Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([CH:19]([CH3:29])[CH2:20][O:21][Si](C(C)(C)C)(C)C)[CH:11]=2)=[O:9])[CH:3]=1.[F:30][C:31]([F:43])([F:42])[C:32]1[CH:33]=[C:34]([CH2:38][C:39](O)=[O:40])[CH:35]=[CH:36][CH:37]=1>>[OH:21][CH2:20][CH:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:42])([F:30])[F:43])[CH:33]=3)[CH:7]=[CH:6][N:5]=2)=[O:9])=[CH:11]1)[CH3:29]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cc(N)ccn2)c2cnccc21
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Product: CC(CO)n1cc(C(=O)c2cc(NC(=O)Cc3cccc(C(F)(F)F)c3)ccn2)c2cnccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Prepared according to method described for Method 1 (Example 19) using (4-aminopyridin-2-yl)[1-(2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]methanone (Enantiomer 1, Preparation 30) and 3-trifluoromethylphenylacetic acid. The residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution, the organic layer collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was dissolved in THF and 10% HCl in dioxane was added. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([NH:6]C(=O)OC(C)(C)C)[CH2:5][CH2:4]1.[ClH:16]>>[ClH:16].[F:1][C:2]([F:15])([F:14])[C:3]1([NH2:6])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)NC1(C(F)(F)F)CC1
Agent: Cl
Product: NC1(C(F)(F)F)CC1

Procedure:
A solution of tert-butyl 1-(trifluoromethyl)cyclopropylcarbamate (0.3 g, 1.3 mmol) in HCl (4 N dioxane, 6.7 mL, 27 mmol) was stirred at ambient temperature overnight. The reaction was then concentrated to yield the crude product as white solid, which was used directly in the next step assuming quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[C:6](Cl)=[O:7].CCN(C(C)C)C(C)C.[NH2:24][CH:25]1[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]1>C(Cl)Cl>[NH2:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]([NH:24][CH:25]2[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]2)=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)NC2CCC(N(C)C)CC2)ccc1N
Reaction time: 2 h
Yield: 113.9 %

Procedure:
3-methoxy-4-nitro-benzoyl chloride (Intermediate 189; 1.0 g, 4.64 mmol) was dissolved in DCM (20 mL) and cooled on an ice bath. DIPEA (970 uL) was added dropwise. 1-amino-4-dimethylaminocyclohexane (ABChem. Inc.; 660 mg, 4.64 mmol) was dissolved in DCM (10 mL) and added to the reaction solution. The reaction mixture was brought back to room temperature and stirred for 2 hours. The reaction mixture was washed with brine and NaOH (aq). The organic layer was extracted by filtering through a PTFE cup and evaporated to yield the title compound as an orange solid (1.54 g, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:32]1[N:37]=[N:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[N:37]=[N:36][C:35]([NH:38][C:39](=[O:41])[CH3:40])=[CH:34][CH:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(Cl)nn1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)C)CC2)O3)nn1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester (41.5 mg) and N-(6-chloro-pyridazin-3-yl)-acetamide (25.7 mg) in dioxane (2 mL) a 2 M aqueous Na2CO3 solution (0.125 mL) is added. The mixture is sparged with argon for 10 min and (2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(11) chloride*methyl-t-butylether complex (CAS-number.: 1028206-58-7; 8 mg) is added. The resulting mixture is stirred for 1 h at 150° C. After cooling to room temperature, the mixture is filtered over basic alumina and eluted with N,N-dimethylformamide/MeOH (9:1; 2 mL). The solvent is evaporated and the residue is purified by preparative HPLC (eluent water (+0.1% NH3)/MeOH) to yield the desired product. HPLC (method 13): tR=0.26 min; Mass spectrum (ESI+): m/z=425 [M+H]+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH:18]O>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)=[O:18]
Reactant: CSc1ccc(Oc2ccc(C#N)cc2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CS(=O)c1ccc(Oc2ccc(C#N)cc2)cc1
Temperature: 50 °C
Yield: 95.6 %

Procedure:
To a solution of 4.6 g (0.0191 mole) of 4-(4-(methylthio)phenoxy)benzonitrile dissolved in 50 ml of glacial acetic acid was added dropwise 2.38 g (0.0210 mole) of 30% aqueous hydrogen peroxide. The mixture was heated at 50° C. for 1 hr and most of the solvent removed in vacuo. The crude product was dissolved in CH2Cl2 and washed with 2N aqueous NaOH and water. The organic layer was dried (Na2SO4) and solvent removed in vacuo leaving 4.7 g (95.9% yield) of 4-(4-(methylsulfinyl)phenoxy)benzonitrile as an oil.
