Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.Br[C:15]1[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([F:25])[C:18]([F:26])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(O)(=O)C>[F:25][C:19]1[C:18]([F:26])=[CH:17][CH:16]=[C:15]([NH:7][C:5]2[N:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:3]=[C:2]([CH3:1])[CH:6]=2)[C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1c(Br)ccc(F)c1F
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(Nc2cc(C)nn2-c2ccccn2)ccc(F)c1F
Temperature: 25 °C
Yield: 7.7 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (6.16 g, 35.4 mmol), methyl 6-bromo-2,3-difluorobenzoate (8.11 g, 32.3 mmol), copper acetate (II) (0.49 g, 2.7 mmol) and potassium carbonate (4.46 g, 323 mmol) in N,N-dimethylformamide (30 mL) was heated under reflux for 1 hour under an argon atmosphere, and the solution was allowed to cool to room temperature and poured into water. The solution was made weakly acidic by the addition of acetic acid, and organic matter was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to give the title compound (0.86 g, 8% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O-:26])=[O:25])[CH:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]3[C:19]([C:20]([F:23])([F:21])[F:22])=[C:18]([C:24]([OH:26])=[O:25])[CH:17]=[N:16]3)=[CH:13][CH:14]=2)=[O:7])=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(-n2ncc(C(=O)[O-])c2C(F)(F)F)cc1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1ccc(-n2ncc(C(=O)O)c2C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A mixture of ethyl 1-(4-(4-chlorobenzoylamino)phenyl-5-trifluoromethyl-1H-pyrazole-4-carboxylate (150 mg), 1 N sodium hydroxide aqueous solution (1 ml) and ethanol (2 ml) was stirred at 45° C. for 4 hours. after spontaneous cool, 1 N hydrochloric acid aqueous solution (2 ml) was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was recrystallized from ethanol to give 1-[4-(4-chlorobenzoylamino)phenyl]-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (91 mg) as colorless powder crystals.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CS(C)=O.[C:11]1(C)[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[N:21]=[N:20][C:19]([CH2:22][OH:23])=[N:18]2)[CH:12]=1.CCN(CC)CC>C(Cl)Cl.O>[Cl:4][C:11]1[CH:12]=[C:13]([N:17]2[N:21]=[N:20][C:19]([CH:22]=[O:23])=[N:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(-n2nnc(CO)n2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1nnn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
A solution of oxalyl chloride (4.0 mL, 46 mmol) in CH2Cl2 (100 mL) at −78° C. was added DMSO (6.5 mL, 92 mmol) dropwise. The mixture was stirred for 10 minutes after which the title compound from Example 13.2 (7.92 mg, 41.6 mmol) in CH2Cl2 (30 mL) was added dropwise. The mixture was stirred for an additional 30 minutes and Et3N (2.9 mL, 208 mmol) was added dropwise. The reaction was then allowed to warm to room temperature. Water (150 mL) was then added and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (10-20% EtOAc/hexanes) to yield the title compound as an orange oil (4.98 g, 64%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[CH:11][C:10]=1[NH:21][C:22]([C:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[N:26]([CH3:32])[CH:25]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:12]=[CH:11][C:10]=2[N:21]=[C:22]1[C:24]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[N:26]([CH3:32])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C(=O)Nc2cnc(N3CCOCC3)cc2NCc2ccccc2)cn(C)c1=O
Solvent: CC(=O)O
Product: Cc1cc(-c2nc3cnc(N4CCOCC4)cc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 150 °C
Reaction time: 10 h

