Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1Br)[CH:10]=2)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClCCl.[C:35]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:18]1[C:19]([C:42]3[CH:43]=[CH:44][C:39]([C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:40][CH:41]=3)=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3Br)ccc2c1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(C)(C)C)cc3)ccc2c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
To 5 ml dioxane was added in sequence, 7-(2-bromobenzoylamino)quinoline-3-carboxylic acid ethyl ester (100 mg, 0.25 mmol), potassium carbonate (0.25 ml of 2.0M aqueous solution, 0.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (6.9 mg, 0.0125 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10.2 mg, 0.0125 mmol) and 4-tert-butylbenzeneboronic acid (111.5 mg, 0.63 mmol). The resulting mixture was degassed and placed under a nitrogen atmosphere. The degassing procedure was repeated 5 times and the reaction mixture was heated under reflux under nitrogen overnight. The reaction mixture was then cooled to room temperature and poured into water. The aqueous mixture was extracted with ethyl acetate and the ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was purified by preparative thick layer chromatography, eluting with 60:40 hexamethyl acetate to yield the title compound (99 mg, 87.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O)([O-:11])=[O:10]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Into a 100 mL round bottom flask was added 4-bromophenol (2.07 g, 12.0 mmol), 2-nitrophenylboronic acid (1.00 g, 5.99 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h. Reaction mixture was then filtered through celite. The filtrate was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 5% EtOAc in hexane.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[C:9]([CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:10][C:11]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([CH:22]=1)[C:13]([NH:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[O:14].[CH3:38][N:39]1[CH:43]=[C:42](B(O)O)[CH:41]=[N:40]1>COCCOC.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>[CH3:38][N:39]1[CH:43]=[C:42]([C:8]2[C:9]([CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:10][C:11]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:12]([CH:22]=2)[C:13]([NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH:41]=[N:40]1
Reactant: Cn1cc(B(O)O)cn1
Reactant: O=C(Nc1cccnc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
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: COCCOC
Product: Cn1cc(-c2cc(C(=O)Nc3cccnc3)c(OCc3ccccc3)cc2CN2CCOCC2)cn1
Temperature: 120 °C

Procedure:
Na2CO3 (0.23 ml, 0.23 mmol) and palladium tetrakis (7.91 mg, 6.84 μmol) were added to 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 2; 55 mg, 0.11 mmol) and (1-methyl-1H-pyrazol-4-yl)boronic acid (17.23 mg, 0.137 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120° C. in a microwave for one hour and the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a white solid. 27 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.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>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:5]3=[N:6][CH:7]=[C:2]([C:31]4[CH:30]=[CH:29][C:28]([N:25]5[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]5)=[CH:33][CH:32]=4)[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9]2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
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: [Cs+]
Solvent: COCCOC
Product: COc1ccc(Cn2nc(C)c3cc(-c4ccc(N5CCN(C)CC5)cc4)cnc32)cc1
Temperature: 80 °C

Procedure:
The starting material 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (145 mg, 0.44 mmol, 1 eq) and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (159) (135 mg, 0.44 mmol, 1 eq) in DME (10 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (280 mg, 0.88 mmol, 2 eq) followed by addition of Pd(PPh3)4 (15 mg, 0.01 mmol), degassing and purging under argon for additional 10 min. The reaction mixture was heated at 80° C. for 12 h in a sealed tube. After completion of the reaction, the solvents were removed and reaction mixtures were extracted into EtOAc, dried over Na2SO4 and the solvents distilled off. The crude material was submitted for flash column purification using 5% MeOH/CHCl3 to obtain off-white solid compound 1-(4-methoxybenzyl)-3-methyl-5-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[3,4-b]pyridine 160 in 65 mg quantity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].COC1C=C(C=CC=1OC)C=O.C(N)(C)C.[OH-].[Na+].[Cl:34][CH:35]([Cl:39])[C:36](Cl)=[O:37]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:6][N:7]([CH:8]([CH3:10])[CH3:9])[C:36](=[O:37])[CH:35]([Cl:39])[Cl:34]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: COc1ccc(CNC(C)C)cc1OC
Agent: COc1ccc(C=O)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)N
Solvent: Cc1ccccc1
Product: COc1ccc(CN(C(=O)C(Cl)Cl)C(C)C)cc1OC
Temperature: 0 °C

