Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:21]4[CH:22]=[N:23][C:24]([O:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:25][CH:26]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[NH2:20][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[N:12]=[C:13]([C:21]3[CH:22]=[N:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)[C:14]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AH) (1.00 g, 0.0022 mol) was triturated in acetone (20 mL) and 5N hydrochloric acid solution was added dropwise. The mixture was stirred at ambient temperature for 20 hours and neutralized with saturated sodium bicarbonate solution. The precipitate was collected by filtration, washed with water twice and dried to give 4-[4-amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclo-hexanone as an off-white solid (purity 94% (HPLC), 0.90 g, 0.0022 mol)):
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8]/C=C\[Sn](CCCC)(CCCC)CCCC)[CH3:7].N#N.CO.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2[CH:48]=O)=[CH:31][CH:30]=1>C1COCC1>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH3:47])[C:36]=2/[CH:48]=[CH:7]/[CH:6]=[O:8])=[CH:31][CH:30]=1
Reactant: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Reactant: CCCC[Sn](/C=C\OCC)(CCCC)CCCC
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Temperature: -78 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
n-BuLi (1.6M in hexanes, 1.52 ml, 2.43 mmol) was added to a solution of cis-1-ethoxy-2-(tri-n-butylstannyl)ethylene (1.06 gm, 2.94 mmol) in dry THF (7.5 ml) at -78° C. The mixture was stirred for 11/4 hours, then cooled to -100° C. (liquid N2 /methanol) and treated with a solution of 4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinecarboxaldehyde (707 mg, 2.43 mmol) in THF (3.0 ml). Forty-five minutes after the addition, the temperature was raised to -78° C. and the mixture was stirred for an additional 50 minutes. The solution was then stirred in an ice bath for 5 minutes and subsequently quenched with H2O (8 ml) and 10% HCl (8 ml). After stirring at room temperature for 1.5 hours, the mixture was made basic with 10% NaOH (10 ml) and extracted twice with Et2O. The combined Et2O layers were washed with H2O and brine, dried (Na2SO4), filtered and stripped to yield a solid. The solid was washed with cold Et2O. The Et2O washings were stripped and triturated with cold hexane to give additional solid, which was pooled with the above solid to give 586 mg (76%) (E)-3-[4-(4-fluorophenyl)-2-methyl-6-phenyl-3-pyridinyl]-2-propenal. Analytically pure material was obtained by recrystallization from hot hexane/EtOAc.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([O:10][CH2:11][CH:12]3[O:14][CH2:13]3)[C:4]=2[CH:3]=[N:2]1.[NH3:15]>C(O)C>[OH:14][CH:12]([CH2:13][NH2:15])[CH2:11][O:10][C:9]1[C:4]2[CH:3]=[N:2][S:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: c1cc(OCC2CO2)c2cnsc2c1
Reactant: N
Solvent: CCO
Product: NCC(O)COc1cccc2sncc12
Reaction time: 3 h

Procedure:
4.0 g of 1-(1,2-benzisothiazol-4-yloxy)-2,3-epoxy-propane in 100 ml of aqueous ammonia and 300 ml of ethanol are left to stand for 3 hours at 35° C. The mixture is concentrated, the semi-crystalline residue is dissolved in ethanol and a solution of hydrogen chloride in ether is added dropwise. The hydrochloride which precipitates is filtered off, washed with dry ether and dried.
Reaction SMILES: C(N(CC)CC)C.C(O[C@H:12]1[NH:15][C:14](=[O:16])[C@@H:13]1[C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])(=O)C.[C:27]([S:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[S:30])[CH2:28][CH3:29].Cl>C(#N)C.[Cl-].[Zn+2].[Cl-].[Cu]Cl.ClCCl>[Si:20]([O:19][C@@H:17]([C@@H:13]1[C@@H:12]([C@H:28]([C:27]([S:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[S:30])[CH3:29])[NH:15][C:14]1=[O:16])[CH3:18])([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: CCC(=S)Sc1ccccc1
Agent: Cl[Cu]
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)Sc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 68.4 %

