Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O:19][C:20]1[CH:28]=[C:27]([O:29][C:30](=O)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:19][C:20]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:23])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Oc1ccc(C(=O)O)c(OC(=O)c2ccccc2)c1)c1ccccc1
Reactant: NCCCN1CCCCC1
Product: O=C(NCCCN1CCCCC1)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 94.8 %

Procedure:
Condensation between 1-(3-aminopropyl) piperidine (427 mg) and 2,4-dibenzoyloxybenzoic acid (1.0 g) is carried out in the same manner as in Example 7, i) to yield 1-[3-(2,4-dibenzyloxybenzoyl)aminopropyl]piperidine (1.2 g).
Reaction SMILES: [C:1]1(=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>C(Cl)(Cl)Cl>[Cl:14][S:10]([C:6]1[CH:7]=[CH:8][C:3]2[CH2:2][C:1](=[O:9])[C:4]=2[CH:5]=1)(=[O:12])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C1Cc2ccc(S(=O)(=O)Cl)cc21
Reaction time: 5 h

Procedure:
Benzocyclobutenone (2.36 g, 0.02mol) was added slowly to a strongly stirred chlorosulfuric acid (3 mL) in chloroform (10 mL) solution. After the addition was done, the reaction mixture was stirred for 5 hours. Then the chloroform was evaporated, and the residue was precipitated in water yielding fine pink crystals. m.p. 80° C.; IR (KBr, cm−1): 1762; UV (λmax, methanol) 272 nm.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Cl.[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(=[NH:9])[NH2:8].N12CCCCC1C=NCCC2>C(#N)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:8]=[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[N:9]=1
Reactant: N=C(N)CCCCN1C(=O)c2ccccc2C1=O
Reactant: C=C(Cl)C#N
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Product: Nc1ccnc(CCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A solution of 2-chloroacrylonitrile (1.75 g.) in acetronitrile (10 ml.) was added over 15 minutes to an ice-cooled mixture of 1-amidino-4-phthalimidobutane hydrochloride (5.64 g.), acetonitrile (50 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (6.08 g.). The mixture was stirred for a further two hours and then evaporated to dryness. The residue was treated with water (50 ml.) and the mixture extracted with ethyl acetate (2×50 ml.). The combined ethyl acetate extracts were extracted with N hydrochloric acid (3×30 ml.) and the combined aqueous extracts neutralised with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extracts were evaporated to dryness and the residue recrystallised from acetonitrile to give 4-amino-2-(4-phthalimidobutyl)pyrimidine (2.5 g.), m.p. 139°-140°.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][C:8]1[N:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18]3[CH:29]=[CH:28][C:21]([C:22]([NH:24][CH:25]4[CH2:27][CH2:26]4)=[O:23])=[CH:20][C:19]=3[O:30][CH3:31])[CH:14]=2)[N:9]=1.[C:32](O)(=[O:35])[C:33]#[CH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[CH:25]1([NH:24][C:22](=[O:23])[C:21]2[CH:28]=[CH:29][C:18]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]=[C:8]([NH:7][C@@H:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[NH:1][C:32](=[O:35])[C:33]#[CH:34])[N:17]=[CH:16]4)=[C:19]([O:30][CH3:31])[CH:20]=2)[CH2:27][CH2:26]1
Reactant: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3N)ncc2c1
Reactant: C#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N[C@H]1CCC[C@H]1Nc1ncc2cc(-c3ccc(C(=O)NC4CC4)cc3OC)ccc2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.8 %

Procedure:
A mixture of 4-(2-(((1R,2S)-2-aminocyclopentyl)amino)quinazolin-6-yl)-N-cyclopropyl-3-methoxybenzamide (0.11 mmol), propiolic acid (0.010 mL, 0.17 mmol), HATU (64 mg, 0.17 mmol) and DIEA (0.06 mL, 0.34 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 45 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was purified by silica gel chromatography to yield N-cyclopropyl-3-methoxy-4-(2-(((1R,2S)-2-propiolamidocyclopentyl)amino)quinazolin-6-yl)benzamide (Compound 13) (35 mg, 69%). MS (ES+) C27H27N5O3 requires: 469, found: 470 [M+H]+.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]#[C:14][C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)[CH:30]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]>CCOC(C)=O.CO.[Pd]>[C:1]([C:4]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][CH2:14][C:15]2[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=[C:17]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:33][CH2:32]4)[CH:30]=3)[N:16]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 4-(4-((4-((2-(1-carbamoylcyclopropyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A76 (0.405 g, 0.680 mmol) and 10% Pd/C (wetted with ca. 53% water, 0.200 g) in EtOAc (30 mL) and MeOH (15 mL) was stirred under an atmosphere of H2 at room temperature for 16 hours. The mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo. Purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-10% MeOH in DCM) gave a yellow oil which was further purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 10-90% EtOAc in petroleum benzine 40-60° C.) to give the title compound A77 as a yellow solid (0.213 g, 52%). LCMS-D: rt 3.62 min; m/z 600 [M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[N:13]=[C:12]2[NH:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1)(=O)=O.[NH:34]([CH3:36])[CH3:35]>CO>[ClH:33].[ClH:33].[Cl:33][C:28]1[CH:27]=[C:26]([NH:25][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([CH2:8][CH2:7][CH2:6][N:34]([CH3:36])[CH3:35])[CH:10]=3)[N:15]=[C:14]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[N:13]=2)[CH:31]=[CH:30][C:29]=1[F:32]
Reactant: CNC
Reactant: CS(=O)(=O)OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Solvent: CO
Product: CN(C)CCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Product: Cl
Temperature: 150 °C
Yield: 24 %