Reaction SMILES: Cl[CH:2](P(=O)(OCC)OCC)[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:14])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:16])([CH3:15])[C:5]=2[CH:4]=1.[C:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)#[N:26].Cl>CS(C)=O>[CH3:14][C:9]1([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:16])[C:5]2[CH:4]=[C:3]([C:2]#[C:31][C:30]3[CH:33]=[CH:34][C:27]([C:25]#[N:26])=[CH:28][CH:29]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(C#N)cc3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
A solution of 13.8 g (0.123 mole) of potassium tert.-butylate in 65 ml of dimethyl sulfoxide was added dropwise in the course of 30 minutes to a solution of 22.6 g (0.06 mole) of diethyl 1-chloro-1-(5,6,7,8-tetrahydro-5,5,8,8-tetraMethylnaphth-2-yl)-methylphosphonate (about 85% strength) and 7.86 g (0.06 mole) of 4-cyanobenzaldehyde in 190 ml of dry dimethyl sulfoxide at room temperature. Stirring was continued for 1 hour, after which the mixture was poured onto 1 liter of ice water and acidified with a little dilute hydrochloric acid, and the resulting crystals were filtered off under suction. Recrystallization from ethanol gave 9.2 g (49%) of the title compound of melting point 157° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:33]C=C)[CH:8]=[C:9]([C:11]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)([OH:16])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)=[O:5])[CH3:2].[O-:36][Mn](=O)(=O)=O.[K+]>CC(C)=O.O>[OH:36][CH2:2][CH:1]1[O:3][C:4](=[O:5])[C:6]2=[CH:10][C:9]([C:11]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[N:21]=[CH:20]4)([OH:16])[C:12]([F:15])([F:13])[F:14])=[CH:8][N:7]2[CH2:33]1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C(=O)OCC
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1OC(CO)Cn2cc(C(O)(c3ccc4c(cnn4-c4ccc(F)cc4)c3)C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
To a chilled (0° C.) solution of 1-allyl-4-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}-1H-pyrrole-2-carboxylic acid ethyl ester (100 mg, 0.2 mmol, 1 equiv.) in 3 mL of acetone and 1 mL of water was added a solution of KMnO4 (39 mg, 0.25 mmol, 1.2 equiv.) in 3 mL of acetone and 1 mL of water. The ice bath was removed and the reaction was warmed to room temperature. After 2 hours, the reaction was filtered through CELITE® filter aid and the filter cake washed with acetone. The filtrate was concentrated in vacuo diluted with water and extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (5-95% CH3CN/water 0.1% TFA). The fractions were combined and concentrated to remove CH3CN. The aqueous residue was made basic with saturated aqueous sodium bicarbonate and extracted with EtOAc to provide 25 mg of the title compound as a white solid. MS m/z 476.16 (MH+).