Procedure:
To a suspension of anhydrous zinc chloride (56 mg) in acetonitrile (1.6 ml) cooled to 0° C. was added triethylamine (0.17 ml). After stirring for 10 minutes at 0° C., to the solution were added copper(I) chloride (41 mg), (3R,4R)-4-acetoxy-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-oxoazetidine (79 mg) and phenyl dithiopropionate (75 mg). The reaction mixture was stirred at 0° C. for 2 hours. The mixture was poured into a stirred mixture of dichloromethane (5 ml) and 1N aqueous hydrochloric acid solution (5 ml). The organic layer was separated, washed with water, aqueous sodium bicarbonate solution and brine, and dried. The solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:4, V/V) to afford a mixture (5:1) (77 mg) of (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1R)-1-{(phenylthio)thiocarbonyl}ethyl]- 2-oxoazetidine and (3S,4S)-3-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(1S)-1-{(phenylthio)thiocarbonyl}ethyl]-2-oxoazetidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41])([O-:32])=[O:31]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:40]([NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])=[O:41])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-nitrophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 554.8.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]([CH:8]=[N:9][OH:10])[CH2:2]2.[Cl:11]N1C(=O)CCC1=O>>[OH:10][N:9]=[C:8]([Cl:11])[CH:3]1[CH2:4][CH2:5][CH:6]2[CH:1]([CH2:7]2)[CH2:2]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=CC1CCC2CC2C1
Product: ON=C(Cl)C1CCC2CC2C1

Procedure:
N-Hydroxybicyclo[4.1.0]heptane-3-carbimidoyl chloride (I-12E) was prepared by reaction of bicyclo[4.1.0]heptane-3-carbaldehyde oxime and N-chloro-succinimide following the same protocol as described for I-6B. MS m/z 174.0 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:30][C:28]([F:29])([F:31])[O:27][C:23]1[CH:22]=[C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:32])=[O:3])=[CH:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3cccc(OC(F)(F)F)c3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCCCC#Cc3cccc(OC(F)(F)F)c3)cc21

Procedure:
In analogy to the procedure described for example 1 e], {6-[5-(3-trifluoromethoxy-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as green crystals.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([O:24][CH2:25][CH3:26])([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])[CH2:9]1)C1C=CC=CC=1.[ClH:27]>[Pd].C(O)C>[ClH:27].[CH2:25]([O:24][C:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:26]
Reactant: CCOc1ccccc1OCC1(OCC)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOc1ccccc1OCC1(OCC)CCNC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of 10.4 g (0.029 mole) of 1-benzyl-3-ethoxy-3-[(2-ethoxyphenoxy)methyl]pyrrolidine in 100 ml of 200 ethanol was treated with palladium/carbon catalyst and shaken at 70° C. under a hydrogen atmosphere for 16 hours. No hydrogen was absorbed. The catalyst was removed by filtration, the filter cake washed with 50 ml of 200 ethanol, the filtrate transferred to a Parr reaction bottle and treated with 29 ml of 1.00N hydrochloric acid. Palladium/carbon catalyst was added and the reaction mixture was shaken under a hydrogen atmosphere at 70° C. for 16 hours. The catalyst was removed by filtration, and the filtrate evaporated under reduced pressure (9.0 g). The product hydrochloride crystallized on standing and was recrystallized twice from isopropanol-isopropyl ether: 5.7 g, (65%), m.p., 109°-112° C. The salt was dried under vacuum.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.Cl.[CH3:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[NH2:20].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[CH3:16][O:17][C:18](=[O:23])[C:19]([NH:20][C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[Br:1])=[O:14])([CH3:22])[CH3:21]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.5 %

