Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]([CH3:30])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[NH2:24]>>[CH3:22][C:23]([NH:24][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:25]1[S:26][CH:27]=[CH:28][N:29]=1)[CH3:30]
Reactant: O=C(O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1nccs1
Product: CC(C)(NC(=O)c1ccc(C2CCCO2)c(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-(tetrahydro-furan-2-yl)-pyridine-2-carboxylic acid (Example 125 b) and α,α-dimethyl-2-thiazolemethanamine (CAN 1082393-38-1) as starting materials, MS (EI): m/e=428.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.C(OC([NH:40][C@H:41]([C:46](O)=O)[C:42]([CH3:45])([CH3:44])[CH3:43])=O)(C)(C)C>>[ClH:28].[NH2:40][C@@H:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:46][N-:2][C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:32])[F:30])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CC(C)(C)[C@H](N)C[N-]c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride and tert-butoxycarbonyl-L-tert-butylglycine by using the same method as in Example 96.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=[C:8]([O:23][CH3:24])[CH:7]=1)=[O:5].[CH3:26][Li].Cl>C1COCC1>[CH3:24][O:23][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH3:26])[C:14]2[O:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:9]=1
Reactant: [Li]C
Reactant: COc1ccc(-c2cc3cc(OC)cc(C(=O)N(C)OC)c3o2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(OC)cc(C(C)=O)c3o2)cc1
Reaction time: 1 h
Yield: 67 %

Procedure:
To a cooled (−78° C.) solution of 121 (0.6 g, 1.7 mmol) in THF (10 ml) was added Methyl lithium (3.4 ml of 1.0M in THF) and the reaction was stirred for 1 hr. The solution was then poured into 2 N HCl and extracted with EtOAc which was separated, dried over MgSO4, and concentrated to give a solid which was triturated with MeOH and collected by filtration to give 122 as a white solid (0.35 g, 67%); 1H NMR (CDCl3) δ 7.78(d, 2 H, J=8.7 Hz), 7.44 (d, 1 H, 2.6 Hz), 7.24 (s, 1 H), 6.99 (d, 2 H, J=8.7 Hz), 6.89 (s, 1 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 2.96 (s, 3 H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=3)[C:4]=2[CH:3]=1.[C:18]([C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1)([CH3:20])=[CH2:19].O.C([O-])(=O)C.[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:17][C:13]1[N:12]=[C:11]([N:10]2[C:4]3[CH:3]=[C:2]([C:25]4[CH:24]=[N:23][CH:22]=[C:21]([C:18]([CH3:20])=[CH2:19])[CH:26]=4)[N:7]=[CH:6][C:5]=3[CH:8]=[N:9]2)[CH:16]=[CH:15][CH:14]=1
Reactant: Fc1cccc(-n2ncc3cnc(Cl)cc32)n1
Reactant: C=C(C)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: C=C(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Temperature: 150 °C

Procedure:
A mixture of 6-chloro-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (1.759 mmol; 437.3 mg), 3-isopropenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.638 mmol; 646.6 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.1759 mmol; 147 mg), potassium acetate hydrate (2.638 mmol; 1.3 mL) and sodium carbonate (2.638 mmol; 1.3 mL) in Acetonitrile (10 mL) in a pressure tube was heated under microwave at 150° C. for 5 min. The mixture was cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was concentrated. The residue was purified on silica eluted with 0 to 6% MeOH in DCM to afford 1-(6-fluoro-2-pyridyl)-6-(5-isopropenyl-3-pyridyl)pyrazolo[4,3-c]pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.Cl[C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1>>[CH3:20][NH:19][C:17]([C:13]1[CH:12]=[C:11]([O:8][C:6]2[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=2[CH3:9])[NH2:1])[CH:16]=[CH:15][N:14]=1)=[O:18]
Reactant: Cc1ccc(N)cc1O
Reactant: CNC(=O)c1cc(Cl)ccn1
Product: CNC(=O)c1cc(Oc2cc(N)ccc2C)ccn1

Procedure:
Entry 18: According to Method A2, Step 4, 5-amino-2-methylphenol was reacted with 4-chloro-N-methyl-2-pyridinecarboxamide, which had been synthesized according to Method A2, Step 3b, to give 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 5-(Trifluoromethyl)-2-methoxyphenyl isocyanate was reacted with 3-(2-(N-methylcarbamoyl)-4-pyridyloxy)-4-methylaniline according to Method C1a to afford the urea.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 2 h
Yield: 94.8 %

Procedure:
1-(Bromomethyl)-4-nitrobenzene (1.08 g, 5.00 mmol) was added to a vigorously stirred mixture of tert-butyl piperazine-1-carboxylate (1.02 g, 5.50 mmol) and sodium carbonate (0.583 g, 5.50 mmol) in DMF (5 mL) at room temperature and the resulting mixture stirred for two hours. Water (25 mL) was added, and the resulting suspension was allowed to stand for five minutes then filtered. The collected solid was washed with water (25 mL) and air-dried to give the title compound (I92) (1.523 g, 95% yield); 1H NMR (400 MHz, CDCl3) δ 8.32-8.10 (m, 2H), 7.51 (d, J=8.8 Hz, 2H), 3.59 (s, 2H), 3.52-3.39 (m, 4H), 2.43-2.34 (m, 4H), 1.45 (s, 9H). LCMS Method C: rt 4.58 min, m/z 266.1 [M-tBu+2H]+, 222.1 [M-Boc+2H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:10]=1.[NH2:37][C:38]1[C:46]([F:47])=[CH:45][C:44](I)=[CH:43][C:39]=1[C:40]([OH:42])=[O:41].C(=O)(O)[O-].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[NH2:37][C:38]1[C:46]([F:47])=[CH:45][C:44]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=4)(=[O:28])=[O:29])[C:12]3=[N:13][CH:14]=2)=[CH:43][C:39]=1[C:40]([OH:42])=[O:41]
Reactant: Nc1c(F)cc(I)cc1C(=O)O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])O
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(N)c(C(=O)O)c3)cc12
Yield: 78.6 %

Procedure:
163 mg (0.323 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine, 13 mg (0.016 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct, and 100 mg (0.356 mmol) of 2-amino-3-fluoro-5-iodo-benzoic acid were placed in a microwave vial. To the vial were added 2 mL of acetonitrile and 2 mL of a saturated aqueous solution of sodium bicarbonate. The vial was sealed and purged with nitrogen and evacuated with vacuum (3×). The vial was irradiated in a microwave at 90° C. for 300 seconds. The resulting mixture was diluted with ethyl acetate and washed with water. The aqueous layer was back extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes. The clean fractions were concentrated to afford 135 mg (0.254 mmol, 78% yield) of 2-amino-3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid as a brown residue. MS: m/z 532.0 (M+H+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][C:16](OC)=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>ClCCl>[CH2:1]([O:4][C:5]1[C:6]([CH2:20][CH3:21])=[C:7]([CH2:15][CH2:16][OH:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(CC(=O)OC)c(CC)c(OCC=C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=CCOc1cc(CCO)c(CC)c(OCC=C)c1
Temperature: -78 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
Methyl 3,5-diallyloxy-2-ethylphenylacetate (0.84 g, 2.9 mmol) obtained in Example 5, Step 3 was dissolved in dichloromethane (15 mL). After the solution was cooled to −78° C. in an atmosphere of nitrogen, a 1.0 mol/L solution of diisobutylaluminum hydride in toluene (8.4 mL, 8.4 mmol) was added dropwise thereto, followed by stirring at −78° C. for 4 hours. To the reaction mixture was added a saturated aqueous solution of potassium sodium tartrate (50 mL), and the mixture was stirred at room temperature for 3 hours and then extracted with ethyl acetate (0.10 L×2). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/9-1/1) to obtain 2-(3,5-diallyloxy-2-ethylphenyl)ethanol (0.74 g, 97%). 1H-NMR (CDCl3, 270 MHz) δ (ppm): 6.37 (brs, 2H), 6.11-5.98 (m, 2H), 5.47-5.35 (m, 2H), 5.30-5.23 (m, 2H), 4.52-4.49 (m, 4H), 3.82 (q, J=6.8 Hz, 2H), 2.88 (t, J=6.8 Hz, 2H), 2.64 (q, J=7.4 Hz, 2H), 1.10 (t, J=7.4 Hz, 3H)
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]3=[O:22])[CH2:5][CH2:4]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)=[CH:43][C:42]=1O>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:2][N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[O:17][C:16]([C:19]([NH:40][C:41]2[CH:42]=[CH:43][C:44]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:45][CH:46]=2)=[O:20])=[CH:15][C:14]3=[O:22])[CH2:7][CH2:8]1
Reactant: CN1CCN(c2cccc3c(=O)cc(C(=O)O)oc23)CC1
Reactant: Nc1ccc(N2CCOCC2)cc1O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c(=O)cc(C(=O)Nc4ccc(N5CCOCC5)cc4)oc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
8-(4-methyl-1-piperazinyl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 1) (400 mg, 1.23 mmol) was suspended in anhydrous N,N-dimethylformamide (20 ml) and triethylamine (0.69 ml, 4.92 mmol) was added to give a clear solution. The following were added in order: 1-hydroxybenzotriazole (HOBt (205 mg, mol)), O-(1H-Benzotriazol-1-yl)-N,N,N′,N′-pentamethylene-uronium tetrafluoroborate (TBTU (435 mg, 3.1 mmol)) then 4-(dimethylamino)pyridine (25 mg). After stirring for 5 min at room temperature, 4-(4-morpholinyl)Aniline (Reference Example 21) (220 mg, mmol). The reaction stirred overnight at room temperature. The solution was concentrated in vacuo, the remains were partitioned between chloroform/saturated sodium bicarbonate, extracted (×3) with chloroform, dried (MgSO4) and concentrated in vacuo to give the crude product.