Procedure:
(This method is representative of method G4 and G5. These two methods can be implemented in a similar way except for substitution of the appropriate solvent and temperature) A solution of 3.-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate (40 mg, 82 mmol) and 40% Me2NH aqueous (1 mL) in methanol (2 mL) was placed in a microwave reaction vial. The mixture was heated under microwave irradiation conditions at 150° C. for 30 minutes after which the solvent was removed in vacuo. The crude product was obtained, which was purified by column chromatography on basic silica gel (eluted with ethyl acetate/methanol 1:0→5:1). The HCl salt generated by 4 M HCl in dioxane was crystallized from 2-propanol to give 10 mg of N-(3-chloro-4-fluorophenyl)-6-(3-(dimethylamino)propyl)-2-(pyridin-3-yl)quinazolin-4-amine dihydrochloride as pale brown powder (24%). LCMS m/z=436 (M+1) (Method C) (retention time=1.68 min). 1H NMR (300 MHz, DMSO) δ 10.59 (s, 1H), 10.18 (s, 1H), 9.51 (s, 1H), 8.98-8.76 (m, 2H), 8.65 (s, 1H), 8.26 (dd, J=6.8, 2.6 Hz, 1H), 8.05-7.74 (m, 4H), 7.54 (t, J=9.1 Hz, 1H), 3.19-3.03 (m, 2H), 2.97-2.83 (m, 2H), 2.78 (s, 3H), 2.77 (s, 3H), 2.16 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a suspension of 4-bromophenylacetic acid (2.15 g) and potassium carbonate (2.76 g) in N,N-dimethylformamide (15 mL) was added methyl iodide (0.94 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1-5/1) to give methyl 4-bromophenylacetate (2.09 g). This material was dissolved in tetra hydrofuran (50 mL). To the solution was added methylmagnesium bromide (3.0 mol/L diethyl ether solution, 7.0 mL) under ice-cooling, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added 1 mol/L hydrochloric acid (30 mL), and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1-2/1) to give 1-bromo-4-[2-hydroxy-2-(methyl)propyl]benzene (1.58 g) This material was dissolved in N,N-dimethylformamide (20 mL) To the solution was added 55% sodium hydride (0.32 g) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. To this mixture were added benzyl bromide (0.98 mL) and tetra(n-butyl)ammonium iodide (0.51 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=99/1-95/5) to give 4-[2-benzyloxy-2-(methyl)propyl]-1-bromobenzene (1.2 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 46 using this material instead of 1-bromo-2-fluoro-4-methoxy-benzene.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]([CH2:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][CH2:36]O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:39]>ClCCl>[Br:39][CH2:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][CH2:27][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCOCCOCCCOc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOCCOCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
Triphenylphosphine (2.01 g) in dry dichloromethane (16 ml) was added dropwise over 20 min to a stirred solution of 3-[2-(3-phenoxypropoxy)ethoxy]-1-propanol (1.5 g), and carbon tetrabromide (2.54 g) in dry dichloromethane (27 ml) at 0° C. under nitrogen. The solution was allowed to warm to room temperature and stirred under nitrogen for 4 h. The solution was purified by FCC eluting with System F (4:1) to give the title compound (1.75 g) as a colourless oil. T.l.c. (System F 1:1) Rf 0.55
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].[C:11]([O-:14])([O-])=O.[Cs+].[Cs+].CI.CC(C)=[O:21]>>[OH:21][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CC(C)=O
Reactant: CC(O)c1ccccc1O
Agent: [Cs+]
Solvent: CI
Product: COc1ccccc1CCO
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 10 g of 2-(2-hydroxyphenyl-ethanol in 200 ml of acetone there are added 35.3 g of Cs2CO3 and then a solution of 6.5 ml of methyl iodide in 40 ml of acetone. The reaction mixture is stirred for 50 minutes at room temperature, is filtered and is concentrated by evaporation. The residue is partitioned between diethyl ether and water. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (dichloromethane/diethyl ether=97:3), yielding the title compound; Rf (dichloromethane/diethyl ether=97:3)=0.34; HPLC Rt =9.31 minutes.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][Cl:14])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].C1C[O:20][CH2:19]C1>CO>[Cl:14][CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][CH2:8][CH2:9]1.[CH3:19][O:20][CH2:13][CH2:12][CH2:11][CH2:10][C:5]1([C:3]([OH:2])=[O:4])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: C1CCOC1
Reactant: COC(=O)C1(CCCCCl)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCC1(C(=O)O)CCCC1
Product: O=C(O)C1(CCCCCl)CCCC1
Temperature: 42.5 °C
Yield: 22 %
Yield: 68 %

