Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:31])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:27](=[CH:28][CH:29]=1)[O:26][C:11]1([CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:30].[OH-].[Na+]>>[C:20]1([CH2:19][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:30])[C:8]4[C:27](=[CH:28][CH:29]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:31])=[O:2])[CH:7]=4)[O:26]3)[CH2:12][CH2:13]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCCc3ccccc3)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCCc3ccccc3)CC1)O2
Yield: 99.2 %

Procedure:
(E)-3-{1′-(3-Phenyl-propyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (173 mg, 0.41 mmol) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-(3-phenyl-propyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid as a white solid (165 mg, 98%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-(3-phenyl-propyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Removal of the THP protecting group following the procedure described in Example 2, Step D gave (E)-3-{1′-(3-phenyl-propyl)l-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride salt as a white solid (48 mg).
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:31])=[O:30])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:25]=[CH:26][S:27][CH:28]=3)=[CH:20][CH:19]=2)[N:10]=1)(C)(C)C.C(OC(=O)CN(C(OC(C)(C)C)=O)C1C=CC=C(C(S(C2C=CC=CN=2)(=O)=O)NCC2C=CC(C3SC=CN=3)=CC=2)N=1)(C)(C)C>>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:29]([CH:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[CH:26][S:27][CH:28]=2)=[CH:20][CH:19]=1)[C:11]1[N:10]=[C:9]([NH:8][CH2:7][C:6]([OH:45])=[O:5])[CH:14]=[CH:13][CH:12]=1)(=[O:31])=[O:30]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3cscn3)cc2)S(=O)(=O)c2ccccn2)n1
Agent: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(C(NCc2ccc(-c3nccs3)cc2)S(=O)(=O)c2ccccn2)n1
Product: O=C(O)CNc1cccc(C(NCc2ccc(-c3cscn3)cc2)S(=O)(=O)c2ccccn2)n1
Yield: 53.4 %

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 3-(b) except for using tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(thiazol-4-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate (230 mg, 0.353 mmol) obtained in Example 16-(a) in place of tert-butyl[tert-butoxycarbonyl(6-{(pyridin-2-ylsulfonyl)[4-(thiazol-2-yl)benzyl]aminomethyl}pyridin-2-yl)amino]acetate to afford the title compound (93.5 mg) as a white solid. (Yield: 53%)
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[O:8]=[S:9]1(=[O:36])[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:33]([NH2:35])=[O:34])[CH:20]=[C:21](B4OC(C)(C)C(C)(C)O4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:7][C:5]1[N:6]=[C:2]([C:21]2[CH:22]=[C:23]3[C:18](=[C:19]([C:33]([NH2:35])=[O:34])[CH:20]=2)[NH:17][CH:16]=[C:15]3[CH:12]2[CH2:11][CH2:10][S:9](=[O:8])(=[O:36])[CH2:14][CH2:13]2)[S:3][CH:4]=1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Reactant: Brc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2nc(Br)cs2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reaction time: 0.67 h
Yield: 4.6 %

Procedure:
To a microwave vial was added 2,4-dibromo-1,3-thiazole (0.035 g, 0.143 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (0.060 g, 0.143 mmol) and potassium carbonate (0.059 g, 0.429 mmol) along with 1,4-dioxane (1.073 mL)/water (0.358 mL). The mixture was degassed with nitrogen and Pd(PPh3)4 (0.017 g, 0.014 mmol) was added. The reaction mixture was heated in the microwave under ‘high’ absorption setting for 40 minutes at 150° C. The reaction mixture was filtered through a Thiol SPE cartridge (500 mg) eluting with 1:1 MeOH/DCM (10 mL). The eluent was concentrated under nitrogen and purified by RP-HPLC on an X-Bridge C18 column with Acetonitrile/Water (0.1% NH4OH), giving 3 mg (4.6%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18]1[CH2:22][NH:21][C:20](=[O:23])[CH:19]=1.[H-].[Na+].O>CS(C)=O.C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:21]3[CH2:22][C:18]([O:17][CH3:16])=[CH:19][C:20]3=[O:23])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: COC1=CC(=O)NC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.1 %

