Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH2:28][CH3:29])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O-:23])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:31]([O:37][CH2:38]I)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:26][O:27][CH2:28][CH3:29])[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH2:38][O:37][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[O:22])=[C:15]([CH2:18][O:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(COC)CS[C@H]12)c1csc(N)n1

Procedure:
The procedure described in Example 7 was repeated, except that sodium 7-[2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido]--3-methoxymethyl-3-cephem-4-carboxylate and iodomethyl pivalate were used, to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:42][NH2:43]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:42][NH:43]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Reactant: NN
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 150 °C
Yield: 33.5 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(4-methylphenyl)-3-piperidinecarboxamide (90 mg, 0.209 mmol), 3 mL of EtOH, Hunig's base (0.11 mL, 0.627 mmol), and hydrazine anhydrous (0.026 mL, 0.836 mmol) were added, and the resulting yellow mixture was heated at 150° C. for 150 minutes under microwave conditions. The solution turned black. LCMS showed mainly product with 10% of remaining starting material. The black solids were filtered, and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH, and purified by HPLC (CH3CN/H2O w/0.1% HCO2H) to afford a formic acid salt of the title compound (31 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.49 (m, 1H), 1.70-1.95 (m, 2H), 1.98-2.12 (m, 1H), 2.25 (s, 3H), 3.16 (m, 1H), 3.48 (m, 1H), 4.49 (m, 2H), 4.74-4.99 (m, 1H), 7.11 (t, J=8.3 Hz, 2H), 7.39 (d, J=7.8 Hz, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.74 (d, J=3.0 Hz, 1H), 7.89 (d, J=10.1 Hz, 1H), 9.97 (d, J=12.4 Hz, 1H), 12.03 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[CH2:10][CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1.[CH:15]1([N:21]([C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=2)N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:21]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:23]4[C:24]([C:10]=3[CH2:9][C:8](=[O:13])[NH:7][C:6]=2[CH:14]=1)=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:32][CH:33]=4
Reactant: O=C1CCC(=O)c2ccc(Cl)cc2N1
Reactant: CCOC(=O)c1ccc(N(N)C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)c1c(n2C2CCCCC2)-c2ccc(Cl)cc2NC(=O)C1
Temperature: 85 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A mixture of 8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (1.18 g, 5.65 mmol) and ethyl 4-(N-cyclohexylhydrazino)benzoate (1.14 g, 4.35 mmol) in acetic acid (11 ml) was stirred at 85° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, and conc. sulfuric acid (0.55 ml) was added to the reaction mixture. The mixture was stirred at 85° C. for 3 hr. The mixture was allowed to cool, and the reaction mixture was poured into water (230 ml) and extracted with a mixed solvent of ethyl acetate (200 ml) and ethanol (30 ml). The organic layer was washed twice with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Water (10 ml) and ethanol (10 ml) were added to the obtained crude product and the precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent (10 ml) of water:ethanol (1:1) and dried in vacuo to give ethyl 3-chloro-12-cyclohexyl-6-oxo-5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indole-9-carboxylate (0.97 g, yield 39%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH2:21])=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1.[Li+].[OH-]>N1C=CC=CC=1.C1COCC1>[Br:11][C:12]1[C:13]([F:22])=[C:14]2[C:20]([NH:21][C:8](=[O:9])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)=[CH:19][NH:18][C:15]2=[N:16][CH:17]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
Picolinoyl chloride hydrochloride (501 mg, 2.82 mmol) was added to a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (324 mg, 1.41 mmol, Example 1, Step H) in pyridine (5 mL). The reaction was stirred at room temperature for 10 minutes, and the pyridine was removed in vacuo. The residue obtained was dissolved in THF (5 mL), treated with 2N LiOH (3 mL), and stirred for 20 minutes. THF was then removed in vacuo, and water (20 mL) was added. The solid formed was collected by filtration and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (389 mg, 82% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.17 (br s, 1H), 10.39 (s, 1H), 8.76 (d, 1H), 8.40 (d, 1H), 8.17-8.15 (m, 1H), 8.09 (dt, 1H), 7.87 (d, 1H), 7.71-7.68 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:22])([CH3:24])[CH3:23])=[CH:19][CH:20]=2)[S:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=2)(=[O:35])=[O:34])[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(C(C)(C)C)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step B was prepared following the method described in Step B of Example 1 from 3-{3-[(4-tert-butyl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester of Step A and pyridine-2sulfonyl chloride hydrochloride, of Preparation 47 using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 8.62 (m, 1H), 7.90 (m, 1H), 7.81 (m, 1H), 7.41 (m, 1H), 7.17 (d, 2H), 7.09 (m, 1H), 6.99 (m, 3H), 6.92 (m, 2H), 4.48 (s, 2H), 4.43 (s, 2H), 3.65 (s, 3H), 2.80 (t, 2H), 2.51 (t, 2H), 1.24 (t, 9H); MS 481 (M+1).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[O-]CC.[Na+].[C:9]1(=[O:13])[CH2:12][CH2:11][CH2:10]1>C(O)C>[N+:1]([CH2:4][C:9]1([OH:13])[CH2:12][CH2:11][CH2:10]1)([O-:3])=[O:2]
Reactant: C[N+](=O)[O-]
Reactant: O=C1CCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])CC1(O)CCC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.3 %