Procedure:
1,5-Dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (4-benzylamino-6-morpholin-4-yl-pyridin-3-yl)-amide II-3′ (73.000 mg; 0.168 mmol) is dissolved in acetic acid (2.1 g) and stirred at 150° C. for 10 h in the microwave. The reaction mixture is concentrated under reduced pressure. The residue is purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: DCM/MeOH=100%/0% to 90%/10%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure. The residue is then dissolved in acetonitrile:water 1:1 and freeze dried
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:25]C1C=CN=C(CN)C=1>>[Cl:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH2:18][NH:17][C:11]2[N:10]=[C:9]([NH:8][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=2)[CH:24]=1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Reactant: NCc1cc(Cl)ccn1
Agent: Cl
Product: Cc1nc(NCc2cc(Cl)ccn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using [(4-chloropyridin-2-yl)methyl]amine instead of (pyridin-2-ylmethyl)amine. The crude product was purified by crystallization from ethanol (10 mL) to afford the titled compound as the hydrochloride salt as a white solid. 1H NMR (300 MHz, methanol-d4) δ ppm 1.16-1.28 (m, 5H), 1.55-1.75 (m, 5H), 1.96 (s, 3H), 2.32 (s, 3H), 3.80 (s, 1H), 4.70 (s, 2H), 7.39 (d, J=3.76 Hz, 1H), 7.48 (s, 1H), 8.46 (d, J=5.10 Hz, 1H); MS (ESI) m/z 346.0, 348.1 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]([Cl:17])[C:12]([C:15]#[N:16])=[N:13][CH:14]=2)[CH2:4]1.[C:18](O)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[Cl:17][C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:4]2)[CH:14]=[N:13][C:12]=1[C:15]#[N:16]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: N#Cc1ncc(N2CCC[C@@H](N)C2)nc1Cl
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C#N)c(Cl)n3)C2)cc1
Temperature: 25 °C

Procedure:
(R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87) (1.5 g) was treated with 30 mL “4N HCl in dioxane” at RT for 1 h. The mixture was concentrated in vacuo to dryness to afford (R)-5-(3-aminopiperidin-1-yl)-3-chloropyrazine-2-carbonitrile hydrochloride (134) in quantitative yield. Compound 134 (1.20 g, 4.4 mmol) and p-anisic acid (1.34 g, 8.8 mmol) were dissolved in 20 mL DMF with DIEA (3.82 mL, 22.0 mmol). To it was added PyBOP (4.58 g, 8.8 mmol). The mixture was stirred at RT for 30 m. It was diluted with EtOAc (200 mL), washed with 1N NaOH and water. The organic phase was dried, concentrated and subjected to flash column with 0 to 50% EtOAc in DCM to isolate (R)—N-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-4-methoxybenzamide, compound 135 (yield >90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[CH:11]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:9][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH2:22](I)[CH2:23][CH3:24]>>[CH2:22]([N:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:21][C:6]=3[C:7](=[O:20])[C:8]1=2)[CH2:23][CH3:24]
Reactant: CCCI
Reactant: COC(=O)c1cc(=O)c2oc3ccc(Cl)cc3c(=O)c2[nH]1
Product: CCCn1c(C(=O)OC)cc(=O)c2oc3ccc(Cl)cc3c(=O)c21
Yield: 33.9 %