Procedure:
A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (15 g) and 4-methoxy-3-pyrrolin-2-one (8.5 g) in dimethylsulfoxide (40 ml) was stirred and sodium hydride (80% dispersion in oil, 2.2 g) was added. The mixture was stirred at room temperature for 5 hours. Water (50 ml) was slowly added, and the resulting solution extracted with ethyl acetate (2×50 ml). After drying the organic layer with sodium sulfate the solvent was removed under reduced pressure and the residual oil chromatographed on silica gel (4% methanol in methylene chloride). The product obtained was dissolved in diethylether and precipitated with pentane to afford 4 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-methoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 256° C.
Reaction SMILES: [CH2:1]([S:5][CH:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]=1)[C:7]#[N:8])[CH2:2][CH2:3][CH3:4].[CH3:23][O-].[Na+].CI.O>CO>[CH2:1]([S:5][C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]=1)([CH3:23])[C:7]#[N:8])[CH2:2][CH2:3][CH3:4]
Reactant: C[O-]
Reactant: CCCCSC(C#N)c1cccc(C(=O)c2ccccc2)c1
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: O
Product: CCCCSC(C)(C#N)c1cccc(C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
90 mg of alpha-(butylthio)(m-benzoylphenyl)-acetonitrile was dissolved in 1 ml of anhydrous methanol, and 0.15 ml of a 2.7 M methanol solution of sodium methoxide was added in an atmosphere of argon under ice cooling, followed by addition of 0.05 ml of methyl iodide. The temperature of the mixture was brought to room temperature, and the mixture was stirred for 30 minutes. Water (20 ml) was added, and the mixture was extracted with 20 ml of ether three times. The extract was washed with 10 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; benzene) to afford 82 mg (yield 87%) of alpha-(butylthio)-alpha-(m-benzoylphenyl)propionitrile as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][C:6]1[C:15]2[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:21]([C:25]1[CH:29]=[C:28]([N:30]=[C:31]=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([C:25]1[CH:29]=[C:28]([NH:30][C:31]([NH:1][C:2]2[CH:20]=[CH:19][CH:18]=[C:4]([O:5][C:6]3[C:15]4[N:14]=[C:13]([CH3:16])[C:12](=[O:17])[NH:11][C:10]=4[N:9]=[CH:8][CH:7]=3)[CH:3]=2)=[O:32])[N:27]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nc2c(Oc3cccc(N)c3)ccnc2[nH]c1=O
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)c(C)nc34)c2)cc1
Yield: 57 %

Procedure:
Method F2 was used with 8-(3-aminophenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to afford the title compound as a white solid (89 mg, 57%).
Reaction SMILES: C([O-])(=O)C.[K+].[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17](Br)=[CH:16][N:15]=1)([CH3:9])([CH3:8])[CH3:7].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:51]1[CH:56]=[C:55]([Cl:57])[CH:54]=[C:53]([F:58])[C:52]=1[C:59]1[N:60]=[N:61][N:62]([CH3:64])[N:63]=1>CS(C)=O.[Pd].CCOC(C)=O.O>[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([C:51]2[CH:56]=[C:55]([Cl:57])[CH:54]=[C:53]([F:58])[C:52]=2[C:59]2[N:60]=[N:61][N:62]([CH3:64])[N:63]=2)=[CH:16][N:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NCc1ncc(Br)cc1F
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2Br)n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2cnc(CNC(=O)OC(C)(C)C)c(F)c2)n1
Temperature: 90 °C

Procedure:
A mixture of potassium acetate (3.10 g, 31.6 mmol), tert-butyl[(5-bromo-3-fluoropyridin-2-yl)methyl]carbamate (3.21 g, 10.5 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.94 g, 11.6 mmol) in a sealed tube reaction vessel capped with a rubber septum was dissolved in 10 mL of DMSO. This heterogeneous mixture was then evacuated and purged with nitrogen three times prior to introduction of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with DCM (1:1) (0.385 g, 0.530 mmol). The heterogeneous mixture was then evacuated and purged with nitrogen twice before the septum was replaced with a teflon screw-top cap. This sealed vessel was then heated to 90° C. for 2 hours. After cooling to ambient temperature, potassium carbonate (2.91 g, 21.1 mmol), water (10.5 mL), 5-(2-bromo-4-chloro-6-fluorophenyl)-2-methyl-2H-tetrazole (3.38 g, 11.6 mmol) and additional palladium catalyst (0.385 g, 0.530 mmol) were added and the reaction was sealed again. After heating to 80° C. for 1 hour, the reaction was cooled, quenched with water, and partitioned between EtOAc and water. The mixture was filtered through a plug of celite with EtOAc. The aqueous layer was extracted once with EtOAc. The combined organic layers were washed with additional water and then brine prior to drying over sodium sulfate. Filtration and solvent removal provided material which was subjected to chromatography on silica gel eluting with 0-15% EtOAc in hexanes to yield tert-butyl({5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}methyl)carbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Yield: 75.2 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.100 g, 0.290 mol) was dissolved in acetone (10 ml) and after adding thereto anhydrous sodium carbonate (0.080 g, 0.579 mmol) and benzyl bromide (0.059 g, 0.347 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (0.114 g, 0.261 mmol, 90%).
Reaction SMILES: [N:1]([CH:4]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)[CH2:5][CH3:6])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>C1COCC1.O>[N:8]1[CH:9]=[CH:10][N:11]=[CH:12][C:7]=1[CH:4]([NH2:1])[CH2:5][CH3:6]
Reactant: CCC(N=[N+]=[N-])c1cnccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCC(N)c1cnccn1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
The 2-(1-azidopropyl)pyrazine (56 mg) was dissolved in the THF (5 ml) and water (1 ml) and the PS-PPh3 (225 mg) added. The reaction mixture was heated to 50° C. and left to stir for approx. 20 hours. The mixture was filtered under vacuum and rinsed with DCM (a precipitate formed and re-dissolved with MeOH) then MeOH. The filtrate was evaporated to yield the title compound as a yellow oil which was used without further purification. [M+H]+ 138.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:9][NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH3:25]
Reactant: Cc1ccccc1B(O)O
Reactant: CNc1ccncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CNc1ccncc1-c1ccccc1C
Temperature: 80 °C
Yield: 12.3 %