Procedure:
Under a nitrogen atmosphere, nitromethane (116 mL, 2.14 mol) and sodium ethoxide (2.6 g of 96% pure material, 36 mmol) were sequentially added to a solution of cyclobutanone (50.0 g, 713 mmol) in ethanol (71 mL), and the resulting solution was stirred at room temperature for 4 days. Some of the ethanol was removed under reduced pressure, and water (100 mL) was added. The resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were washed sequentially with water (2×80 mL) and brine (40 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by vacuum distillation under high vacuum at 70° C. to provide 46.1 g of 1-(nitromethyl)cyclobutanol as an orange liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([NH2:11])[NH:8][N:7]=1.[C:12]([C:14]([C:24](=O)[CH3:25])=[CH:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)#[N:13].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([CH:15]2[N:8]3[N:7]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[N:10]=[C:9]3[NH:11][C:24]([CH3:25])=[C:14]2[C:12]#[N:13])=[CH:17][CH:18]=1)#[N:21]
Reactant: Nc1nc(-c2cccs2)n[nH]1
Reactant: CC(=O)C(C#N)=Cc1ccc(C#N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(-c3cccs3)nc2N1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, 3-(2-thienyl)-1H-1,2,4-triazole-5-amine (318 mg, 1.9 mmol) and 4-(2-cyano-3-oxobut-1-en-1-yl)benzonitrile (300 mg, 1.5 mmol, 0.8 eq.) were dissolved in DMF (3 ml), and solid sodium bicarbonate (803 mg, 9.6 mmol, 5 eq.) was added. The mixture was stirred at 55° C. for 12 h. The mixture was then filtered, and the DMF from the filtrate was distilled off under reduced pressure. The residue was purified by preparative HPLC (Kromasil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). The product was obtained as a solid (73.7 mg, 91% pure, 12% of theory).
Reaction SMILES: [O:1]=[C:2]1[C:12]2[CH:11]=[C:10]3[O:13][CH2:14][O:15][C:9]3=[CH:8][C:7]=2[C:4]2([CH2:6][CH2:5]2)[N:3]1[CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1.[ClH:31]>C(O)C>[ClH:31].[NH:21]1[CH2:22][CH2:23][CH:18]([CH2:17][CH2:16][N:3]2[C:4]3([CH2:6][CH2:5]3)[C:7]3[CH:8]=[C:9]4[O:15][CH2:14][O:13][C:10]4=[CH:11][C:12]=3[C:2]2=[O:1])[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3cc4c(cc3C23CC3)OCO4)CC1
Agent: Cl
Solvent: CCO
Product: O=C1c2cc3c(cc2C2(CC2)N1CCC1CCNCC1)OCO3
Reaction time: 5 h
Yield: 46.2 %