Procedure:
To a solution of 1-(4-chlorobutyl)cyclopentane carboxylic acid methyl ester (30 mmol, 6.56 g) in a mixture of THF (60 mL) and methanol (60 mL) was added 1 N sodium hydroxide (60 mL). The mixture was heated to 40-45° C. for 15 h at which point TLC analysis of the reaction mixture indicated the absence of starting material and it was cooled to room temperature. The solvent was removed under vacuum and the residue was diluted with water (100 mL) and extracted with ether (2×100 mL) to remove any neutral impurities. Then, the basic aqueous layer was acidified with 1 N hydrochloric acid and the product was extracted with ethyl acetate (2×75 mL). The combined extracts were washed with brine solution and were dried over anhydrous sodium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the residue was purified by silica gel column chromatography to afford 4.2 g (68%) of 1-(4-chlorobutyl)cyclopentane carboxylic acid as a liquid and 1.3 g (22%) of 1-[4-(methoxy)butyl]cyclopentane carboxylic acid as a viscous oil. HR MS (C11H20O3): Obs mass, 200.0175. Calcd mass, 200.0143 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=O)[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:7]2.ClS([N:23]=C=O)(=O)=O.Cl>C(#N)C.CO>[NH2:23][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=1
Reactant: CCOC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)c1cc(N)c2c(Cl)cc(Cl)cc2n1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A 12-L three-neck flask equipped with a mechanical mixer, a condenser, and thermocouple was charged with Compound 4 (0.94 mole, 269.1 g) in acetonitrile (ACN; about 4 L), after which chlorosulfonyl isocyanate (0.99 mole, 86 mL) was added (dropwise) via the dropping funnel. Upon completion of the addition, the resulting reaction mixture was refluxed for about 28 minutes. The pH of the mixture was about 0 at this point. The mixture then was cooled slightly, while adding saturated HCl in methanol (MeOH; 500 mL). Subsequently, the mixture was refluxed for about 1 hour, and then allowed to cool to room temperature overnight, during which time crystals formed. The crystals were collected on a sintered glass frit and rinsed with acetonitrile (400 mL and 500 mL). The filter cake was then transferred to a 12 L reactor with a mechanical stirrer. Deionized (DI) water (900 mL) and saturated Na2CO3 (500 mL) were added to afford mixture having a pH of about 10. Next, the solids in the mixture were collected and slurry rinsed with DI water (3×500 mL). The rinsed product was dried via lyophilization to afford about 268.79 g (63.3% yield) of Compound 5.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:13]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:30][C:27]([C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:25]=1[OH:26])[C:20]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=1)=[O:21])([CH3:28])[CH3:29]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
1.88 g (10 mmoles) of p-nitrobenzylamine hydrochloride, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.38 ml (10 mmoles) of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 25 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with the minimum quantity of ethyl acetate. After concentration of the solution under reduced pressure, the residue is precipitated from a mixture of ethyl acetate/diethyl ether (1/4) and filtered. The crystals are washed abundantly with diethyl ether in order to finally produce, after drying, a white powder with a yield of 74% (2.85 g). Melting point: 230-231° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([CH3:21])([CH3:20])[CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1>C1C=CC=CC=1.[Zn]>[OH:19][C:16]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([Br:8])[CH:18]=2)[C:13]([CH3:21])([CH3:20])[CH2:14][CH2:15]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(Br)cc21
Temperature: 25 °C