Procedure:
A mixture of 126 g N-(3,4-dimethoxybenzyl)-N-isopropyl amine (prepared by condensing 3,4-dimethoxybenzaldehyde and isopropylamine and hydrogenating the conversation product b.p. 77.5°-77.8°/0.03 mbar) and 250 ml of toluene is stirred in a 750 ml 4-neckflask until the amine is dissolved. Then 120 g of 20% sodium hydroxide is added thereto and the reaction-mixture is cooled in a CO2 /alcohol bath to a temperature of -10°/-15°. A mixture of 89 g of dichloroacetic acid chloride in 100 ml of toluene is then added dropwise while stirring to the cold reaction mixture. A white precipitate forms immediately. When everything is added, what takes about 11/2hours, the cooling bath is removed and the reaction mixtured is stirred until room temperature has been reached. Then it is poured into an ice-water mixture. The phases are separated and the water-phase is extracted with toluene. The organic layer is then washed twice with 1N hydrochloric acid and twice with water, dried and concentrated. There remain 176 g (91.7% of the theory) or a clear sticky oil with a refraction index of nD22 1.5495 which eventually crystallizes m.p. 69°-72°.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH2:5][CH2:6][NH2:7].[CH3:11]O>>[ClH:1].[CH3:11][O:9][C:8](=[O:10])[C@H:3]([CH2:4][CH2:5][CH2:6][NH2:7])[NH2:2]
Reactant: NCCC[C@H](N)C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H](N)CCCN
Reaction time: 8 h
Yield: 97 %

Procedure:
Into a stirred suspension of L-(+)-ornithine hydrochloride (Aldrich) in methanol was bubbled anhydrous hydrochloric acid gas until the solution was saturated. The reaction mixture was capped with a rubber septum and stirring was continued overnight at room temperature. The solvent was then stripped under reduced pressure and the residue triturated with ether. The resulting solid was dried under reduced pressure to afford L-(+)-ornithine methyl ester hydrochloride as a white solid (97% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:26](OCC)[O:27]CC)=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:26]=[O:27])=[C:5]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C(OCC)OCC)=C(C(=O)OCC)C1c1ccccc1OC
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1OC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of diethyl 2-methyl-4-(2-methoxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (447.5 mg) in acetone (7.5 ml) was added 6 N-hydrochloric acid (0.2 ml) and stirred at room temperature for an hour. The resultant mixture was treated in a similar manner to Example 2-4), to give reddish yellow crystals of diethyl 2-methyl-4-(2-methoxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (373.2 mg). The product was recrystallized from a mixture of diethyl ether and n-hexane to give the pure product, m.p. 111° to 112° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[OH-].[NH4+:14]>C(Cl)Cl>[NH2:14][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1
Reactant: Clc1cc(-n2cccn2)ncn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cc(-n2cccn2)ncn1

Procedure:
In sealed tube, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine and 2.5 ml of concentrated ammonium hydroxide were warmed at 140° C. for 30 hours. The reaction mixture was dissolved in methylene chloride, and washed with water. The organic fraction was dried over anhydrous sodium sulfute, and distilled off. A residue was recrystallized from methanol to yield 148 mg of 6-amino-4-(1-pyrazolyl)pyrimidine, a flaking crystal having a melting point of 236.5°-237° C.,
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[O:11][N:10]=2)[CH2:3]1.[O:21]1[CH2:23][C@H:22]1[CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[CH:35]=1>C(O)(CC)(C)C>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([CH2:8][N:4]2[CH2:5][CH2:6][N:7]([CH2:23][C@@H:22]([OH:21])[CH2:24][O:25][C:26]3[CH:27]=[CH:28][C:29]4[S:33][C:32]([CH3:34])=[N:31][C:30]=4[CH:35]=3)[C@@H:2]([CH3:1])[CH2:3]2)[CH:13]=1
Reactant: Cc1nc2cc(OC[C@@H]3CO3)ccc2s1
Reactant: C[C@H]1CN(Cc2cc(-c3ccccc3F)on2)CCN1
Solvent: CCC(C)(C)O
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(Cc4cc(-c5ccccc5F)on4)C[C@@H]3C)ccc2s1
Temperature: 95 °C
Reaction time: 24 h