Procedure:
To a reaction vessel, all compound XV obtained in the above step and 750 ml ethanol were added. The mixture was heated until dissolved completely, 36 ml concentrated hydrochloric acid was added, the reaction was kept at about 50-55° C. for 5 h, concentrated to about 200 ml under reduced pressure, 900 ml ethyl acetate was added dropwise, cooled and filtered, the filter cake was washed and dried, and 24.3 g compound II-5 was obtained, with yield of 46.2% (calculated according to compound IX-1). 1H NMR (D2O): δ 1.06 (t, 2H, J=6.7 Hz), 1.32-1.46 (m, 6H), 1.60 (m, 1H), 1.91 (d, 2H, J=13.5 Hz), 2.91-3.03 (m, 4H), 3.39 (d, 2H, J=12.8 Hz), 5.90 (s, 2H), 6.18 (s, 1H), 6.68 (s, 1H); MS (ESI): m/z 315 [M-Cl]+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH2:26][OH:27].Cl>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH2:26][OH:27])[CH2:14][CH2:13]1
Reactant: OCCI
Reactant: Fc1c(C2CCNCC2)cccc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCN1CCC(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine (0.45 g, 1.82 mmol), acetonitrile (20 ml), potassium carbonate (0.6 g, 1.1 mmol) and 2-iodoethanol (0.16 ml, 2.0 mmol). Yield: 0.35 g (66%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 224-226° C. MS m/z (relative intensity, 70 eV) 291 (M+, 1), 260 (bp), 217 (5), 189 (3), 177 (7).
Reaction SMILES: Br[CH2:2][C:3]([CH3:5])=[CH2:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1>CC(N(C)C)=O>[CH3:12][C:13]1[CH:14]=[C:15]([C:22]2[CH:26]=[N:25][N:24]([CH2:4][C:3]([CH3:5])=[CH2:2])[CH:23]=2)[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=1
Reactant: Cc1cc(-c2cn[nH]c2)cc([N+](=O)[O-])c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: C=C(C)Cn1cc(-c2cc(C)cc([N+](=O)[O-])c2)cn1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
3-Bromo-2-methylprop-1-ene (4.19 g, 31.0 mmol) and cesium carbonate (13.5 g, 41.3 mmol) were added to a solution of 4-(3-methyl-5-nitrophenyl)-1H-pyrazole (4.20 g, 20.7 mmol) in dimethylacetamide (41 mL) and stirred at 70° C. for 18 h. The mixture was allowed to cool to room temperature, passed through CELITE, washed with methanol, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-50% EtOAc/Hexane) to afford 4-(3-methyl-5-nitrophenyl)-1-(2-methylallyl)-1H-pyrazole. MS ESI calc'd. for C14H16N3O2 [M+H]+ 258. found 258.
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:14])[NH:6]2.[NH:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH:20]=O.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>CO>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:20]/[C:16]1[NH:15][CH:19]=[CH:18][CH:17]=1)/[C:5](=[O:14])[NH:6]2
Reactant: O=C1Cc2c(ccc([N+](=O)[O-])c2F)N1
Reactant: O=Cc1ccc[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: O=C1Nc2ccc([N+](=O)[O-])c(F)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1,3-dihydro-4-fluoro-5-nitro-2H-indol-2-one (400 mg, 2.04 mmol) (Starting Material 10) in MeOH (4 mL), was successively added at room temperature pyrrole-2-carboxaldehyde (220 mg, 2.25 mmol) (Aldrich) and tetrabutyl ammonium hydroxide (4.5 mL, 1.0 M solution in MeOH)(Aldrich). The mixture was stirred at r.t. for 12 h, then quenched with 1N HCl. The yellow precipitate was collected by suction filtration, washed with water and dried in a vacuum oven. (Yield 510 mg,92%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[CH:11][C:12]3[C:17]([NH:18][C:19]4[C:24]([C:25]([NH:27][CH3:28])=[O:26])=[CH:23][N:22]=[CH:21][CH:20]=4)=[N:16][C:15]([C:29]4[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=4[F:36])=[N:14][C:13]=3[N:37]=2)=CC=1>FC(F)(F)C(O)=O>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17]([NH:18][C:19]3[C:24]([C:25]([NH:27][CH3:28])=[O:26])=[CH:23][N:22]=[CH:21][CH:20]=3)=[N:16][C:15]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:30]=3[F:36])=[N:14][C:13]=2[N:37]=1
Reactant: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)ccc12
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2nc(N)ccc12
Temperature: 40 °C

