Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:18])=[O:17])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[NH:5][CH2:4]1.Cl.[CH3:27][N:28]([CH3:44])[CH2:29][CH2:30][O:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[NH:37][C:36]([C:41](O)=[O:42])=[CH:35]2.CCN=C=NCCCN(C)C>CC(N(C)C)=O>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][C:14]([S:16]([NH:19][CH2:20][CH2:21][OH:22])(=[O:17])=[O:18])=[CH:15][C:9]=3[C:8]([N+:23]([O-:25])=[O:24])=[CH:7][C:6]=2[N:5]([C:41]([C:36]2[NH:37][C:38]3[C:34]([CH:35]=2)=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH3:44])[CH3:27])=[CH:40][CH:39]=3)=[O:42])[CH2:4]1
Reactant: O=[N+]([O-])c1cc2c(c3ccc(S(=O)(=O)NCCO)cc13)C(CCl)CN2
Reactant: CN(C)CCOc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CN(C)CCOc1ccc2[nH]c(C(=O)N3CC(CCl)c4c3cc([N+](=O)[O-])c3cc(S(=O)(=O)NCCO)ccc43)cc2c1
Reaction time: 4 h
Yield: 20.7 %

Procedure:
(Scheme C). A mixture of compound 121 (46 mg, 0.11 mmol), 5-[2-(dimethylamino)ethoxy]indole-2-carboxylic acid hydrochloride (37 mg, 0.13 mmol) and EDCI (83 mg, 0.44 mmol) in DMA (3 mL) was stirred under a N2 atmosphere for 4 h. The mixture was then partitioned between CH2Cl2 and cold (0° C.) 5% aqueous KHCO3. The aqueous portion was extracted with cold CH2Cl2 (×4) and the combined extracts were washed with H2O (×2), brine (×2), dried and evaporated. The residue was dissolved in CH2Cl2/MeOH and the solvents were evaporated under reduced pressure until precipitation began. The precipitate was filtered off and washed with MeOH to give 35 (14 mg, 21%): mp 205-210° C.; 1H NMR [(CD3)2SO] δ 11.73 (s, 1H), 9.30 (s, 1H), 8.85 (d, J=1.6 Hz, 1H), 8.43 (d, J=8.9 Hz, 0.1H), 8.03 (dd, J=8.9, 1.6 Hz, 1H), 7.92 (t, J=5.4 Hz, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.22 (d, J=1.4 Hz, 1H), 7.21 (d, J=2.3 Hz, 1H), 6.94 (dd, J=8.9, 2.4 Hz, 1H), 4.97 (t, J=10.3, Hz, 1H), 4.74 (dd, J=10.9, 2.3 Hz, 1H), 4.68-4.61 (m, 2H), 4.19-4.09 (m, 2H), 4.07 (t, J=5.9 Hz, 2H), 3.43-3.35 (m, 21H), 2.88 (q, J=5.8 Hz, 21H), 2.66 (t J=5.8 Hz, 2H), 224 (s, 6H). HRMS (FAB) calcd. for C28H3035ClN5O7S (MH+) m/z 616.1633, found 616.1630.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: BrCCCCCOCCc1ccccn1
Product: c1ccc(CNCCCCCOCCc2ccccn2)cc1

Procedure:
From 2-[2-[(5-bromopentyl)oxy]ethyl]pyridine (6.04 g) and benzylamine (33 ml). After 1 h at 130° the reaction mixture was cooled and partitioned between ethyl acetate (400 ml) and 8% aqueous sodium bicarbonate (250 ml). The final product was purified by FCC eluting with ethyl acetate-triethylamine (100:1) to give the title compound as a pale yellow oil (4.18 g), t.l.c. (ethyl acetate+few drops triethylamine) Rf 0.14.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH2:22][CH3:23])[N:21]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][CH3:23])[N:21]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: CCc1csc(N)n1
Solvent: Brc1ccccc1
Product: CCc1csc(NC(=O)c2c(O)cc(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 56 %