Reaction SMILES: C(O)(=O)C.O.[N+:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[F:18])([O-])=O.[H][H]>[Pt]=O.[Fe].C(O)C>[F:18][C:10]1[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:9]=1[NH2:6]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1cc([N+](=O)[O-])ccc1F
Yield: 89.3 %

Procedure:
To a mixture of 40 ml of glacial acetic acid, 5 ml of water, and 8.32 g (0.0447 mole) of 2,4-dinitrofluorobenzene were added 0.10 g (0.00044 mole) of platinum oxide and 0.50 g (0.0090 mole) of powdered iron. Subsequently, 160 ml of ethanol was added to this mixture, and the entire reaction mixture was placed in a 500 ml Parr hydrogenation reactor. The reaction was stopped after 144 psi of hydrogen had been absorbed, and the reaction mixture was then filtered. The filtrate was evaporated under reduced pressure, and the residue was passed through a pad of silica gel, eluting with methylene chloride. The solvent was evaporated from the eluate under reduced pressure, producing 6.23 g of crude 2-fluoro-5-nitroaniline, m.p. 90°-92° C. Analysis of the nmr spectrum of this material showed it to be at least 85% pure 2-fluoro-5-nitroaniline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:43][C:44]1[S:45][C:46]([CH3:50])=[C:47]([CH3:49])[N:48]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:43][C:44]2[S:45][C:46]([CH3:50])=[C:47]([CH3:49])[N:48]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1nc(N)sc1C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4nc(C)c(C)s4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 84.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (40 mg) was dissolved in chloroform (1.2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (20 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 5 min. Next, 2-amino-4,5-dimethylthiazole hydrochloride (24 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was concentrated, and the residue was then purified by chromatography (chloroform:acetone=2:1) to give the title compound (25.8 mg, yield 42%).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[C:3]1=O.[CH2:17]([O:24][CH2:25][CH2:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:17]([O:24][CH2:25][CH2:26][N:27]1[C:2]2[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[O:9])[C:3]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C(Br)CCCC1C(=O)N1CCCCC1
Reactant: c1ccc(COCCNc2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: O=C(C1CCCc2c1c1ccccc1n2CCOCc1ccccc1)N1CCCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 27.7 %

Procedure:
A mixture of 2-bromo-6-(piperidine-1-carbonyl)-cyclohexanone (20) (1.5 g, 5.2 mmol) and (2-benzyloxy-ethyl)-phenyl-amine (21) (3.2 g, 10.4 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (5 mL) and dry zinc chloride (2.13 g, 15.6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and washed with 2 N HCl (30 mL), water (2×30 mL) and aqueous potassium carbonate solution (2×30 mL) then dried and concentrated in vacuo. The crude material was purified by SCX cartridge and then silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (30-100% B, 12 g, 41 CV, 30 mL/min) to afford 600 mg (27%) of [9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazol-4-yl]-piperidin-1-yl-methanone (22) as an oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 21.5, 21.7, 24.5, 25.7, 26.3, 273, 37.7, 42.8, 43.1, 46.7, 60.2, 68.7, 73.1, 108.2, 108.7, 117.8, 118.9, 120.5, 126.4, 127.3, 127.4, 128.1, 136.2, 137.8, 172.9.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.[C:18]([CH2:20][C:21]([CH:23]1[CH2:32][CH2:31][CH2:30][CH2:29][C:24]21[O:28][CH2:27][CH2:26][O:25]2)=O)#[N:19]>C(#N)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:20]([C:18]#[N:19])=[C:21]([CH:23]4[CH2:32][CH2:31][CH2:30][CH2:29][C:24]54[O:28][CH2:27][CH2:26][O:25]5)[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: N#CCC(=O)C1CCCCC12OCCO2
Reactant: O=Cc1cccc2nonc12
Reactant: Nc1cc[nH]n1
Solvent: CC#N
Product: N#CC1=C(C2CCCCC23OCCO3)Nc2n[nH]cc2C1c1cccc2nonc12
