Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[N:18]=[C:17]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=[CH:15][CH:14]=1.C1C[O:28][CH2:27]C1>>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][O:19][C:17]1[N:18]=[C:13]([CH:27]=[O:28])[CH:14]=[CH:15][CH:16]=1
Reactant: C1CCOC1
Reactant: CN(C)CCOc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN(C)CCOc1cccc(C=O)n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
n-BuLi 2.5 M in hexane (1.2 mL, 3 mmol, 3 eq) was added at −70° C. to a solution of the product from the previous step, N-{2-[(6-bromo-2-pyridinyl)oxy]ethyl}-N,N-dimethylamine (245 mg, 1 mmol) in dry THF (10 mL). The reaction mixture was stirred at −70° C. for 1 h 30 min. Ethyl formate (freshly distilled over P2O5) was added at −70° C., and the reaction mixture was stirred at −70° C. for 2 hours. The reaction was quenched with addition of water. The reaction mixture was extracted with 3 portions of DCM. Combined organic phase were dried with MgSO4, filtrated and evaporated to give the desired product, 6-[2-(dimethylamino)ethoxy]-2-pyridinecarbaldehyde (192 mg, 0.988 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[N:20][CH:19]=[N:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([F:30])[CH:24]=1.C(O)(C)C>Cl>[ClH:1].[Br:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]4[CH:21]=[N:20][CH:19]=[N:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[C:25]([F:30])[CH:24]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Reactant: Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCCn1cncn1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
suspension of 4-chloro-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline (214 mg, 0.7 mmol), 4-bromo-2-fluoroaniline (160 mg, 0.84 mmol) in isopropanolic hydrogen chloride (1 ml of a 5M solution) and isopropanol (5 ml) was heated at 80° C. for 1 hour. The mixture was allowed to cool, the precipitate was collected by filtration, washed with isopropanol and then ether and dried under vacuum at 70° C. to give 4-(4-bromo-2-fluoroanilino)-7-(2-(1,2,4-triazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (55 mg, 15%). 1H NMR Spectrum (DMSOd6) 3.99(s, 3H); 4.62(t, 2H); 4.75(t, 2H); 7.37(s, 1H); 7.5-7.7(m, 2H); 7.81(d, 1H); 8.04(s, 1H); 8.24(s, 1H); 8.63(s, 1H); 8.84(s, 1H); 11.52(s, 1H) MS-ESI: 459 [MH]+
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.C(#N)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:6]2[C:2](=[O:1])[CH2:3][CH2:4][C@H:5]2[C:7]([OH:9])=[O:8])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: CC#N
Product: O=C(O)[C@@H]1CCC(=O)N1c1ccc(Cl)cc1
Reaction time: 0.17 h

Procedure:
To a stirred suspension of (S)-5-oxo-pyrrolidine-2-carboxylic acid (775 mg, 6 mmol) in acetonitrile (10 mL) 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (1.8 mL, 12 mmol) is added at room temperature. After 10 min di-μ-hydroxy-bis[N,N,N′,N′-tetramethylenediamine)-copper (II) chloride (Cu-TMEDA) (300 mg, 0.65 mmol) is added to the clear solution. The bluish green colored mixture is stirred for 10 min and 4-chlorophenylboronic acid (1 g, 6.4 mmol) is added. After 20 h acetonitrile is evaporated in vacuo, the concentrate taken up in ammonium chloride (150 mL) and the aqueous layer is washed with ethyl acetate (3×100 mL). The aqueous layer is cooled in an ice-bath, treated with 1 N sulfuric acid to pH 2 and extracted with ethyl acetate (3×100 mL). Combined organic extracts washed with brine (2×50 mL), dried over anhydrous Na2SO4 and solvent removed in vacuo to give the title compound as an off-white solid. ESI m/z 240 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:24]([C:25]1[C:26]([CH3:28])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:29])[CH3:32]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 83 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, ethyl acetoacetate and acetic acid, concentrated sulfuric acid was added, followed by the same treatment as in Reference Example 1, to yield 6,7-dimethoxy 4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylic acid ethyl ester (83%), which was then recrystallized from ethanol to yield a colorless prismatic crystal having a melting point of 147 to 148° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[CH:22]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:38][CH:37]=1)[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[CH:22]([CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([O:44][CH3:45])=[O:43])=[CH:40][CH:41]=1)[CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C(=O)OC)cc2)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1.54 g (9.0 mmol) of 1-bromo-4-chlorobutane [CAS Reg. No. 6940-78-9] and 7.33 g (22.5 mmol) of anhydrous cesium carbonate are added to a solution of 1.0 g (2.25 mmol) of methyl 4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 