Procedure:
210 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 117 mg of 2-amino-4-ethylthiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 5.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 150 mg of 1,6-dimethyl-N-(4-ethylthiazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 21) represented by the formula:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[N:14](CC2C=CC(OC)=CC=2OC)[C@@H:13]1[CH2:28][N:29]1[N:33]=[C:32]2[CH2:34][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][C:31]2=[N:30]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:28][N:29]1[N:30]=[C:31]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][C:32]2=[N:33]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc3c(n2)CN(C(=O)OC(C)(C)C)C3)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2nn(C[C@H]3NC(=O)[C@H]3NC(=O)OCc3ccccc3)nc2C1
Temperature: 90 °C
Yield: 51.8 %

Procedure:
Slurried tert-butyl 2-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl)-4,6-dihydropyrrolo[3,4-d][1,2,3]triazole-5(2H)-carboxylate (85.5 mg, 0.144 mmol), potassium peroxydisulfate (51.8 mg, 0.186 mmol) and potassium phosphate, dibasic (57 mg, 0.33 mmol) in ACN/water (2 mL, 2:1) for 5 min, then heated to 90° C. for 1.5 h. More potassium peroxydisulfate (13.9 mg, 0.050 mmol) was added and it was heated for an additional hour. More potassium peroxydisulfate (12.1 mg, 0.043 mmol) was added and it was heated an additional hour, whereupon the slurry was partially concentrated in vacuo then partitioned between saturated NaHCO3 (aq) and EtOAc. After separating the layers, the aqueous was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-100%) to afford contaminated product (33 mg), which was repurified by reverse phase HPLC (XSELECT CSH, C18, 5μ, 30×100 mm, ACN/H2O with 0.1% formic acid buffer, 60 mL/min). The title compound (12.1 mg, 19%) was obtained as a white solid. Rt=0.78 min, m/z=433.2 (M+1) Method 2m_acidic. 1H NMR (500 MHz, DMSO-d6) δ 8.40 (s, 1H), 8.17 (d, J=9.7 Hz, 1H), 7.42-7.26 (m, 5H), 5.05 (s, 2H), 5.04-4.99 (m, 1H), 4.58 (d, J=6.6 Hz, 2H), 4.40 (d, J=4.7 Hz, 4H), 4.22 (q, J=6.5 Hz, 1H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16]
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 813.7 %

Procedure:
Ethyl 4-hydroxybenzoate (16.6 g), geranyl bromide (23.9 g), and potassium carbonate (27.6 g) were refluxed in acetone (200 ml) with stirring for 1 hour . The reaction mixture, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum. To the residue dissolved in ethanol (150 ml) were added sodium hydroxide (3.90 g) and water(50 ml) and the mixture was refluxed with stirring for 1 hour. After being concentrated under a vacuum, the reaction mixture was acidified with hydrochloric acid and then extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride and then was concentrated under a vacuum. The resulting solid was recrystallized from n-hexane/ethyl acetate mixed solution, thereby yielding 223 g of the aimed compound.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[NH:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]([NH2:13])=[O:12])[CH3:3].[O:14]1[CH2:24][CH:15]1[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>C(O)CCCC>[C:11]([CH2:10][N:5]1[C:6](=[O:9])[CH2:7][N:8]([CH2:24][CH:15]([OH:14])[CH2:16][C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[CH:4]1[CH:2]([CH3:1])[CH3:3])(=[O:12])[NH2:13]
Reactant: CC(C)C1NCC(=O)N1CC(N)=O
Reactant: CC(C)COC(=O)CC1CO1
Solvent: CCCCCO
Product: CC(C)COC(=O)CC(O)CN1CC(=O)N(CC(N)=O)C1C(C)C
Yield: 49.1 %

Procedure:
A solution of 1.2 g (6.4 mmol) of 2-(1-methylethyl)-5-oxo-1-imidazolidineacetamide and 2 g of 2-methylpropyl 3,4-epoxybutanoate in 40 ml of anhydrous pentanol was stirred at 80° C. for 48 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in 15 ml of 15% HCl, washed with 2×25 ml dichloromethane, basified with sodium carbonate and extracted with 3×35 ml dichloromethane. The organic layer was dried and evaporated to afford 1.08 g of the title compound as a colorless oil (mixture of two diastereoisomers, Rf 0.27 and 0.32 respectively (dichloromethane/methanol 9:1; silica gel plates). Mass spectrum (E.I., 70 eV, 1.5 mA), m/z=300 (M+ --C3H7). IR spectrum (neat): 3400, 3200, 1730 and 1690 cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH3:9].[CH3:10][C@H:11]1[NH:16][CH2:15][CH2:14][N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1>>[CH2:17]([N:13]1[CH2:14][CH2:15][N:16]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH3:9])[C@H:11]([CH3:10])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Reactant: CSc1ccccc1Br
Product: CSc1ccccc1N1CCN(Cc2ccccc2)C[C@H]1C
Yield: 26 %