Procedure:
Using the methods descried in Example 2, the protected amine compound, 4-[7-[Bis-(4-methoxy-benzyl)-amino]-2-(5-chloro-2-fluorophenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-N-methyl-nicotinamide, was prepared. The two methoxybenzyl protecting groups were then removed as follows. A suspension of 4-[7-[Bis-(4-methoxy-benzyl)-amino]-2-(5-chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-N-methyl-nicotinamide (1.96 g; 3.14 mmol) in neat trifluoroacetic acid (30 mL) was heated to 40° C. for 30 h. The reaction mixture was evaporated to dryness and purified by silica gel chromatography (dichloromethane/EtOAc gradient 95/5 to 5/95) to afford 4-[7-Amino-2-(5-chloro-2-fluoro-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-N-methyl-nicotinamide (0.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10]Cl.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][N:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH2:16]1
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(CC(=O)c2ccc(Cl)cc2Cl)CC1

Procedure:
1-(2,4-dichlorophenyl)-2-chloroethan-1-one(1 mmol) and methylpiperazine (4 mmol) in 8 ml DMF was stirred for 8 h at room temperature. The reaction mixture was concentrated in vacuo and extracted into ethyl acetate and the organic layer was washed with water and dried with sodium sulfate. The residue after concentration in vacuo was purified by column chromatography eluting with 10% methanol in methylene chloride to yield 1-(2,4-dichlorophenyl)-2-(4-methylpiperazinyl)ethane-1-one. The ethanone was taken up in DMF-DMA and heated to 80° C. for 6 h. The reaction mixture was cooled and concentrated in vacuo and the residue containing the enaminone was purified by column chromatography. 1 mmol of the enaminone obtained above, 1 mmol of amino{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}carboxamidine hydrochloride and 3 mmol of Cs2CO3 was suspended in DMF and heated to 90° C. for fourteen hours. The reaction was cooled and concentrated in vacuo. The residue was partitioned between water and ethyl acetate and the layers separated. The organic layers were dried with sodium sulfate and after solvent removal were chromatographed on silica gel eluting with 5-10% methanol in methylene chloride to obtain {2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[4-(2,4-dichlorophenyl)-5-(4-methylpiperazinyl)pyrimidin-2-yl]amine as a yellow powder after lyophilization.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.Cl[C:11]1[N:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[N+:17]([C:14]1[CH:13]=[N:12][C:11]([N:4]2[CH:5]3[CH2:8][CH2:9][N:1]([CH2:7][CH2:6]3)[CH2:2][CH2:3]2)=[N:16][CH:15]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: C1CN2CCC(CC2)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cnc(N2CCN3CCC2CC3)nc1
Reaction time: 15 h

Procedure:
A mixture of 1,4-diazabicyclo[3.2.2]nonane (0.87 g, 6.90 mmol), 2-chloro-5-nitro-pyrimidine (1.56 g, 6.27 mmol) and dioxane (75 ml) was stirred at room-temperature for 15 h. Aqueous sodium bicarbonate (20 ml, 10%) was added followed by extraction with ethylacetate (3×20 ml). The organic phase was dried and evaporated and a yellow powder was isolated. Yield 0.86 g (55%). Mp 135-139° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][C:15]4[S:16][CH:17]=[CH:18][C:19]=4[C:12]=3[NH:11][N:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(O)(=O)C>[Br:20][C:17]1[S:16][C:15]2[CH2:14][C:13]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[N:10][NH:11][C:12]=3[C:19]=2[CH:18]=1
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 80 °C
Yield: 91 %

Procedure:
6-(4-Methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.13 g, 0.5 mmol) was added with a solution of bromine in glacial acetic acid (0.5 mL of a 3 M solution). The reaction mixture was heated at 80° C. for 12 hr. The solution was cooled to room temperature and poured into ice water. The resultant precipitate was filtered, washed with water to provide the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.16 g, 0.46 mmol) as yellow solid in 91% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:10][C:5]=2[NH:4][C:3]1=[O:20].IC.[C:23]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([B:11]3[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:17])[O:15]3)=[CH:10][C:5]=2[N:4]([CH3:23])[C:3]1=[O:20]
Reactant: O=C([O-])[O-]
Reactant: Cn1c(=O)[nH]c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)n(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reaction time: 23 h