Procedure:
1.0 g 1-bromo-naphthalene-2-carboxylic acid and 0.61 g 2,2-dimethylglycine methyl ester hydrochloride were suspended in 30 ml of dichloromethane and 10 ml of DMF. 1.31 ml N-methylmorpholine, 0.70 g 1-hydroxybenzotriazole and, finally, 0.99 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and the reaction stirred at room temperature for 14 h. The reaction mixture was chromatographed on silica (ethyl acetate/heptane) without aqueous work-up to give 1.3 g 2-[(1-bromo-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: Cl.[NH2:2]O.[Br:4][C:5]1[C:6]([CH3:16])=[C:7]([C:12]([O:14][CH3:15])=[O:13])[S:8][C:9]=1[CH:10]=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.Cl>C(#N)C.N1C=CC=CC=1.C(OCC)(=O)C>[Br:4][C:5]1[C:6]([CH3:16])=[C:7]([C:12]([O:14][CH3:15])=[O:13])[S:8][C:9]=1[C:10]#[N:2]
Reactant: COC(=O)c1sc(C=O)c(Br)c1C
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)c1sc(C#N)c(Br)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Hydroxylamine hydrochloride (5 g, 72 mmol) was added to a solution of methyl 4-bromo-5-formyl-3-methylthiophene-2-carboxylate (16.5 g, 63 mmol) in acetonitrile (175 mL) and pyridine (30 mL). The resulting solution was stirred at room temperature for 2 h, then trifluoroacetic anhydride (21.3 mL, 153 mmol). After 3 h the reaction mixture was poured into ethyl acetate and aqueous hydrochloric acid. The organic layer was separated, washed with hydrochloric acid and water, dried over sodium sulphate and evaporated. The resulting raw material was triturated with 90 mL of a water/ethyl alcohol mixture (1:1) and dried under vacuum to give 15 g of the title compound, used in the following step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH:17][C:18]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)[CH2:21]2)=[O:19])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[N:6][CH:7]=1.C[Si]([C:47]#[C:48][C:49]1[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>COCCOC.C(N)CCC.O.[Cu](I)I.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>[C:13]([O:12][C:10](=[O:11])[CH2:9][C@H:8]([NH:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26](=[O:42])[CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[O:36])[CH2:33][CH2:34]2)[CH2:21]1)=[O:19])[C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:47]#[C:48][C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH:3]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: C[Si](C)(C)C#Cc1ccc(O)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: COCCOC
Solvent: CCCCN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(C#Cc2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a degassed solution of tert-butyl 4-[3-((3R)-3-{[(1S)-1-(5-bromopyridin-3-yl)-3-tert-butoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (400 mg, 0.61 mol), copper iodide (14 mg, 70 μmol), tetrakis(triphenylphosphine)palladium(0) (71 mg, 60 μmol) and 4-[(trimethylsilyl)ethynyl]phenol (234 mg, 1.23 mmol) in 1,2-dimethoxyethan (3.5 mL) and n-butyl amine (0.91 mL) was added a 1 M tetra-n-butyl ammonium fluoride solution in THF (800 μL, 0.8 mmol) over 60 minutes at 80° C. After 10 additional minutes at 80° C. the mixture was diluted with water after cooling to room temperature and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 338 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-{5-[(4-hydroxyphenyl)ethynyl]pyridin-3-yl}-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([Mg]Cl)([CH3:17])[CH3:16].O.CCOC(C)=O>C1COCC1.C(OCC)C.C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH:15]([CH3:17])[CH3:16])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)[Mg]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, first 700 mL of a THF/diethyl ether mixture (2:1) and then a solution of 53.0 mL (283 mmol) of N-benzyl-4-piperidone in 200 mL of a THF/diethyl ether mixture (2:1) were slowly added at −15° C. to 200 mL (400 mmol, 2 M in THF) of isopropylmagnesium chloride solution and the reaction mixture was stirred for 1 hour between −3° C. and −6° C. While cooling with ice, 600 mL of water was slowly added dropwise and the mixture was stirred for 30 minutes. Then 400 mL of EtOAc and 100 mL of diethyl ether were added. The organic phase was separated off and dried over sodium sulfate. After the desiccant and solvent had been eliminated, the residue was purified by chromatography (silica gel, DCM/MeOH/NH3 98:2:0.2). Yield: 9.85 g (15% of theoretical); C15H23NO (M=233.349); calc.: molpeak (M+H)+: 234; found: molpeak (M+H)+: 234; HPLC-MS: 4.1 minutes (method G).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([O:20]C)=[O:19].[OH-].[Na+]>CO>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:17])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=[O:19]
Reactant: COC(=O)c1c(-c2cccc(OC(F)(F)F)c2)noc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Yield: 72.7 %

Procedure:
In a similar manner as described in Preparation Example 25, by using methanol (60 mL), methyl 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylate (6.0 g, 19.85 mmol) and 3% sodium hydroxide aqueous solution (60 mL), a white solid required compound (4.16 g, 14.43 mmol, 73%) was obtained.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:16][CH:17]=[CH:18][C:11]=12.[CH3:19][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[C:31]3[C:35]([CH:36]=[C:37](B4OC(C)(C)CC(C)(C)O4)[CH:38]=2)=[N:34][N:33](C2CCCCO2)[CH:32]=3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:21].O>O1CCOCC1>[CH3:21][CH:20]([N:22]1[C:26]([C:27]([NH:29][C:30]2[CH:38]=[C:37]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]4[NH:16][CH:17]=[CH:18][C:11]=34)[CH:36]=[C:35]3[C:31]=2[CH:32]=[N:33][NH:34]3)=[O:28])=[CH:25][CH:24]=[N:23]1)[CH3:19]
Reactant: CC(C)n1nccc1C(=O)Nc1cc(B2OC(C)(C)CC(C)(C)O2)cc2nn(C3CCCCO3)cc12
Reactant: Brc1ccnc2[nH]ccc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1nccc1C(=O)Nc1cc(-c2ccnc3[nH]ccc23)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A microwave vial was charged with Solvias catalyst (7 mg), tripotassium phosphate (84 mg) and 4-bromo-1H-pyrrolo[2,3-b]pyridine (commercial from Sinova, 29 mg). 1-(1-Methylethyl)-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1H-pyrazole-5-carboxamide (65 mg) in 1,4-dioxane (0.5 ml) was added, followed by water (0.1 ml) and the reaction was heated under microwave irradiation for 10 min at 120° C. The reaction was washed through a silica cartridge, preconditioned with methanol, with methanol. The solvent was removed under a stream of nitrogen, then washed with DCM and water. The resultant solution was evaporated under a stream of nitrogen. The residue was dissolved in DMSO:methanol (1 ml, 1:1, v/v) and purified by MDAP (method A). Appropriate fractions were dried under a stream of nitrogen. The residue was dissolved in methanol, 2 M HCl (aq) (3 drops) was added and the solution was left to stand for 30 min. The solvent was removed under a stream of nitrogen and the residue was dissolved in methanol, washed with methanol through an aminopropyl cartridge preconditioned with methanol and dried under a stream of nitrogen to give title compound, 20 mg.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH3:6])=[O:4].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[C:17]([NH2:36])=[N:18][CH:19]=[C:20]([C:22]2[C:23]([CH2:33][O:34][CH3:35])=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:36][C:17]1[N:18]=[CH:19][C:20]([C:22]2[C:23]([CH2:33][O:34][CH3:35])=[N:24][N:25]([CH:27]3[CH2:28][CH2:29][N:30]([CH2:2][C:3]([NH:5][CH3:6])=[O:4])[CH2:31][CH2:32]3)[CH:26]=2)=[CH:21][C:16]=1[C:8]1[O:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: CNC(=O)CCl
Reactant: COCc1nn(C2CCNCC2)cc1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5o4)c3)c(COC)n2)CC1
Temperature: 75 °C