Procedure:
To a solution of 3-[((3S)-3-methylpiperazinyl)methyl]-5-(2-fluorophenyl)isoxazole (28 mg, 0.10 mmol) in tert-amyl alcohol (5 mL) was added 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole (22 mg, 0.10 mmol). The reaction mixture was stirred at 95° C. for 1 day. It was then cooled, concentrated, and purified by preparative chromatography (1:19 methanol:methylene chloride) to afford (2R)-3-((2S)-4-{[5-(2-fluorophenyl)isoxazol-3-yl]methyl}-2-methylpiperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol (M+1=497.27).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][C:3]=1[O:13][CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:13][CH3:14])=[C:2]([F:1])[CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2cc[nH]c(=O)c2cc1F
Product: COc1cc2ccnc(Cl)c2cc1F
Yield: 55 %

Procedure:
A solution of 7-fluoro-6-methoxyisoquinolin-1(2H)-one (3.1 g, 16.05 mmol) in POCl3 (25 ml) was refluxed for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with cold water. The aqueous solution was basified by solid sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography (20% ethyl acetate in pet ether) to get desired compound (1.9 g, 55%) as off-white solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.22-8.20 (d, J=8 Hz, 1H), 7.97-7.94 (m, 1H), 7.49-7.48 (m, 1H), 7.18-7.16 (d, J=8 Hz, 1H), 4.04 (s, 3H); MS: MS m/z 211.7 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH:17]1[CH2:20][CH2:19][CH2:18]1)[C:7]2=[O:21].[CH3:22][C@@H:23]1[C:27]2[NH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:26]=2[C:25](=[O:40])[NH:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO.C(Cl)Cl>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[C:13]([NH:12][C:9]1[N:8]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:7](=[O:21])[C:6]2[C:11](=[C:2]([C:29]3[NH:28][C:27]4[C@@H:23]([CH3:22])[NH:24][C:25](=[O:40])[C:26]=4[CH:30]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1C1CCC1
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C5CCC5)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 45 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of 8-bromo-2-(tert-butylamino)-3-cyclobutylquinazolin-4(3H)-one (254.1 mg, 0.725 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Example 705; 238 mg, 0.907 mmol), potassium phosphate (462 mg, 2.176 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos precatalyst, 2nd generation; Aldrich; 28.6 mg, 0.036 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (0.750 mL) was stirred under argon at 45° C. for 1 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide (R)-2-(tert-butylamino)-3-cyclobutyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (206.3 mg, 0.509 mmol, 70% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, s), 7.87 (1H, dd, J=7.7, 0.9 Hz), 7.80 (1H, dd, J=7.7, 0.9 Hz), 7.61 (1H, s), 7.13 (1H, t, J=7.7 Hz), 6.72 (1H, s), 5.81 (1H, s), 4.48-4.64 (2H, m), 2.63 (2H, td, J=11.3, 5.0 Hz), 2.01-2.18 (2H, m), 1.56-1.70 (2H, m), 1.48 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 406.0 (M+H)+.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[ClH:17].[CH3:18]O>O1CCOCC1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:18])=[O:8].[ClH:17]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCC(=O)N1

Procedure:
N-Boc-Pyr-OH (5 g, 23.45 mmol) was dissolved in MeOH (50 ml), and HCl in dioxane (4N, 30 ml) was added. After refluxing for 12 h, the solvent was removed in a rotary evaporator and H-Pyr-OMe hydrochloride was obtained as product. Yield: 3.84 g (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:14][OH:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1-c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-[1,1′-biphenyl]-2-yl)methanol (2.0 g, 8.4 mmol) in CH2Cl2 (30 mL) was added Dess-Martin Periodinane (4.3 g, 10 mmol). The reaction mixture was stirred at RT for 2 h and then the solids were filtered and the resultant filtrate was concentrated in vacuo. Purification by normal phase silica gel column (EtOAc:PE=1:50) afforded 5-bromo-[1,1′-biphenyl]-2-carbaldehyde as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH3:24][Li].Cl>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][C:19]([OH:23])([CH3:24])[CH:20]([CH3:21])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)C(C)(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: -50 °C