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (235 mg, 0.857 mmol) and iodomethane (0.267 mL, 4.29 mmol) in DMF (10 mL) was added K2CO3 (592 mg, 4.29 mmol). The reaction mixture was stirred for 23 h and the product was then precipitated with water. The title compound was collected by filtration. LCMS-ESI+ (m/z): [M+H]+ calcd for C15H22BN2O3: 289.2; found: 289.1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[C:4]([Cl:13])[N:3]=1.[NH2:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1.CCN(CC)CC>CN1C(=O)CCC1>[Cl:13][C:4]1[N:3]=[C:2]([NH:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Fc1ccc2cc(Cl)nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(Cl)cc3ccc(F)cc23)C1
Temperature: 160 °C
Yield: 71.3 %

Procedure:
To a solution of 1,3-dichloro-7-fluoroisoquinoline (1 g, 4.6 mmol) in NMP (15 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.72 g, 9.3 mmol) and Et3N (1.4 g, 14 mmol). The reaction mixture was heated at 160° C. for 2 hours. The mixture was subsequently partition between H2O (20 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (3×20 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with petroleum ether and ethyl acetate (PE/EA=10:1-5:1 gradient) to give the title compound (1.2 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.26-8.23 (d, J=10.8 Hz, 1H), 7.82-7.80 (dd, J1=8.8 Hz, J2=5.2 Hz, 1H), 7.68-7.67 (d, J=5.6 Hz 1H), 7.63-7.60 (t, J=8.8 Hz, 1H), 7.10 (s, 1H), 4.63-4.53 (m, 1H), 3.70-3.66 (m, 1H), 3.48-3.45 (m, 1H), 3.29-3.26 (m, 1H), 2.23-2.18 (m, 1H), 2.03-1.97 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH:14]([CH3:16])[CH3:15]>>[I:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1cccc2ccc(I)nc12
Reactant: CC(C)Br
Product: CC(C)Oc1cccc2ccc(I)nc12
Yield: 84 %

Procedure:
Reaction of 2-iodo-quinolin-8-ol 8 with 2-bromopropane following the method described in Example 8 gave 2-iodo-8-isopropoxyquinoline 9 in 84% yield. 9: 1H NMR (CDCl3): δ 7.75-7.67 (m, 2H), 7.45 (dd, J=7.0 and 8.0, 1 H), 7.33 (dd, J=1.2 and 8.0, 1 H), 7.12 (dd, J=1.2 and 7.0, 1 H), 4.80 (m, 1H), 1.49 (d, J=5.9, 6 H). To a stirred solution of 9 (29 mg, 0.093 mmol) and PdCl2(PPh3)2 (5 mg) in THF (2.5 mL) under an argon atmosphere at RT was added dropwise over 5 min 2-pyridylzinc bromide (0.370 mL of a 0.5 M solution in THF, 0.185 mmol). After 2 h, saturated NH4Cl (5 mL) was added and the mixture extracted with dichloromethane (10 mL×3). The combined extracts were washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. Subsequent column chromatography on silica (dichloromethane/MeOH, 19:1) gave 2-(pyrid-2-yl)-8-isopropyloxyquinoline as a yellow solid. The isopropyl ether was cleaved according to the procedure of Example 8, to give 2-(Pyrid-2-yl)-8-hydroxyquinoline P1 (22 mg, 89%) (data in Table 5).
Reaction SMILES: [C:1]([Si:5]([CH3:39])([CH3:38])[O:6][CH:7]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][CH2:9][CH:10]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:12]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=2)[C:11]1=[O:31])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OC(=O)C)C.[Pd]>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([N:12]2[CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[CH:10]([CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:38])[CH3:39])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:11]2=[O:31])=[CH:23][CH:24]=1
Reactant: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc([N+](=O)[O-])cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc(N)cc2)c1
Yield: 84.4 %

Procedure:
A reaction is performed with 3.0 g (5.5 mmol) of product 4 in 50 ml ethylacetate and 1.0 g of palladium charcoal 10% for 2 h at 5 bar of a hydrogen atmosphere using an autoclave. The reaction solution is filtrated, evaporated and separated by chromatography on silica gel (methylenehloride/methanol=10/1). 2.4 g (86%) of product 5 is obtained in form of a colourless compound in solid form: C31H40N2O3Si (516.76) MS (ESI+) 517.4 (M+H+).