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH2:38]([OH:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[H-].[Na+].Cl>CN(C=O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([O:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:21]=1
Reactant: OCc1ccccc1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(OCc3ccccc3)nc(N)nc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 500 mL of dry round-bottomed flask were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (6, 8.0 g, 15.2 mmol) and anhydrous benzyl alcohol (128 mL). To another 250 mL of dry round-bottomed flask were charged NaH (60% in mineral oil, 2.44 g, 60.8 mmol) and anhydrous DMF (40 nth). The suspension was stirred at 0° C. in an ice-water bath. Benzyl alcohol (27 mL) was added drop-wise via a syringe. A solution was slowly formed and it was transferred to the nucleoside suspension quickly under a nitrogen atmosphere at room temperature. The mixture was heated to 50° C. and stirred. The reaction was complete after 3 h and cooled to ambient temperature. It was neutralized by the addition of 4 N HCl to ca. pH=7 (12 mL). The solution was concentrated under reduced pressure (4 mbar, 90° C. bath). The cloudy residue was diluted with dichloromethane (100 mL) and washed with water (3×30 mL), brine (30 mL) and dried over Na2SO4. The suspension was filtered and the filtrate was concentrated under reduced pressure to an oily residue. This was purified by column chromatography (Analogix, 0 to 8% gradient of MeOH in DCM). The product eluted at 4% MeOH in DCM. The product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a white foam solid (4.57 g, 11.7 mmol, 77.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([O:21]C(OC(C)(C)C)=O)=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(C(=O)OC(C)(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc(O)cn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 4-[tert-butoxycarbonyl-(5-tert-butoxycarbonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (6.75 g, 13.7 mmol, 1.0 equiv) in a mixture of THF/methanol (1:1) (100 mL) at 3° C. was added drop by drop a solution of 1 M LiOH (34.2 mL, 34.5 mmol, 2.5 equiv) and after the addition was completed the mixture warmed up to rt. After 18 h, the reaction mixture was poured into cold water and extracted three times with dichloromethane. The combined organic layers were washed with brine and water, dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 4.31 g (80%) of the title compound as orange foam. MS (ISP): =394.1 [M+H]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2([CH:22](B(O)O)[CH2:21][CH2:20][CH2:19]2)[C:11]1=[O:26].C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>COCCOC.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>[C:5]([C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[NH:10][C:11](=[O:26])[C:12]23[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: O=C1Nc2ccccc2C12CCCC2B(O)O
Reactant: N#Cc1cccc(Br)c1
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
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)C2(CCCC2)C(=O)N3)c1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 3-bromobenzonitrile (0.5 g, 2.6 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycol dimethyl ether (20 cm3) was stirred under N2 for 20 minutes. To this mixture was then added (spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl)boronic acid (0.9 g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm3). The solution was brought to reflux for 18 hours and then cooled to room temperature, poured into 2N NaOH and extracted with EtOAc (×3). The combined extracts were washed with water, brine, dried (MgSO4), and evaporated. The residue was purified by column chromatography (SiO2, EtOAc, hexane) to afford the title compound (0.30 g, 40%) as an off-white solid. mp: 217-219° C.; 1H NMR (DMSO-d6) δ 10.4 (s, 1H), 8.2 (s, 1H), 8.0 (d, 1H, J=8.1 Hz), 7.8 (d, 1H, J=7.7 Hz), 7.6 (m, 2H), 7.5 (dd, 1H, J=1.8, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0-1.9 (m, 8H); MS [M−H]−=287.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[C:6]([O:8]C)=[O:7].Cl.O>[OH-].[Na+].CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
A mixture of methyl 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoate (16.0 g) in 2N aqueous sodium hydroxide solution (65 mL) and methanol (100 mL) was stirred at room temperature for 1 hr, and the mixture was acidified with 6N hydrochloric acid (pH=3-4). Water was added to the reaction mixture, and the precipitate was collected by filtration. The solid was washed with ethyl acetate and water to give the title compound (8.07 g). To the filtrate was added saturated brine, and the mixture was extracted with ethyl acetate/2-propanol. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (4.10 g).
