parts of cis-ethyl 4-(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate; mp. 139.2° C. The mother liquor was concentrated. The precipitated product was filtered off, yielding a second fraction of 5 parts of cis-ethyl 4-(benzoylamino)-3-(phenylmethoxy)-1-piperidinecarboxylate.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=O.Cl.NC1[N:23]=[CH:24][NH:25][C:26]=1[C:27]([NH2:29])=[O:28].C(=O)(O)[O-].[Na+]>C(O)(=O)C.ClCCl>[N:13]1([C:10]2[CH:9]=[CH:8][C:7]([C:5]3[N:23]4[CH:24]=[N:25][C:26]([C:27]([NH2:29])=[O:28])=[C:19]4[N:2]=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CN(C)C=CC(=O)c1ccc(N2CCOCC2)cc1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3ccc(N4CCOCC4)cc3)ccnc12
Yield: 78.3 %

Procedure:
A mixture of 15.0 g of 3-dimethylamino-4'-morpholinoacrylophenone (prepared as described in Example 13) and 7.26 g of 4-amino-5-imidazolecarboxamide hydrochloride in 250 ml of glacial acetic acid was stirred and heated at reflux for 5 hours. The solution was evaporated in vacuo to give a black oil that was then dissolved in dichloromethane and then saturated sodium bicarbonate solution was added. A precipitate was formed which was collected by filtration as a yellow crystalline solid. The solid was triturated with ether then filtered to give 11.3 g of the product of the example as yellow crystals, mp 274°-277° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>C1COCC1>[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:23])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1Br
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2Br)c(Cl)c1
Reaction time: 24 h
Yield: 67.3 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.00 g, 5.01 mmol) and 2-bromophenyl isocyanate (0.62 ml, 5.01 mmol) in THF (20 ml) was added Et3 N (0.14 ml, 1.00 mmol) at room temperature. After 1 day stirring, 2-bromophenyl isocyanate (0.60 ml, 5.01 mmol) was added to the reaction mixture and stirred 24 h. The reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 4-[N′-(2-bromophenyl)ureido]-3-chlorophenylacetate (1.34 g, 67%) as a colorless powder. 1H-NMR (CDCl3) δ 3.58 (s, 3H), 3.70 (s, 2H), 6.98 (m, 3H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 7.32 (m, 1H), 7.51 (m, 2H), 8:05 (m, 1H); MS (ESI) m/z 398 (M++1), 400 (M++3), 402 (M++5).