Procedure:
(2R)-4-Benzyl-2-methyl-1-(2-methylthiophenyl) piperazine was prepared in 26% yield from ortho-bromothioanisole and (R)-3-methyl-1-benzylpiperazine in a manner similar to Preparation 1A. LRMS (ESI+): 223.2 (M+1)
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:22].Br.CCN(C(C)C)C(C)C.[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36]>CN(C=O)C>[N:33]1([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH:1][C@H:2]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[CH:20][CH:21]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:36].[BrH:22]
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
1 g (2.19 mmol) of H-L-Arg-pNA.2HBr is dissolved in 10 ml of DMF, and 0.854 ml (6.57 mmol) of DIEA is then added. In another vessel, a solution of 4.71 mg (2.19 mmol) of Boc-L-Pro-OH in 50 ml of DMF is neutralized with 0.285 ml of DIEA. The two solutions are mixed and 970 mg of Bop are then added while the resulting mixture is kept at RT, with stirring, the pH being kept at between 7.0 and 8.0 throughout the reaction by the addition of small portions of DIEA. After one hour, the reaction is complete and the reaction mixture is evaporated to dryness under vacuum; the evaporation residue is taken up with an AcOEt/MeOH mixture and extracted with a 0.5 M aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, concentrated and precipitated in ether (MeOMe or EtOEt) to give 877 mg (yield: 70%) of the expected product.
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN(C)[CH:18]=[O:19]>CCOCC>[Br:3][C:4]1[CH:9]=[C:8]([CH:18]=[O:19])[CH:7]=[CH:6][N:5]=1
Reactant: Brc1ccnc(Br)c1
Reactant: CN(C)C=O
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2,4-dibromo-pyridine (1.90 g, 8.02 mmol) in dry Et2O (40 mL) was treated with n-BuLi (3.36 mL of a 2.5M solution in hexanes, 8.42 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min. N,N-Dimethyl-formamide (0.78 mL, 10.03 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h and stirred at this temperature for 20 min. The reaction was quenched by the addition of sat. aq. NH4Cl (30 mL). The layers were separated and the aq. layer extracted with Et2O (3×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (10:1 to 2:1 hept-EA) gave the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.44.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=[CH:7][CH:8]=1)[CH3:2].C(C1C=C(C=CC=1)N)C.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:13][C:12]1[C:11](=[N:10][NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=2)[C:14]([NH2:15])=[N:32][N:31]=1
Reactant: NN
Reactant: CCc1cccc(NN=C(C#N)C#N)c1
Agent: CCc1cccc(N)c1
Solvent: O
Solvent: N#CCC#N
Product: CCc1cccc(NN=C2C(N)=NN=C2N)c1
Yield: 10 %