Procedure:
Prepared from methyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano-[3,2-b]pyridine-2-carboxylate (4.5 g, 0.015 mole) and n-propyl iodide (9.1 g, 0.054 mole) by the method described for Ex. 7. Recrystallization from methanol gave white crystals (1.77 g, 35%), m.p. 240°-244°.
Reaction SMILES: [Al].O[N:3]=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]>O.C(OCC)C.[Hg](Cl)Cl>[NH2:3][CH:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C#N)=NO
Agent: Cl[Hg]Cl
Agent: [Al]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(N)C#N
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
To aluminum foil (25 g) was added a solution of mercury(II) chloride (10 g, 0.37 mol) in water (1 L). The mixture was swirled for 5 min, and then the turbid solution was decanted off. The resulting aluminum amalgam was washed successively with water, methanol and diethyl ether. To amalgam suspended in diethyl ether (500 mL) at 0° C., was added a solution of ethyl 2-hydroxyimino-2-cyanoacetate (100 g, 0.70 mol) in diethyl ether (300 mL), followed by water (50 mnL), maintaining a gentle reflux. After 1 h of stirring, the mixture was filtered and the filtrate was washed with water, brine and dried (Na2SO4). Removal of the solvent gave the title compound as a white solid (67 g, 74%). 1H NMR (250 MHz, CD3OD)δ 4.45 (m, 2H), 2.49 (s, 1H), 1.38 (m, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[O:32]1[CH2:33][CH2:34][N:29]([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([CH2:11][C:12]4[CH:28]=[CH:27][C:15]5[N:16]=[C:17]([NH:19][C@@H:20]6[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]6[OH:26])[S:18][C:14]=5[CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH2:30][CH2:31]1
Reactant: C1COCCN1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)cnc43)cc2s1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(N5CCOCC5)cnc43)cc2s1
Temperature: 100 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-iodo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Step 2 of Example 96 (150 mg, 0.30 mmol) in DMSO (3 mL) were added morpholine (156 μL, 1.78 mmol), CuI (23 mg, 0.12 mmol), L-proline (14 mg, 0.12 mmol), and K2CO3 (123 mg, 0.89 mmol). The resulting mixture was flushed with argon, the reaction vessel was sealed and the mixture was heated at 100° C. for 2 h, then at 110° C. for 2 h. LCMS analysis showed that the reaction complete. The reaction mixture was cooled to rt, filtered through a Celite plug, and the filtrate was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-morpholino-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (15 mg, 11%) as a tan powder. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.22 (d, J=2.3 Hz, 1H), 8.03 (d, J=7.2 Hz, 1H), 7.63 (br s, 2H), 7.24-7.34 (m, 1H), 7.14-7.22 (m, 1H), 5.42 (s, 2H), 3.70-3.83 (m, 4H), 3.48-3.55 (m, 2H), 3.07-3.15 (m, 4H), 2.03 (d, J=10.2 Hz, 1H), 1.87 (d, J=9.6 Hz, 1H), 1.61 (br s, 2H), 1.22 (d, J=7.3 Hz, 4H). LCMS (ESI) m/z 465 (M+H)+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[I-].[Na+].CN(C=O)C.[Br:13][C:14]1[C:15]([C:26]#[N:27])=[N:16][N:17]([CH2:24][CH3:25])[C:18]=1[CH2:19][CH2:20][CH2:21][CH2:22]Cl>O>[C:1]([O:4][CH2:22][CH2:21][CH2:20][CH2:19][C:18]1[N:17]([CH2:24][CH3:25])[N:16]=[C:15]([C:26]#[N:27])[C:14]=1[Br:13])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCn1nc(C#N)c(Br)c1CCCCCl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(C#N)c(Br)c1CCCCOC(C)=O
Temperature: 100 °C
Yield: 80.5 %

Procedure:
Potassium acetate (1.69 g, 17.2 mmol), sodium iodide (255 mg, 1.7 mmol), and DMF (17 mL) were added to 4-bromo-5-(4-chlorobutyl)-1-ethyl-1H-pyrazole-3-carbonitrile (1.0 g, 3.4 mmol, prepared as described in Parts A-E of Example 19), and the reaction was heated at 100° C. for two hours under a nitrogen atmosphere and allowed to cool to ambient temperature. Water was added, and the resulting mixture was extracted with diethyl ether. The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on a HORIZON HPFC system (40+M cartridge, eluting with hexanes/ethyl acetate in a gradient from 90:10 to 60:40) to provide 0.86 g of 4-(4-bromo-5-cyano-2-ethyl-2H-pyrazol-3-yl)butyl acetate.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:12]2[CH2:16][CH2:15][CH2:14][C@H:13]2O)[CH:8]=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[OH:22])([CH3:4])[CH3:3].[ClH:23]>>[Cl:23][CH:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[S:11][C:9]1[CH:10]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:6]([OH:22])=[C:7]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=1
Reactant: CC(C)(C)c1cc(S[C@@H]2CCC[C@H]2O)cc(C(C)(C)C)c1O
Reactant: Cl
Product: CC(C)(C)c1cc(SC2CCCC2Cl)cc(C(C)(C)C)c1O