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a solution of ethyl 2-cyclohexanonecarboxylate (25 g) in toluene (200 mL) was added ethyleneglycol (10.1 g) and p-toluenesulfonic acid (2.8 g) at room temperature and the mixture was heated under reflux with Dean-Stark apparatus for five hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) as a colorless oil. To a solution of acetonitrile (7.2 g) in THF (700 mL) was added n-BuLi (160 mmol) at −78° C. Further, ethyl 1,4-dioxa-spiro[4,5]decane-6-carboxylate (31 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-cyano-2-(1,4-dioxa-spiro[4,5]decan-6-yl)ethan-2-one (14.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.8 g), 3-aminopyrazole (0.5 g) and 1-cyano-2-(1,4-dioxa-spiro[4,5]-decan-6-yl)ethan-2-one (1.2 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give 4-(2,1,3-benzoxadiazol-4-yl)-5-cyano-4,7-dihydro-6-(1,4-dioxa-spiro[4,5]decan-6-yl)-2H-pyrazolo[3,4-b]pyridine (1.3 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].CO[CH2:13][Cl:14].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH2:13][Cl:14])=[C:6]([F:8])[CH:7]=1
Reactant: COCCl
Reactant: COc1ccc(F)cc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cc(CCl)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
17.6 g (0.11 mol) of 2-chloro-4-fluoroanisole was dissolved in a dichloromethane solution of 1N titanium tetrachloride, and 88.3 g (1.10 mol) of methoxymethyl chloride was dropwise added thereto at room temperature, followed by stirring at room temperature for 5 hours. After completion of the reaction, the reaction solution was poured into water, followed by stirring at room temperature for 2 hours, and then the aqueous phase was removed. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. Then, the obtained residue was purified by silica gel column chromatography to obtain 15.5 g (yield: 68%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 3.89(3H,s), 5.00(2H,s), 6.97(1H,d), 7.18(1H,d)ppm.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=2.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.[C:25](=[O:28])(O)[O-].[Na+].C(=O)=O>C(O)(=O)C.O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]#[N:12])=[C:2]([N:1]3[CH:18]=[CH:22][CH:21]=[CH:20]3)[NH:3]2)=[CH:8][CH:7]=1)([O-:15])=[O:14].[CH2:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([O:28][CH3:25])[CH:5]=2)[C:10]([C:11]#[N:12])=[CH:2]1)[CH3:22]
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1c(N)[nH]c2cc([N+](=O)[O-])ccc12
Reactant: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C#N)c2ccc(OC)cc21
Product: N#Cc1c(-n2cccc2)[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) was treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution was heated to reflux for 14 h. After cooling to ambient temperature, the solution was poured into water (100 mL), and solid sodium bicarbonate was added until CO2 evolution ceased. The mixture was extracted with EtOAc (2×100 mL), and the extracts were washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material was separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:15]([NH2:18])[CH2:16][CH3:17].[CH:19]1([CH2:25][NH:26][C:27]2[CH:28]=[C:29]([CH:42]=[CH:43][CH:44]=2)[O:30][C:31]2[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH:38]=2)[CH:36]=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCCl>[CH:19]1([CH2:25][NH:26][C:27]2[CH:44]=[CH:43][CH:42]=[C:29]([O:30][C:31]3[CH:32]=[CH:33][C:34]([N+:39]([O-:41])=[O:40])=[C:35]([CH2:36][NH:18][CH2:15][CH2:16][CH3:17])[CH:38]=3)[CH:28]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCCN
Reactant: O=Cc1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(Oc2cccc(NCC3CCCCC3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaBH(OAc)3 (0.0080 mol) was added to a mixture of propylamine (0.0054 mol) and 5-[3-(cyclohexylmethyl-amino)-phenoxy]-2-nitro-benzaldehyde (0.00054 mol) in DCE (100 mL). Then the reaction mixture was stirred overnight at room temperature and washed with a saturated NaHCO3 solution. The organic layer was separated, dried (MgSO4), and filtered, and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:14]3[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:20][N:21]=[C:22]=[O:23].CC(C)=O.C(Cl)Cl>CCOC(C)=O.[Cu]Cl>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][N:11]=[C:10]([NH:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:14]=2[CH:15]=1