Procedure:
A solution of 2-chloro-N-methyl-acetamide (0.027 ml) in DMF (1 ml) was added to a stirred mixture of 3-(1,3-benzoxazol-2-yl)-5-[3-(methoxymethyl)-1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (100 mg) and potassium carbonate (68 mg) in DMF (5 ml) at 25° C. under argon. The resulting solution was heated at 75° C. overnight. The DMF was evaporated and the residue was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (5 microns silica, 30 mm diameter, 150 mm length) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions were evaporated to afford 2-[4-[4-[6-amino-5-(1,3-benzoxazol-2-yl)-3-pyridyl]-3-(methoxymethyl)pyrazol-1-yl]-1-piperidyl]-N-methyl-acetamide (53.0 mg) as a solid. NMR Spectrum: (DMSOd6) 1.98-2.06 (m, 2H), 2.09 (dd, 1H), 2.14 (dd, 1H), 2.22-2.31 (m, 2H), 2.64 (d, 3H), 2.86-2.93 (m, 2H), 2.95 (s, 2H), 3.41 (s, 3H), 4.11-4.19 (m, 1H), 4.41 (s, 2H), 7.41-7.48 (m, 2H), 7.66 (bs, 2H), 7.75 (q, 1H), 7.78 (dd, 1H), 7.84 (dd, 1H), 8.19 (s, 1H), 8.43 (d, 1H), 8.50 (d, 1H); Mass spectrum: M+H+ 476.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C=O.[C:15](OCC)(=[O:17])C>CS(C)=O.C[O-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][OH:17])[C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.91 %

Procedure:
Methyl 2-(4-fluorophenyl)acetate (5.0 g, 29.73 mmol), NaOMe (0.08031 g, 1.487 mmol) and paraformaldehyde (0.9374 g, 31.22 mmol) were dissolved/suspended in 200 mL of DMSO and allowed to stir overnight at ambient temperature. The reaction was quenched with the addition of 1000 mL of ice-cold water. The reaction was neutralized with the addition of HCl solution, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water twice, once with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. Column chromatography on silica gel eluting with 25:75 hexanes:ethyl acetate afforded methyl 2-(4-fluorophenyl)-3-hydroxypropanoate (3.0 g, 50.91% yield) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:9](Cl)=[CH:8][C:6](=[O:7])[N:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:4].C([O-])(=O)C.[Na+].Cl.[NH2:23][OH:24]>COCCO>[CH3:1][N:2]1[C:9]([NH:23][OH:24])=[CH:8][C:6](=[O:7])[N:5]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]1=[O:4]
Reactant: Cn1c(Cl)cc(=O)n(C2CCCCC2)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Product: Cn1c(NO)cc(=O)n(C2CCCCC2)c1=O
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 7 g of 1-methyl-3-cyclohexyl-6-chlorouracil, 18 g of sodium acetate (trihydrate), 7 g of hydroxylamine hydrochloride and 100 ml of methyl-cellosolve is boiled for 1 hour and, when cold, the insolubles are removed by filtration. The filtrate is concentrated and recrystallized from water-ethanol. By the above procedure is obtained 4 g of 1-methyl-3-cyclohexyl-6-hydroxyaminouracil, melting point: 153°-155° C.