Procedure:
40 ml of tetrahydrofuran was added to a flask that had been dried overnight at 100° C. in vacuo and 4.5 g (0.0134 mole) of the ketone of Example 12 was added. All processes were done under an argon atmosphere. The solution was cooled to about -50° C. in a dry ice/acetone bath and 19.16 ml (0.026 mole) of 1.4 M methyl lithium in tetrahydrofuran was added dropwise maintaining the temperature to about -60° C. to -50° C. When addition was complete, the reaction mixture was warmed to about 0° C. and 1 N hydrochloric acid was added. The reaction mixture was extracted three times with ethyl acetate, the extracts combined, washed with water twice, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was chromatographed on silica to give the title compound identical with that of Example 15.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].[C:8]([O:11]CC)(=[O:10])[CH3:9].C([O-])(=O)C.[Na+]>O>[C:8]([O-:11])(=[O:10])[CH3:9].[C:2]([NH2+:6][OH:7])([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)[NH2+]O
Yield: 92.1 %

Procedure:
N-tert-Butylhydroxylamine hydrochloride (19.7 g, 98%, 0.15 mol) was dissolved in water (40 g) at +20° C. Ethyl acetate (118 g) and sodium acetate (19.3 g, 0.24 mol, 1.5 equiv.) were added. A slurry was formed initially but then dissolved. After 2 h the bluish organic phase was separated and concentrated giving an opaque, yellow oil (20.6 g, 88%) that solidified upon standing in the refrigerator. Chromatographic purity (GC): 97.0 area %.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[CH:31](OC)[N:32]([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[C:17]([N:18]=[CH:31][N:32]([CH3:34])[CH3:33])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27][CH3:28])=[C:13]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N=CN(C)C)cc2cc1OCc1ccccc1
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 87.4 %

Procedure:
In a round bottom flask containing 10 mL of toluene is added 3-amino-6-benzyloxy-7-methoxynaphthalene-2-carboxylic acid tert-butyl ester (3.0 g, 7.9 mmol) and dimethylformamide dimethyl acetal (5.4 mL, 31.6 mmol) under a positive nitrogen flow. The mixture is stirred at 120° C. for 1.5 hour, then cooled to room temperature. The volatiles are removed under reduced pressure and the resulting residue dried in vacuo for 15 h to yield 3.0 g of 6-benzyloxy-3-(dimethylamino-methyleneamino)-7-methoxy-naphthalene-2-carboxylic acid tert-butyl ester as a dark oil.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:31])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:33][C:34]#[N:35])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:31])[C:15]([C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH3:26])[C:18]=1[CH2:27][CH2:28][CH2:29][CH3:30])=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(O)ccc3c2)c2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)c2ccccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
A mixture of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.09 g, 4.36 mmol), prepared in the previous step, bromoacetonitrile (364 μL, 5.23 mmol) and potassium carbonate (3.01 g, 21.8 mmol) in 50 mL of DMF was stirred under nitrogen at room temperature for 16 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.00 g, 88%) as a brown solid foam, MS m/z: 518 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:14]([C:19](=O)[CH3:20])[C:15]([O:17][CH3:18])=[O:16].[NH2:22][C:23]([CH3:33])=[CH:24][C:25](=[O:32])[CH2:26][CH2:27][CH:28]1[CH2:31][CH2:30][CH2:29]1>C(O)C>[CH:28]1([CH2:27][CH2:26][C:25]([C:24]2[CH:13]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[O:3][C:2]([CH3:1])=[CH:11][C:10]4=[O:12])[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:19]([CH3:20])[NH:22][C:23]=2[CH3:33])=[O:32])[CH2:29][CH2:30][CH2:31]1
Reactant: CC(N)=CC(=O)CCC1CCC1
Reactant: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)CCC2CCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
50 mg (0.175 mmol) of methyl 2-[(2-methyl-4-oxo-4H-chromen-8-yl)methylene]-3-oxobutanoate are dissolved with 38 mg (0.227 mmol) of 5-amino-1-cyclobutylhex-4-en-3-one in 3 ml of ethanol and heated under reflux under argon for 24 h. The reaction mixture is purified by preparative HPLC. Concentration of the fractions results in 43 mg (56% of theory) of the title compound as a white solid.