Procedure:
The product of Example 7 (0.40 g, 0.0012 mole) was stirred with concentrated hydrochloric acid (5 ml) at room temperature for 20 hours. The solid was removed by filtration, washed with water and air dried to give the product as a white powder. The product was purified by silica gel chromatography to give a white solid. The structure was supported by NMR.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[S:6][C:7]3[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[CH:16]1[C:28]2[NH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:2]([N:27]4[C:28]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:21]5[C:26]4=[CH:25][CH:24]=[CH:23][CH:22]=5)=[CH:3][C:4]=3[C:8]=2[CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc2sc3ccc(Br)cc3c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Brc1ccc2sc3ccc(-n4c5ccccc5c5ccccc54)cc3c2c1
Temperature: 25 °C
Yield: 51 %

Procedure:
A mixture of 29.1 g (85.2 mmole) 2,8-dibromodibenzo[b,d]thiophene, 14.2 g (85.2 mmole) of carbazole, 0.12 g (0.54 mmole) of palladium(II) acetate, 0.4 g (1.14 mmol) of 2-(dicyclohexylphosphino)biphenyl, 10 g (104 mmole) sodium tert-butoxide and 300 ml toluene were refluxed under nitrogen for about overnight, then cooled to room temperature, the organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica(hexane-dichloromethane) to give product 18.6 g (51%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[ClH:6].[Br:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N+:12]([O-])=[CH:13]2>>[Br:7][C:8]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[C:13]2[Cl:6]
Reactant: Cl
Reactant: COc1ccc2c[n+]([O-])ccc2c1Br
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1Br
Temperature: 90 °C
Yield: 110.1 %

Procedure:
POCl3 (6.5 ml) was added to the 5-bromo-6-methoxyisoquinoline-N-oxide hydrochloride (1.22 g) and the mixture heated at 90° C. for 6 h. Excess POCl3 was removed in vacuo and the remaining solid washed with water, filtered and dried in vacuo to give 5-bromo-1-chloro-6-methoxyisoquinoline (1.26 g).
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[N:17][OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32]Br)[CH2:26]1)=[O:24])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][O:18][N:17]=[C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:15][CH2:16][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: ON=C1c2ccccc2CCC1c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2c3ccccc3CCC2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 240 h
Yield: 34 %

Procedure:
A mixture of the above oxime (1.0 g, 4.2 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (2.2 g, 6.3 mmol, EP 374801), potassium carbonate (1.5 g, 11 mmol) and acetone (25 ml) was stirred at ambient temperature for 10 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (150 g, heptane/ethyl acetate=7/3) to give 0.6 g of (R)-1-(2-(((2-phenyl-1,2,3,4-tetrahydro-1-naphthylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19](=O)[CH3:20])=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH2:14][O:13][C:12]=3[CH:18]=2)=[CH:4][CH:3]=1.C([O:24][C:25]([C:27]1[CH:50]=[CH:49][C:30]2[N:31]([CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:32]([C:34]3[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([CH:41]=O)[CH:35]=3)=[N:33][C:29]=2[CH:28]=1)=[O:26])C.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:19]3[CH:20]=[CH:41][C:36]4[C:37](=[CH:38][CH:39]=[C:34]([C:32]5[N:31]([CH:43]6[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]6)[C:30]6[CH:49]=[CH:50][C:27]([C:25]([OH:26])=[O:24])=[CH:28][C:29]=6[N:33]=5)[CH:35]=4)[N:40]=3)=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH2:14][O:13][C:12]=3[CH:18]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1cc2c(cc1-c1ccc(Cl)cc1)OCCCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc5c(cc4-c4ccc(Cl)cc4)OCCCO5)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 83.8 %