Procedure:
To a suspension of Zn (1.20 g, 18.4 mmol) in 10 mL benzene at 100° C. was slowly added a solution of ethyl 2-bromoacetate (658.0 mg, 3.94 mmol) and 3,4-dihydro-4,4-dimethyl-7-bromo-naphthalen-1(2H)-one (Compound G, 500.0 mg, 1.97 mmol) in 20.0 mL benzene. The resulting mixture was heated for 2 h, cooled to room temperature, and the solution decanted from the residual solids. The solids were washed with EtOAc and the combined organic layers were washed with cold 15% H2SO4, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents undr reduced pressure and column chromatography (10% EtOAc-hexanes) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1]N1C2=NC=C(C3C=CN=CC=3)C=C2C(N)=N1.[CH2:18]([NH:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:36])[N:22]=1)[CH3:19]>>[CH2:18]([N:20]([CH3:1])[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:36])[N:22]=1)[CH3:19]
Reactant: CCNc1nn(C)c2ncc(-c3ccncc3)cc12
Reactant: Cn1nc(N)c2cc(-c3ccncc3)cnc21
Product: CCN(C)c1nn(C)c2ncc(-c3ccncc3)cc12

Procedure:
E-56. Following the procedure described in Example E-1 but using in place of 1-methyl-5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amine a molar equivalent quantity of N-ethyl-1-methyl-5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amine, it is contemplated that there can be obtained N-ethyl-N,1-dimethyl-5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:25]1[C:26]2[CH:33]=[CH:32][N:31]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[C:27]=2[N:28]=[CH:29][N:30]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:22][CH:21]([NH:23][C:25]3[C:26]4[CH:33]=[CH:32][N:31]([S:34]([C:37]5[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=5)(=[O:35])=[O:36])[C:27]=4[N:28]=[CH:29][N:30]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: NC1CN(C(=O)CNc2cc(Cl)cc(Cl)c2)Cc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CN(C(=O)CNc5cc(Cl)cc(Cl)c5)Cc5ccccc54)ncnc32)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of 2-(3,5-dichlorophenylamino)-1-(4-amino-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (0.2 g, 0.6 mmol) in DMF was added 4-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (0.17 g, 0.57 mmol) and DIEA (0.11 g, 0.85 mmol). The reaction mixture was stirred at 90° C. overnight, the mixture was diluted with EtOAc (100 mL) and washed with water (20 mL×3). The EtOAc layer was concentrated in vacuo to give a mixture which was purified by column chromatography (silica gel, gradient EtOAc in Hexanes) to give (0.160 g, 57%) of the titled intermediate. 1H NMR (CDCl3, 400 MHz): δ 8.41 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.54 (d, 1H, J=3.6 Hz), 7.33-7.19 (m, 6H), 6.83-6.67 (m, 3H), 6.35 (s, 2H), 5.35-5.25 (m, 1H), 5.18 (d, J=16.4 Hz, 1H), 4.76 (d, J=16.4 Hz, 1H), 4.51 (dd, J=1.8, 16 Hz, 1H), 4.33 (t, J=1.8 Hz, 1H), 3.82 (dd, J=1.8, 10 Hz, 1H), 3.72 (d, J=5.2 Hz, 1H), 2.38 (s, 3H). LCMS: M/z: (M+1):621
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:28]4[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=[CH:26][C:27]=4[O:30][CH3:31])=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: COc1ccc(OC)c(B(O)O)c1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Product: COc1ccc(OC)c(-c2ccc(OC3CN(C(=O)Nc4cccnn4)C3)nc2)c1
Yield: 83 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (100 mg, 0.25 mmol) was reacted with 2,5-Dimethoxybenzeneboronic acid (Cas. No 107099-99-0, 69 mg, 0.38 mmol) to afford title compound (84 mg, 83%) as an off-white powder. LCMS: (Method B) RT=1.19 min; m/z=408 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:37]S(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:5]([CH3:14])([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:37][CH2:36][CH2:35][C:33]3[N:34]=[C:30]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:31][C:32]=3[CH3:48])=[CH:11][CH:12]=2)[C:4]([OH:23])=[O:3])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
Standard Procedure (B) was utilized to prepare the title compound from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3) δ 8.00-7.97 (m, 2H), 7.43-7.41 (m, 3H), 7.18 (d, 2H, J=8.99 Hz), 6.93-6.82 (m, 6H), 4.21 (t, 2H, J=6.65 Hz), 3.21 (d, 1H, J=14.08 Hz), 3.13 (d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.65 Hz), 2.39 (s, 3H), 1.36 (s, 3H); HRMS (ES+) m/z exact mass calcd for C28H27NO5F 476.1873, found 476.1871.