Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:11]2=[CH:12][CH:13]=[CH:14][N:10]2[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[O:6]1)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1C=CC=CC=1>[CH2:35]([O:34][C:32]([N:2]([CH2:4][CH:5]1[C:11]2=[CH:12][CH:13]=[CH:14][N:10]2[CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[O:6]1)[CH3:1])=[O:33])[CH3:36]
Reactant: CN(C)CC1Oc2ccccc2C(c2ccccc2)n2cccc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)N(C)CC1Oc2ccccc2C(c2ccccc2)n2cccc21
Temperature: 65 °C

Procedure:
To a mixture of 11-dimethylaminomethyl-5-phenyl-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (9.92 g) and potassium carbonate (4.28 g) in 150 ml of benzene was added ethyl chloroformate (5.9 ml). This was heated at 65° C. for 6 hours, then added to water and extracted with ethyl ether (4×). The combined organics were washed with water, dried and concentrated to give 10.5 g of an oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.096 g, 0.25 mmol) and 4-chlorobenzenesulfonyl chloride (0.070 g, 0.33 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.06 mL, 0.45 mmol), and the mixture was stirred for 15 minutes at room temperature. Once no starting material was seen by analytical LCMS, the solution was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl>C1(C)C=CC=CC=1>[C:2]1([CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCN1CCNCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: Cc1ccccc1
Product: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Yield: 23.8 %

Procedure:
In a reactor equipped with a water trap (Dean-Stark trap), a mixture of benzhydrol (5.0 g), 1-(2-hydroxyethyl)piperazine (3.5 g), camphor-10-sulfonic acid (14 g), and toluene (80 mL) was refluxed for 6 hours. Then, 1N-hydrochloric acid was added and the mixture was separated into two phases. The aqueous layer was made basic with 5 N aqueous sodium hydroxide, saturated with sodium chloride, and extracted with chloroform. The extract was washed with a small amount of saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to provide 1.9 g of the title compound. Yield 24%. This compound was not further purified but directly submitted to the next reaction.
Reaction SMILES: [C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2].[C:24]1([CH3:36])[CH:29]=[CH:28][C:27]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CC(C)=O>[C:1]([NH:5][C:6](=[S:23])[NH:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH:22][C:34]([NH:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:36])=[CH:25][CH:26]=1)(=[O:32])=[O:31])=[O:35])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1N
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1cc(C(=O)c2ccccc2)ccc1NC(=O)NS(=O)(=O)c1ccc(C)cc1
Temperature: 50 °C
Yield: 29 %

Procedure:
To a suspension of 3-(3-carbomethoxythioureido)-4-aminobenzophenone (1.0 g.; 0.00304 mole) in acetone (5 ml.) is added p-toluenesulfonyl isocyanate (0.6 g.; 0.00304 mole). The suspension is heated to 50° C. and vacuum filtered. The precipitate is washed with acetone and ether and then dried to afford 0.4 g. (29% yield) of 3-(3-carbomethoxythioureido)-4-(3-p-toluenesulfonylureido)benzophenone, m.p. 191°-192° C., dec.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[C:11]([F:13])([F:12])[F:10])=[CH:6][N:7]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)nc1)C(F)(F)F
Yield: 99.1 %