Procedure:
A mixture of 1.26 g (6.75 mmol) (3-bromo-pyridin-4-yl)-methyl-amine, 13 ml toluene, 7 ml 2 N sodium carbonate solution, 234 mg (0.203 mmol) tetrakis(triphenylphosphine)palladium(0) and 1.01 g (7.43 mmol) o-tolylboronic acid was heated under argon at 80° C. for 12 h. After cooling to room temperature, the aqueous phase was separated and washed twice with toluene. The combined organic layers were washed with brine, dried (sodium sulfate) and evaporated. The residue was purified by flash chromatography to yield 164 mg (12%) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C1(C)C=CC=CC=1>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([N+:15]([O-:17])=[O:16])[CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To 15 mL of toluene solution containing 1.5 g of tert-butyl 4-chloro-2-nitrobenzoate, 1.1 g of 2,4-difluorophenylboronic acid, 2.3 g of cesium carbonate, 27 mg of palladium acetate and 25 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl were added sequentially, and the resulting mixture was heated to reflux under nitrogen atmosphere for 8 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and added a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.95 g of tert-butyl 4-(2,4-difluorophenyl)-2-nitrobenzoate as white solid.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:23]([O:27][C:28]1[CH:51]=[CH:50][C:31]([C:32]([NH:34][CH2:35][CH:36]([N:40]2[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]2)[C:37](O)=[O:38])=[O:33])=[CH:30][CH:29]=1)[C:24]#[C:25][CH3:26].Cl.[C:53]([O:57][NH2:58])([CH3:56])([CH3:55])[CH3:54].C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:53]([O:57][NH:58][C:37]([CH:36]([N:40]1[CH2:45][CH2:44][N:43]([S:46]([CH3:49])(=[O:48])=[O:47])[CH2:42][CH2:41]1)[CH2:35][NH:34][C:32](=[O:33])[C:31]1[CH:50]=[CH:51][C:28]([O:27][CH2:23][C:24]#[C:25][CH3:26])=[CH:29][CH:30]=1)=[O:38])([CH3:56])([CH3:55])[CH3:54]
Reactant: CC(C)(C)ON
Reactant: CC#CCOc1ccc(C(=O)NCC(C(=O)O)N2CCN(S(C)(=O)=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(C(=O)NCC(C(=O)NOC(C)(C)C)N2CCN(S(C)(=O)=O)CC2)cc1
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
50 mg (0.4 mmol) of 1-hydroxybenzotriazole then 70 mg (0.4 mmol) of 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride are added to a solution of 100 mg (0.2 mmol) of 3-(4-but-2-ynyloxybenzoylamino)-2-(4-methanesulphonylpiperazin-1-yl)propanoic acid in 2 ml of dichloromethane and 2 ml of dimethylformamide. The reaction medium is stirred for 20 min before adding a mixture containing 30 mg (0.3 mmol) of O-tert-butylhydroxylamine hydrochloride and 40 μl (0.3 mmol) of triethylamine. The mixture is then stirred at ambient temperature for 20 h. Dichloromethane is added, the organic phase is washed with a saturated aqueous solution of sodium hydrogen carbonate then with water, dried over magnesium sulphate, filtered and concentrated under vacuum. 100 mg (85%) of N-[2-tert-butoxycarbamoyl-2-(4-methanesulphonylpiperazin-1-yl)ethyl]-4-but-2-ynyloxy benzamide are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:42])[C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])[CH:20]=4)[CH:17]=3)[N:12](COCC[Si](C)(C)C)[N:11]=2)[CH:5]=1.C(=O)(O)[O-].[Na+]>Cl(O)(=O)(=O)=O.C(O)(=O)C>[CH3:1][N:2]([CH3:42])[C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)=[O:26])[CH:20]=4)[CH:17]=3)[NH:12][N:11]=2)[CH:5]=1
Reactant: CN(C)C(=O)c1cccc(-c2nn(COCC[Si](C)(C)C)c3ncc(-c4cccc(C(=O)N5CCOCC5)c4)cc23)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cccc(-c2n[nH]c3ncc(-c4cccc(C(=O)N5CCOCC5)c4)cc23)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18 %