Reaction SMILES: [F-].[Cs+].Cl[C:4]1[N:9]=[N:8][C:7]([C:10]2[N:19]=[C:18]3[C:13]([C:14]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)=[C:6]([C:31]([F:34])([F:33])[F:32])[CH:5]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C([O-])(O)=O.[Na+]>CN(C)C(=O)C.CCOC(C)=O.CS(C)=O>[N:35]1([C:4]2[N:9]=[N:8][C:7]([C:10]3[N:19]=[C:18]4[C:13]([C:14]([NH:20][C:21]5[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=5)=[CH:15][CH:16]=[N:17]4)=[CH:12][CH:11]=3)=[C:6]([C:31]([F:34])([F:33])[F:32])[CH:5]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4nnc(Cl)cc4C(F)(F)F)ccc23)nc1
Agent: O=C([O-])O
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc(Nc2ccnc3nc(-c4nnc(N5CCOCC5)cc4C(F)(F)F)ccc23)nc1
Temperature: 80 °C

Procedure:
Place CsF (50 mg, 0.33 mmol) in an empty flask. Dissolve 7-[6-chloro-4-(trifluoromethyl)pyridazin-3-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-1,8-naphthyridin-4-amine (19 mg, 0.04 mmol) in N,N-dimethylacetamide (0.2 mL) and add to the CsF. Next, add a solution of morpholine (0.2M toluene, 0.24 mL) and DMSO (0.2 mL). Heat the mixture overnight at 80° C. Cool to room temperature and add EtOAc (1 mL) and sat. NaHCO3 (aq) (1 mL). Extract the organic layer and place directly on an SCX ion-exchange column. First, wash the column with EtOAc/MeOH (90/10). Discard this solution. Wash the column with EtOAc/MeOH/N(Et)3 (90/10/5). Collect and evaporate the wash to yield the title compound. 1H NMR (CDCl3) δ 9.59 (s, 1H), 9.43 (br s, 1H), 9.10 (d, 1H), 8.90 (d, 1H), 8.72 (br s, 1H), 7.90 (dd, 1H), 7.30 (s, 1H), 7.15 (d, 1H), 3.93 (m, 2H), 3.89 (m, 2H). LC/MS (MH+) 523.01. The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][O:19][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccncc1
Temperature: 80 °C
Yield: 35 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-phenoxyquinazoline (95 mg, 0.35 mmol), 4-chloromethyl pyridine hydrochloride (120 mg, 0.74 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (5 ml) were heated at 80° C. for 2 hours. The reaction mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×50 ml). The combined extracts were then washed with water and dried (MgSO4). The solvent was removed by evaporation and the residue trituated with an ethyl acetate/hexane mixture to give 6-methoxy-4-phenoxy-7-(4-pyridylmethoxy)quinazoline (44 mg, 35%) as a white solid. 1H NMR Spectrum: (DMSOd6) 4.02(s, 3H); 5.47(s, 2H); 7.25-7.35(m, 3H); 7.45(s, 1H); 7.4-7.55(m, 4H); 7.62(s, 1H); 8.52(s, 1H); 8.63(dd, 2H) MS-ESI: 360 [MH]+
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][NH:17][N:16]=3)=[N:8][C:4]=2[CH:3]=1.[C:26]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:19]=[CH:18][N:17]([CH3:26])[N:16]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nc[nH]n2)nc2cc(Br)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a vial is added 5-bromo-1-tert-butyl-2-[2-(1H-[1,2,4]triazol-3-yl)-phenyl]-1H-benzimidazole (100 mg, 0.252 mmol) in DMF (1.5 mL), followed by the addition of K2CO3 (70 mg, 0.504 mmol) and MeI (60 mg, 0.423 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with EtOAc, washed with water, brine, dried using anhydrous Na2SO4 and filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 0-3% 7M NH3 in MeOH/CH2Cl2 as the eluent to afford 5-bromo-1-tert-butyl-2-[2-(1-methyl-1H-[1,2,4]-triazol-3-yl)-phenyl]-1H-benzimidazole (37 mg, 36%) as a light brown solid. LCMS (ESMS): m/z 410.58, 412.51 (M++1)