Procedure:
According to Reference Example 8-12, by use of 6-chloro-3-pyridinecarboxaldehyde (1.00 g, 7.06 mmol), (trifluoromethyl)trimethylsilane (1.25 mL, 8.48 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 706 μL, 0.706 mmol) and tetrahydrofuran (20 mL), the mixture was stirred and reacted at room temperature for 1 hour. Then, purification by silica gel column chromatography (chloroform/methanol=9/1) was performed to give 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound DC) (1.48 g, yield: 99%).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14](Cl)=[N:15][OH:16].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>CN(C=O)C>[F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14]1[CH2:26][C:25]([C:23]2[CH:22]=[C:21]([Cl:31])[C:20]([Cl:32])=[C:19]([Cl:18])[CH:24]=2)([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)c(F)c21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)c(F)c21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (257 mg, 1 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (327 mg, 1.2 mmol) in DMF (5 mL) at rt was added TEA (167 μL, 1.2 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 4-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (80 mg; yield 16.1% over 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.461 (s, 1H), 7.891 (s, 2H), 7.754 (t, J=7.0 Hz, 1H), 7.586 (d, J=7.5 Hz, 1H), 4.377 (d, J=18.5 Hz, 1H), 4.291 (d, J=18.5 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=496.0 (M+1, ESI+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:20])([F:19])[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.CC1CCCO1.[C:27]([O:31][C:32](=[O:54])[NH:33][CH:34](S(C1C=CC=CC=1)(=O)=O)[C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=1[S:43][CH3:44])([CH3:30])([CH3:29])[CH3:28]>O>[C:27]([O:31][C:32](=[O:54])[NH:33][CH:34]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][C:36]=1[S:43][CH3:44])[C:13]1[C:14](=[O:18])[CH2:15][CH2:16][CH2:17][C:12]=1[NH:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:19])([F:20])[F:3])[CH:6]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Reactant: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC1CCCO1
Product: CSc1cc(C#N)ccc1C(NC(=O)OC(C)(C)C)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Sodium hydride (60% in mineral oil, 154 mg, 3.85 mmol) is added in portions to a mixture of 3-(3-trifluoromethyl-phenylamino)-cyclohex-2-enone (INTERMEDIATE 3; 960 mg, 3.76 mmol) and 2-methyltetrahydrofuran (8 mL). After 30 min [benzenesulfonyl-(4-cyano-2-methylsulfanyl-phenyl)-methyl]-carbamic acid tert-butyl ester (Step 1, 1.56 g, 3.73 mmol) is added and the mixture is stirred at room temperature for 50 min. Water and 2-methyltetrahydrofuran are added and the phases are separated. The organic phase is dried over Na2SO4 and concentrated under reduced pressure. Yield: 2.13 g. ESI mass spectrum: [M+H]+=532; Retention time HPLC: 1.22 min (Z018_S04).
Reaction SMILES: Cl.N[N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[O:12]=[C:13]1[CH2:18][C:17](=O)[CH2:16][CH2:15][NH:14]1>C(O)C>[CH:9]1[CH:8]=[CH:7][C:6]2[CH2:5][CH2:4][N:3]3[C:11]=2[C:10]=1[C:18]1[C:13](=[O:12])[NH:14][CH2:15][CH2:16][C:17]=13
Reactant: O=C1CCNC(=O)C1
Reactant: NN1CCc2ccccc21
Agent: Cl
Solvent: CCO
Product: O=C1NCCc2c1c1cccc3c1n2CC3
Yield: 201 %

Procedure:
A solution of 1-amino-indoline hydrochloride (1.0 g) and 2,4-dioxopiperidine (663 mg) in absolute ethanol (40 ml) was stirred under nitrogen for 48 h. The solvent was removed in vacuo and the residue was dissolved in diethylene glycol (30 ml) and heated at 200° for 2 h. The solution was allowed to cool, poured into water (200 ml) and extracted with dichloromethane (3×100 ml). The combined, dried organic extracts were evaporated to give an oil (ca. 2.5 g) which was purified by short path column chromatography on silica gel (Merck 7729) eluting with System A (400:10:1) to give the title compound (330 mg) as a solid, m.p. 265°-267°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:24]1([CH2:30][C:31]([NH:33][C:34]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:12]3[N:11]=[CH:10][N:9]=[C:8]4[C:13]=3[N:14]=[CH:15][N:7]4[CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:18][CH:19]=2)=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 4-[9-(Tetrahydro-pyran-2-yl)-9H-purin-6-yloxy]-phenylamine (1.1 g, 3.60 mmol, 1.0 eq.), DCM (10 ml) and phenyl-acetyl isothiocyanate (0.643 g, 3.60 mmol, 1 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was purified by flash column chromatography on silica gel to give 2-phenyl-N-{[(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)amino]-carbonothioyl}acetamide as a white solid (400 mg, 25% yield). 1H NMR (400 MHz, CDCl3): δ 12.40 (s, 1H), 8.80 (s; 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.80 (m, 2H), 7.20 (m, 7H), 5.9 (m, 1H), 4.20 (m, 1H), 3.8 (m, 2H), 2.20 (m, 3H), 1.80 (m, 4H). MS (ESI) for C25H24N6O3S: 489 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][C:5]1(C(OC)=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16].Cl.[OH-:23].[Na+]>>[OH:23][C:5]1([CH2:4][CH2:3][CH:2]([CH3:21])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[CH2:7][C:6]1=[O:16]
Reactant: [OH-]
Reactant: COC(=O)C1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Agent: Cl
Agent: [Na+]
Product: CC(C)CCC1(O)C(=O)CC(=O)c2ccccc21
Yield: 63.2 %