Reactant: Oc1ccc2onc(NCCN3CCOCC3)c2c1
Reactant: CN=C=O
Agent: Cl[Cu]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)Oc1ccc2onc(NCCN3CCOCC3)c2c1
Yield: 32.9 %

Procedure:
To a stirred solution of 3-[[2-(4-morpholinyl)ethyl]-amino]-1,2-benzisoxazol-5-ol (1 g) and a catalytic amount of copper(I)chloride (0.05 g) in EtOAc (100 ml) was added methyl isocyanate (0.26 g). After 24 hours TLC (silica gel, 1:1:20 acetone/MeOL/DCM) showed no starting material. The reaction was filtered through neutral alumina eluting with EtOAc (1 l) and the filtrate was concentrated in vacuo. The residue was further purified by flash chromatography (silica gel) eluting with 1:1:20 acetone/MeOH/DCM to yield 0.4 g of the product, m.p. 135°-136° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH3:26])[NH:11]2)[CH:6]=CC=1)#N.[OH-:27].[Na+].[CH2:29]([OH:31])[CH3:30]>>[C:29]([C:30]1[CH:6]=[C:5]([CH2:9][N:10]2[C:14]3=[N:15][C:16]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[N:17][C:18](=[O:19])[C:13]3=[C:12]([CH3:26])[NH:11]2)[CH:4]=[CH:3][CH:1]=1)([OH:27])=[O:31]
Reactant: [OH-]
Reactant: CCO
Reactant: Cc1[nH]n(Cc2cccc(C#N)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Agent: [Na+]
Product: Cc1[nH]n(Cc2cccc(C(=O)O)c2)c2nc(-c3ccncc3)nc(=O)c1-2
Yield: 25 %

Procedure:
A mixture of 1-(3-cyanophenylmethyl)-3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one (3.4 g, 10.2 mmol), 10 M NaOH (100 ml) and ethanol (100 ml) was refluxed for 7 hours. The mixture was filtered hot, the filtrate was cooled in an ice-bath for 30 minutes and neutralized with acetic acid. The product was collected by filtration and washed with water, ethanol and ether. The solid residue was digested in methanol and the product was collected by filtration and washed with ether. The product was recrystallized from DMF to afford 0.91 g (25%) of 1-(3-carboxyphenylmethyl)3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one as an off-white powder, m.p. >300° C. when dried at 125° C. for 18 hours in high vacuum.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[N:11](COCC[Si](C)(C)C)[N:10]=2)=[CH:3][CH:2]=1.B(F)(F)F.CCOCC.OCN1C2C(=CC=C(/C=C3/C(=O)NC4C/3=CC=CC=4)C=2)C(/C=C/C2C=CN=CC=2)=N1>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[C:19]4/[C:20](=[O:28])[NH:21][C:22]5[C:27]/4=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1nc(/C=C/c2ccncc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Agent: FB(F)F
Agent: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)nn(CO)c2c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccncc3)n[nH]c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A dry-round bottom was charged with (E)-3-((3-((E)-2-(pyridin-4-yl)vinyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (906 mg, 1.83 mmol), and CH2Cl2 (100 mL) under an atmosphere of N2. Boron trifluoride etherate (2.3 mL, 18.3 mmol) was added dropwise and the reaction was stirred for 4 hours at which time LC-MS indicated complete conversion to the partially de-protected material (E)-3-((1-(hydroxymethyl)-3-((E)-2-(pyridin-4-yl)vinyl)-1H-indazol-6-yl)methylene)-indolin-2-one. The CH2Cl2 was removed in vacuo, and then 150 mL of a 2:1 mixture of EtOH/2M HCl was added and the reaction heated to 50° C. for 3 hours at which time LC-MS indicated complete conversion to the title compound. The reaction was cooled with an ice-bath and neutralized with NH4OH to pH˜8, the EtOH was removed and the suspension filtered washing with water. The dried solid was collected and then titurated and filtered several times with 90:10 CH2Cl2/MeOH which gave, after drying, the title compound (353 mg, 53%) as an orange solid. 1H NMR (400 MHz, d6-DMSO) δ 13.57 (s, 1H), 10.64 (s, 1H), 8.57 (d, J=5.16 Hz, 2H), 8.38 (d, J=8.13 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J=16.7 Hz, 1H), 7.80 (s, 1H), 7.71 (d, J=5.16 Hz, 2H), 7.62-7.53 (m, 3H), 7.23 (t, J=8.29 Hz, 1H), 6.91-6.82 (m, 2H); MS ESI 365.1 [M+H]+, calcd for [C23H16N4O+H]+ 365.14.