Procedure:
3,5-Diamino-4-[(3-ethylphenyl)hydrazono]pyrazole was prepared using 99 mg (0.5 mmol) of 2-[(3-ethylphenyl)hydrazono]malononitrile, which was derived from 3-ethylaniline (124 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 12 mg (10%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=O)[NH:12][CH:13]=[N:14]2)[C:3](=[O:5])[CH3:4].C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:31])=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:31][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][CH2:6][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)N(C)CCOc1cccc2nc[nH]c(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N(C)CCOc1cccc2ncnc(Cl)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
N-Methyl-N-{2-[(4-oxo-3,4-dihydroquinazolin-5-yl)oxy]ethyl}acetamide (261 mg, 1.00 mmol) and diiso-propylethylamine (522 μl, 3.00 mmol) were dissolved in DCM (25 ml), and the mixture cooled to 0° C. Phosphorus oxychloride (930 μl, 10 mmol) was added drop wise; the solution was warmed to ambient temperature and stirred for 2 hours. The mixture was cooled to 0° C., and saturated sodium hydrogen carbonate solution (30 ml) was added with vigorous stirring. The stirred mixture was allowed to warm to ambient temperature over 20 minutes. The DCM layer was separated, washed with saturated sodium hydrogen carbonate solution (30 ml), water (30 ml) and brine (30 ml), filtered through a silicone-treated filter paper, and evaporated to give N-{2-[(4-chloroquinazolin-5-yl)oxy]ethyl}-N-methylacetamide as an orange solid (90 mg, 32%); NMR Spectrum (DMSO-d6, 400 MHz, CDCl3) 2.05 (s, 3H), 3.17 (s, 3H), 3.85 (t, 2H), 4.28 (t, 2H), 6.99 (d, 1H), 7.58 (d, 1H), 7.76 (dd, 1H), 8.87 (s, 1H); Mass spectrum 276.4 MH+ (4-OMe derivative—product quenched with MeOH in instrument).
Reaction SMILES: [CH:1]([C:4]1[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[S:7][C:8]=1[CH:9]=[O:10])([CH3:3])[CH3:2].[Mn]([O-])(=O)(=O)=[O:16].[K+]>CC(C)=O.O>[CH:1]([C:4]1[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=2[S:7][C:8]=1[C:9]([OH:16])=[O:10])([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1c(C=O)sc2ccccc12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)c1c(C(=O)O)sc2ccccc12
Temperature: 25 °C
Yield: 72.6 %

Procedure:
A solution of compound 563-E (1.95 g, 9.5 mmol) in acetone (30 mL) was refluxed for 30 min. A mixture of potassium permanganate (3.02 g, 19.1 mmol) in water (10 mL) was added in portions, and the resultant mixture was refluxed for an additional 30 min. The mixture was cooled to ambient temperature and concentrated in vacuo. A solution of aqueous Na2SO3 (1M, 50 mL) was added followed by sulfuric acid (1 M, 50 mL). Two additional portions of Na2SO3 (1M, 20 mL) were added followed by sulfuric acid (1 M, 20 mL), which resulted in the disappearance of the dark brown color. The resultant suspension was diluted with H2O, filtered, washed with H2O and dried under vacuo to afford 1.52 g of compound 563-F as a yellow solid. MS: m/z 221.1 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:41]5[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(C)CC1
Temperature: 60 °C
Yield: 8.3 %

Procedure:
To a solution of 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 35B (225 mg, 0.439 mmol) in DMF (3 mL) was added N-methyl piperazine (0.146 mL, 1.317 mmol) followed by diisopropyl ethylamine (0.229 mL, 1.317 mmol) and tetrabutyl ammonium iodide (162.15 mg, 0.439 mmol). The reaction mixture was heated at 60° C. for 2 days. Formation of the product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (phenomenex phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-yloxy)phenyl)urea (21 mg, 8%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.32 (s, 1H), 8.55 (s, 1H), 7.55 (d, 2H), 7.40 (m, 2H), 7.25 (s, 1H), 6.98 (m, 1H), 6.48 (s, 1H), 4.30 (m, 2H), 4.00 (s, 3H), 2.82-2.25 (m, 10H), 2.15 (s, 3H), 1.28 (s, 9H); LC-MS (ESI) m/z 576 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])[CH2:2][CH3:3].[C:12]([O-])([O-])=O.[K+].[K+].IC.Cl>CN(C=O)C>[CH3:12][O:11][C:10]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(O)cccc1O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCc1c(O)cccc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
2-Propyl resorcinol (1.50 g, 9.86 mmol) was dissolved in DMF (anhydrous, 20 mL) and K2CO3 (681 mg, 4.93 mmol) was added. After stirring for 10 min at rt, iodomethane (0.92 mL, 14.8 mmol) was added and the reaction mixture was stirred for 6 h at 60° C. After cooling to rt, the reaction mixture was acidified with HCl (1 N aqueous solution) and concentrated under reduced pressure. Water was added and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:15) gave 33 mg (24%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 0.97 (t, 3H), 1.54 (m, 2H), 2.61 (t, 2H), 3.81 (s, 3H), 4.68 (br, 1H), 6.47 (m, 2H), 7.03 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[C:5]([Cl:11])=[CH:4][C:3]=1[OH:12].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[Cl:11][C:5]1[C:6]([CH:8]2[CH2:10][CH2:9]2)=[CH:7][C:2]([NH:1][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:3]([OH:12])[CH:4]=1
Reactant: CCOC(=O)C=O
Reactant: Nc1cc(C2CC2)c(Cl)cc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNc1cc(C2CC2)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.5 %