Procedure:
A solution of Example 2C (1 g, 3.47 mmol) in 1 N NaOH (20.8 mL) was stirred at 40° C. for 4 days. The solution was neutralized to pH 7 with 1 N HCl, extracted with ethyl acetate, and the organic layer was concentrated in vacuo. Column chromatography on silica (7% methanol/dichloromethane) afforded the title compound as a white solid (0.54 g, 63.2%).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[C:5]([CH3:13])[C:6]([F:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+]>CO>[F:12][C:6]1[C:5]([CH3:13])=[C:4]2[C:9]([N:10]=[CH:11][C:2]([O:15][CH3:14])=[N:3]2)=[CH:8][CH:7]=1
Reactant: C[O-]
Reactant: Cc1c(F)ccc2ncc(Cl)nc12
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(F)c(C)c2n1
Yield: 96 %

Procedure:
2-Chloro-7-fluoro-8-methylquinoxaline (4.1 g, 20.9 mmol) was suspended in dry methanol and a 25% solution of sodium methoxide in methanol (4.73 ml, 21.9 mmol) was added by syringe. The mixture was heated under reflux for 2 h, then evaporated. The residue was dissolved in dichloromethane and water and the phases were separated. The aqueous phase was extracted twice with dichloromethane, and combined organic fractions were dried and evaporated to give product (3.84 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]([CH3:34])[CH3:33])[CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]([CH:32]([CH3:33])[CH3:34])[CH3:31])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N(C)C(C)C)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N(C)C(C)C)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-isopropyl-N,4-dimethylbenzenesulfonamide (Intermediate 103), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.C[Al](C)C.C([O:20][C:21]([C:23]1[C:28]([NH:29][C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:27][CH:26]=[C:25]([CH3:36])[N:24]=1)=O)C.O>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:21]([C:23]3[C:28]([NH:29][C:30]4[CH:35]=[N:34][CH:33]=[N:32][CH:31]=4)=[CH:27][CH:26]=[C:25]([CH3:36])[N:24]=3)=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: Nc1ccn(-c2ccc(F)cc2)n1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncnc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Nc2cncnc2)c(C(=O)Nc2ccn(-c3ccc(F)cc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(4-Fluoro-phenyl)-1H-pyrazol-3-ylamine (55 mg, 0.31 mmol) was dissolved under inert gas atmosphere in dioxane (2 ml) and trimethylaluminium (0.154 ml, 2M toluene solution) was added. After stirring for 30 min at ambient temperature, 6-methyl-3-(pyrimidin-5-ylamino)-pyridine-2-carboxylic acid ethyl ester (A-1; 20 mg, 0.08 mmol) was added and the reaction mixture was heated at reflux for 18 hours. Upon cooling to room temperature water (0.5 ml) was added and intensive stirring was continued for 5 min. Sufficient sodium sulfate for water absorption and dichloromethane were added while stirring is continued. The resulting solution was then filtered through decalite and washed with dichloromethane. The solvent was evaporated and the final product was obtained after silica gel chromatography using a heptane/ethyl acetate gradient as off-white solid (5 mg, 16%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])=[CH:5][CH:4]=1.[CH3:15]C(CC1C=CC(CO)=CC=1)C(O)=O>>[CH3:15][CH:10]([CH2:9][C:6]1[CH:7]=[N:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1)[C:11]([OH:13])=[O:12]
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Reactant: COC(=O)/C=C/c1ccc(CO)nc1
Product: CC(Cc1ccc(CO)nc1)C(=O)O