Procedure:
1-[8-(4-Chloro-phenyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-ethanone (76 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 132 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.Cl[CH2:25][CH:26]1[O:31][CH2:30][CH2:29][N:28](CC2C=CC=CC=2)[CH2:27]1.COC1C=CC(C2NC(C(N)=O)=C(C3C=CC(OC)=CC=3)N=2)=CC=1>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH:26]3[O:31][CH2:30][CH2:29][NH:28][CH2:27]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: COc1ccc(-c2nc(-c3ccc(OC)cc3)c(C(N)=O)[nH]2)cc1
Solvent: CO
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CNCCO2)cc1

Procedure:
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide with 2-chloromethyl-4-benzylmorpholine, according to the procedure described in example S-1, step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1 ml/min, 0.05M in MeOH, 70° C.). 1H NMR (DMSO) δ 2.59-2.70 (2H, m), 2.90-3.00 (2H, m), 3.41-3.51 (1H, m), 3.69-3.79 (2H, m), 4.00 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 2.38 min; m/z (ES+) 416.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][O:35]C(=O)C4C=CC=CC=4)[C@@H:22]([O:23]C(=O)C4C=CC=CC=4)[C@H:12]3[O:13]C(=O)C3C=CC=CC=3)[CH:9]=[N:10][C:3]=12.[NH3:44]>CO>[NH2:44][C:2]1[N:7]=[N:6][CH:5]=[C:4]2[N:8]([C@@H:11]3[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([OH:23])[C@H:12]3[OH:13])[CH:9]=[N:10][C:3]=12
Reactant: N
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nncc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CO
Product: Nc1nncc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The compound from Step C (420 mg, 0.7 mmol) was added to a solution of ammonia in methanol and stirred in a steel bomb at 150° C. for 6 hours. The reaction mixture was evaporated to dryness to afford a brown oil which was purified on silica gel reverse-phase (C18) using water as eluant to give the title compound (50 mg) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][C:20]=4[O:32][CH3:33])[N:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]2=[O:34])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[CH3:33][O:32][C:20]1[CH:21]=[C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[CH:10][C:9](=[O:34])[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:44](=[O:47])[CH:45]=[CH2:46])[CH:7]=[CH:6][CH:5]=3)[C:13]=2[N:14]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1ncc2ccc(=O)n(-c3cccc(N)c3)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(N5CCN(C)CC5)cc4OC)nc32)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b) (2.17 g, 4.74 mmol) in DCM (30 mL) and THF (30 mL) at 0° C. was treated with DIEA (1.66 mL, 9.49 mmol) and acryloyl chloride (0.46 mL, 5.69 mmol) dropwise over 15 min and stirred at 0° C. After 1.5 h, additional acryloyl chloride (0.20 mL) was added slowly over 10 min then the suspension was stirred at 0° C. for another 20 min. Additional acryloyl chloride (0.1 mL) was added and the reaction mixture stirred another 15 min. The reaction mixture was treated with a saturated solution of NaHCO3, extracted with DCM (5×100 mL), dried over Na2SO4, filtered and concentrated. Purification of the crude residue on a silica gel column (1-20% MeOH in DCM) afforded the desired product as a yellow solid. This material was treated with 20 mL of EtOH and the slurry was filtered through a medium porosity sintered glass frit and washed with additional EtOH (10 mL) and Et2O (3×10 mL) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(71-1)-yl)phenyl)acrylamide (1) (680 mg, 1.33 mmol, 28% yield) as a yellow solid after drying overnight at 36° C. in a vacuum oven. m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.75 (1H, br. s.), 8.17 (1H, br. s.), 7.92 (2H, d, J=9.4 Hz), 7.59 (1H, br. s.), 7.52 (1H, t, 0.1=8.1 Hz), 7.29 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=8.0 Hz), 6.54 (1H, br. s.), 6.37-6.50 (2H, m), 6.20-6.33 (1H, m), 6.03 (1H, br. s.), 5.77 (1H, d, J=10.0 Hz), 3.78 (3H, s), 3.07 (4H, br. s.), 2.43 (3H, s), 2.34 (4H, br. s.).