Procedure:
To a solution of 2-amino-5-chloro-4-cyclopropylphenol (200 mg, 1.01 mmol) in MeOH (20 mL) at RT, AcOH (3 drops) and ethyl glyoxalate (416 mg, 2.02 mmol, 50% in toluene) were added. The mixture was stirred at RT for 2 h and then sodium cyanoborohydride (190 mg, 3.03 mmol) was added to the mixture. The resulting mixture was stirred at 40° C. for 15 h. The mixture was allowed to cool to RT and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel (10-20% methanol/dichloromethane) to afford the desired product (290 mg, 100% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1H), 6.66 (s, 1H), 5.93 (s, 1H), 5.07 (t, J=6.4 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.91 (d, J=6.4 Hz, 2H), 1.92-1.97 (m, 1H), 1.20 (t, J=6.8 Hz, 2H), 0.84-0.87 (m, 2H), 0.51-0.55 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].COC1C=C(NC(C2C3N=C(O[N:47]4[C:51]5[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=5[N:49]=N4)N=CC=3SC=2)=O)C=CC=1OC.N[C@@H]1CCCC[C@@H]1N>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]([C:14]2[C:18]3[N:19]=[C:20]([NH:47][C@@H:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C@@H:50]4[NH2:49])[N:21]=[CH:22][C:17]=3[S:16][CH:15]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC(=O)c2csc3cnc(Cl)nc23)cc1OC
Reactant: COc1ccc(NC(=O)c2csc3cnc(On4nnc5ccccc54)nc23)cc1OC
Agent: N[C@@H]1CCCC[C@@H]1N
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)cc1OC
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A suspension of the mixture of 85 mg of 2-Chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4-dimethoxy-phenyl)-amide and 2-(Benzotriazol-1-yloxy)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4-dimethoxy-phenyl)-amide (from step a) and 0.17 g (1.41 mmole) of cis-1,2-diaminocyclohexane in Dioxane (3 mL) was stirred at 60° C. for overnight. The reaction were cooled down and diluted with CH2Cl2, washed with aqueous Na2CO3, brine, dried over anhydrous Na2SO4, concentrated and purified by flash chromatography (silica gel, 40 g, 0% to 30% MeOH (0.7 N) in CH2Cl2) to 50 mg of 2-(cis-2-Amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (3,4-dimethoxy-phenyl)-amide as light yellow solid. MH+/Z=428.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[CH2:6]([O:13][C:14]([NH:16][CH:17]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:18]([OH:25])[C:19]([F:24])([F:23])[C:20](O)=[O:21])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)C>[CH2:6]([O:13][C:14]([NH:16][CH:17]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[CH:18]([OH:25])[C:19]([F:24])([F:23])[C:20](=[O:21])[CH2:1][CH2:2][CH3:3])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(NC(CC1CCCCC1)C(O)C(F)(F)C(=O)O)OCc1ccccc1
Reactant: CCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCC(=O)C(F)(F)C(O)C(CC1CCCCC1)NC(=O)OCc1ccccc1

Procedure:
To a rapidly stirred solution of n-propylmagnesium bromide (9 mmol) in anhydrous diethyl ether (20 mL) was added dropwise a solution of 0.641 g (2,25 mmol) of 4-benzyloxycarbonylamino-5-cyclohexyl-2,2-difluoro-3-hydroxy pentanoic acid in anhydrous diethyl ether (10 mL). The mixture was refluxed under nitrogen for two hours after the addition of the acid was completed. The crude mixture was then poured onto a mixture of ice and 0.2N HCl (50 mL). The layers were separated and the aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic layers were washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulphate. Filtration and removal of the solvent in vacuo left an oil. The residue was purified by chromatography (silica gel, ethyl acetate/cyclohexane 1:1) to yield the expected ketone.