Procedure:
The title compound was prepared from Intermediate G acid by the same methodology used to make Intermediate B.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C=O)C>[N:32]1([CH2:31][CH2:30][CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]3[CH:11]=[C:10]([O:12][C:13]4[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=4)[CH:9]=[CH:8][C:7]=3[CH2:1]2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: ClCCCN1CCOCC1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCN2CCOCC2)C3)nc1
Temperature: 90 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.300 g, 1.06 mmol), K2CO3 (0.366 g, 2.65 mmol), and 4-(3-chloropropyl)morpholine (0.191 g, 1.16 mmol) in DMF (5.3 mL). Heat at 90° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (150 mL). Wash with 1.0 N NaOH (1×50 mL), brine (1×50 mL), dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 10% (2.0 M NH3 in methanol) in acetone to give the title compound: MS ES+411.2 (M+H)+, HRMS calcd for C23H31N4O3 411.2396 (M+H)+, found 411.2389, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR=5.7 min, 100% purity.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[F:15][C:16]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=2[O:4][CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH:19]=[CH:18][C:17]=1[C:31]1[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Brc1ccccc1OC1CCNCC1
Product: Nc1ncc(-c2ccc(-c3ccccc3OC3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)piperidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H21FN4O, 364.17; m/z found, 365.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 2H), 8.29 (s, 1H), 7.56 (m, 1H), 7.46-7.31 (m, 4H), 7.20 (d, J=8.4, 1H), 7.05 (m, 1H), 6.86 (s, 2H), 4.62-4.66 (m, 1H), 2.91-2.93 (m, 4H), 2.07-1.96 (m, 2H), 1.77-1.65 (m, 2H).
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>C(#N)C>[CH3:19][CH:18]([N:2]1[N:3]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:5]=[N:1]1)[CH3:20]
Reactant: CC(C)I
Reactant: CCOC(=O)c1cn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(C(C)C)n1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 2H-1,2,3-triazole-4-carboxylate (1 g), potassium carbonate (1.76 g) and 2-iodopropane (1.27 ml) in dry acetonitrile (20 ml) was stirred at 50-60° C. under nitrogen for 2 h. Further 2-iodopropane (0.70 ml) was added and the mixture stirred at 50-60° C. under nitrogen for 16 h. After cooling to room temperature, the mixture was filtered through a 2 g SPE-Silica column with ethyl acetate and the filtrate concentrated in vacuo, Purification of the residue by chromatography on silica gel (70 g silica cartridge), eluting with a gradient of 0-25% ethyl acetate in cyclohexane over 40 min gave the title compound (670 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCc1nc(-c2ccc(Cl)cc2)co1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1nc(-c2ccc(Cl)cc2)co1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-oxazolepropionic acid (0.5 g), benzyl bromide (0.25 ml), potassium carbonate (0.33 g) and dimethylformamide (DMF)(10 ml) was stirred for 3 hours at room temperature. The reaction mixture was poured into water to obtain crystals of benzyl 4-(4-chlorophenyl)-2-oxazolepropionate (0.664 g, 98%). Recrystallization from ether-hexane gave colorless prism crystals of mp 66°-67° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:25])(=O)C.[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.N>ClCCl>[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:16](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:29][CH:28]=1
Reactant: COC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Agent: N
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
0.5 g (1.5 mmol) of 1-acetyl-3-(1-methoxy-1-phenyl-methylidene)-5-nitro-2-indolinone are dissolved in 20 ml of dichloromethane and after the addition of 0.57 g (4.5 mmol) of 4-chloroaniline stirred for 72 hours at ambient temperature. Then 3 ml of methanolic ammonia are added and stirred for 48 hours. After removal of the solvent in vacuo the residue is triturated with ether, suction filtered and dried.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:47][C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2ccc(Oc3ccc(OCc4ccccc4)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)cc1

Procedure:
A solution of the product from Example 43D and 4-Methoxy-phenylamine was reacted to provide 4-(4-Benzyloxy-phenoxy)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-N-(4-methoxy-phenyl)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (27 mg, 52%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 3.28 (m, 1 H) 3.74 (s, 3 H) 6.77 (m, 2 H) 6.92 (m, 5 H) 7.64 (m, 2 H) 7.87 (d, J=8.82 Hz, 1 H) 7.96 (dd, J=8.64, 2.02 Hz, 1 H) 8.12 (d, J=2.21 Hz, 1 H) 8.89 (s, 1 H) 8.99 (d, J=8.46 Hz, 1 H) 9.46 (s, 1 H) 10.12 (s, 1 H) 11.41 (s, 1 H); MS (ESI+) m/z 522 (M+H)+.