Procedure:
A solution of N,N-dimethyl-3-(5-(3-(morpholine-4-carbonyl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide in 5% of perchloric acid in acetic acid (1 mL) was stirred for 1 h at room temperature. Saturated sodium bicarbonate solution was then added to the solution slowly until pH 8 and the mixture was stirred for 24 hours at room temperature. Ethyl acetate was then used for extraction and the organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Mass triggered reverse phase HPLC purification afforded N,N-dimethyl-3-(5-(3-(morpholine-4-carbonyl)phenyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)benzamide (7.4 mg, 18% yield over two steps) as light yellow solids. 1H NMR (500 MHz, CDCl3) δ 2.99 (s, 3H), 3.10 (s, 3H), 3.46 (br, 2H), 3.61 (br, 2H), 3.76 (br, 4H), 7.40 (d, J=7.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.52 (m, 2H), 7.64 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.98 (m, 2H), 8.62 (s, 1H), 8.85 (br, 1H). MS: m/z 456.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([CH:5]([N:7]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9](O)[C:8]1=[O:18])[CH3:6])=[O:4].C([OH:21])C>[Pd]>[OH:21][C@@:5]([C:3]([OH:2])=[O:4])([CH3:6])[NH:7][C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: COC(=O)C(C)N1C(=O)C(O)C1c1ccccc1
Agent: [Pd]
Product: C[C@](O)(NC(=O)CCc1ccccc1)C(=O)O
Reaction time: 12 h
Yield: 91.9 %

Procedure:
According to the same procedure as in Example 1, 1-(1-methoxycarbonylethyl)-3-hydroxy-4-phenylazetidin-2-one (513 mg.), which had been obtained in Referential Example 6, was subjected to hydrogenolysis at 50° C. in ethanol under a hydrogen pressure of one atmosphere in the presence of a 10% Pd-C (220 mg.). The reaction was completed in 12 hours. The same after-treatment as in Example 1 was followed to give methyl ester of α-hydroxy-β-phenylpropionylalanine (475 mg., yield: 91.9%), which was an oil. The NMR and IR spectra were completely identical with those of the authentic sample obtained in Example 9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH2:34]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39])[CH3:35].C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]([NH:39][C@@H:38]([CH2:40][OH:41])[C:37]([O:36][CH2:34][CH3:35])=[O:42])=[O:11])[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)[C@@H](N)CO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)[C@H](CO)NC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 25) (5.00 g, 16.76 mmol) in dichloromethane (75 ml) was treated sequentially with 1-hydroxybenzotriazole hydrate (2.49 g, 18.43 mmol), serine ethyl ester hydrochloride (3.13 g, 18.43 mmol) and N,N-diisopropylethylamine (6.13 ml, 35.19 mmol) and the resulting mixture was stirred at 0° C. under a nitrogen atmosphere for 15 minutes. 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.53 g, 18.43 mmol) was then added and the mixture was stirred for 48 hours being allowed to warm to room temperature over this time. The mixture was diluted with dichloromethane (200 ml), washed sequentially with water, aqueous citric acid solution (10% w/v), a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was then purified by column chromatography on silica gel eluting a gradient system of ethyl acetate:pentane (10:90) to (50:50) to afford the title compound as a colourless oil (5.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:21])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)=[O:12].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C[N+](C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([CH3:21])[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1)([OH:12])[C:23]([F:25])([F:24])[F:22]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(Cl)c(C(C)C(=O)c2ccc(=O)n(C)c2)c1
Agent: C[N+](C)(C)C
Agent: [F-]
Product: COc1ccc(Cl)c(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c1

Procedure:
In analogy to Example 165, step 3, 5-[2-(2-chloro-5-methoxy-phenyl)-propionyl]-1-methyl-1H-pyridin-2-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as a light grey foam. MS (m/e)=376.2 [M+H+].