18A) in 15 ml of dry toluene, and the mixture is then stirred at 60° C. for 18 h. The mixture is then filtered, and the filtrate is evaporated to dryness. The crude product obtained is taken up in ethyl acetate and washed twice with saturated sodium bicarbonate solution, and the organic phase dried over sodium sulfate and concentrated. The crude product is then purified by flash chromatography on silica gel (mobile phase: dichloromethane). This gives 0.850 g (1.59 mmol, 70.6% of theory) of a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:18])[N:12]=[C:13](SC)[NH:14][CH:15]=2)=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:35]=[CH:34][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:33][C:13]3[NH:14][CH:15]=[C:10]([CH2:9][C:6]4[CH:5]=[N:4][C:3]([O:2][CH3:1])=[N:8][CH:7]=4)[C:11](=[O:18])[N:12]=3)=[CH:27][CH:26]=2)=[CH:22][CH:21]=1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Reactant: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)cc4)cc3)nc2=O)cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
5-(2-Methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (30 mg, 0.114 mmol, 1 eq) and 2-[4-(4-Chloro-phenoxy)-phenyl]-ethylamine (42.6 mg, 0.171 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 130° C. for overnight. Reaction mixture was evaporated and crude residue (72 mg) was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-{2-[4-(4-Chloro-phenoxy)-phenyl]-ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.020 mmol; yield: 17.5%, HPLC-MS/UV: [M+H]+=464.93; rt: 10.93 min; purity: 95%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 2.77 (t, J=7.02 Hz, 2H), 3.39-3.52 (m, 4H), 3.84 (s, 3H), 6.49 (br.s., 1H), 6.88-7.03 (m, 4H), 7.24 (d, J=7.72 Hz, 2H), 7.40 (d, J=7.02, 2H), 7.61 (s, 1H), 8.44 (s, 2H), 10.92 (br.s., 1H)
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:9][CH2:8][CH2:7][C:4]=2[NH:5][N:6]=1.[CH3:10]C([O-])(C)C.[K+].CI>C1COCC1>[I:1][C:2]1[C:3]2[CH2:9][CH2:8][CH2:7][C:4]=2[N:5]([CH3:10])[N:6]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2c1CCC2
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2c1CCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a solution of 3-iodo-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (305 mg, 1.3 mmol) in THF (8.51 mL) at 0° C. was added KOtBu 1M in THF (1.82 mL, 1.82 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale yellow solution then added MeI (259 mg, 114 μL, 1.82 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (40 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min) to afford the more polar desired 3-iodo-1-methyl-1,4,5,6-tetrahydrocyclopenta[c]pyrazole (177 mg, 714 μmol, 55%) as a white solid. MS (M+H)+=249; 1H NMR (CDCl3) δ: 3.78 (s, 30H), 2.68-2.79 (m, 20H), 2.51-2.58 (m, 4H). The regisomeric product, 3-iodo-2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole, (125 mg, 504 μmol, 39%) was also obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([F:11])[C:5]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[C:7]([C:8]([O:10][CH3:23])=[O:9])=[C:6]([F:11])[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(Br)c(C(=O)O)c2F)CC1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCCCC1CCC(c2ccc(Br)c(C(=O)OC)c2F)CC1
Yield: 101.6 %

Procedure:
17.1 g (46.0 mmol) of trans-6-bromo-2-fluoro-3-(4-pentylcyclohexyl)-benzoic acid were dissolved in 70 ml of acetone, 7.66 g (55.4 mmol) of potassium carbonate and 3.14 ml (50.6 mmol) of methyl iodide were added, and the mixture was refluxed overnight. The batch was filtered, and the solvent was distilled off, giving 18 g (100%) of methyl 6-bromo-2-fluoro-3-(4-pentylcyclohexyl)benzoate as a colourless oil, which was reacted further without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[O:28]1[CH:32]=[CH:31][C:30]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:29]1
Reactant: OB(O)c1ccoc1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccoc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-furanboronic acid in General Procedure A. Purification on silica yielded 231. NMR (CDCl3): 2.66-2.68 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.28-3.31 (m, 4H, 2×CH2), 3.86-3.88 (m, 6H, 3×CH2), 3.98-4.01 (m, 4H, 2×CH2), 7.04 (d, H, ArH, J=1.65 Hz), 7.26 (ms, H, ArH-part under CDCl3), 7.46 (ms, H, ArH), 8.18 (s, H, ArH). MS: (ESI+): MH+ 464.16
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[F:1][C:2]1[C:9]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1cccc(O)c1F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1F

Procedure:
2-Fluoro-3-hydroxybenzaldehyde (16.49 g) was dissolved in dimethylformamide (200 ml) and stirred under an argon atmosphere. Sodium hydride was added (60% in mineral oil, 5.18 g) and the mixture was stirred for 30 minutes. Benzyl bromide was added (16.8 ml) and the mixture was stirred overnight. Reaction mixture was concentrated in vacuo and the resulting residue was partitioned between diethyl ether (200 ml) and water (200 ml). Combined organic extracts were washed with water (400 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography, using a gradient of 0-10% ethyl acetate/iso-hexane as eluent to give the product as a yellow solid (18.41 g) 1H NMR (DMSO-d6) δ 5.20(s, 2H), 7.2-7.6(m, 8H), 10.21(s, 1H)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:25][NH:26][C:27]([NH2:29])=[O:28].C(OCC)(=O)C>N1C=CC=CC=1>[C:20]([C:17]1[CH:16]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:18]=1[OH:19])[C:8](=[N:25][NH:26][C:27]([NH2:29])=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: NNC(N)=O
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C(=NNC(N)=O)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
1.60 g of 3,5-di-t-butyl-4-hydroxybenzophenone and 0.67 g of semicarbazide hydrochloride were dissolved in 12 ml of pyridine, and the solution was refluxed for 6 hours. After the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed with 5% hydrochloric acid and water and dried. The solvent was removed by concentration, and the residue was chromatographed on a silica gel column and recrystallized from diethyl ether to give 3,5-di-t-butyl-4-hydroxybenzophenone semicarbazone.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([N:25]([CH:34]([CH3:36])[CH3:35])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:24]>CN(C=O)C>[CH:34]([N:25]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:23](=[O:24])[CH2:22][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:35])[CH3:36]
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a solution of N-phenyl-benzene-1, 2-diamine(3.08 g) in DMF (35 mL) was added potassium carbonate (2.31 g) and 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (4.79 g) and stirred 18 h at ambient temperature. The solvent was evaporated in vacuo and the resultant oil was dissolved in ethyl acetate (250 mL), washed with 1N HCl (4×100 mL), dried over sodium sulfate, filtered, and concentrated to a brown oil. The oil was subjected to flash chromatogaraphy on silica gel (70 g) eluted with ethyl acetate/hexanes (1:4, 1 L). Fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a tan foam (3.95 g). 1H NMR (300 MHz, CDCl3): d 1.05 (d, J=6.9 Hz, 6H), 3.44 (s, 2H), 3.87 (s, 3H), 4.97 (m, 1H), 5.37 (br s, 1 H) 6.36 (d, J=7.4 Hz, 1H), 6.69 (t, 1H), 6.71-7.21 (m, 11H) TLC (EtOAc/Hexane (1:4)): Rf =0.18.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]([CH2:39][CH2:40][OH:41])[CH2:36][CH2:37][OH:38]>>[OH:41][CH2:40][CH2:39][N:35]([CH2:36][CH2:37][OH:38])[CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:8](=[O:29])[NH:9][C:10]1[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]2[C:18]([F:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[F:23])[C:11]=1[C:26]([NH2:27])=[O:28]
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: NCCCCN(CCO)CCO
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCCN(CCO)CCO)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 2-[(4-amino-butyl)-(2-hydroxy-ethyl)-amino]-ethanol by the procedure analogous to Example 1. MS (APCI, m/z): 502 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH2:12][NH:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[CH:16][C:15]=3[NH2:24])[CH:8]=2)[CH:2]=1.[C:25](OC)(OC)(OC)[CH2:26][CH2:27][CH3:28].Cl.N1C=CC=CC=1>>[CH2:26]([C:25]1[N:13]([CH2:12][C:9]2[CH:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[O:11][N:10]=2)[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:27][CH3:28]
Reactant: Nc1cnc2ccccc2c1NCc1cc(-c2cccnc2)on1
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1nc2cnc3ccccc3c2n1Cc1cc(-c2cccnc2)on1
Yield: 84.5 %

Procedure:
The methods of Part H of Example 35 were used to treat N4-[(5-pyridin-3-ylisoxazol-3-yl)methyl]quinoline-3,4-diamine (0.95 g, 2.98 mmol) with trimethy orthobutyrate (0.57 mL, 3.6 mmol) and pyridine hydrochloride (0.069 g, 0.60 mmol) and purify the product to provide 0.930 g of 2-propyl-1-[(5-pyridin-3-ylisoxazol-3-yl)methyl]-1H-imidazo[4,5-c]quinoline as a tan solid.
Reaction SMILES: [CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH:33]=O)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:1]1([N:7]([CH3:36])[C:8]2[C:9]([CH3:35])=[C:10]([CH:24]=[C:25]([C:27]3[CH:28]=[N:29][C:30]([CH2:33][N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[CH:31][CH:32]=3)[CH:26]=2)[C:11]([NH:13][CH2:14][C:15]2[C:16](=[O:23])[NH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a stirred solution of compound 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methylbenzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 8 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford 3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-5-(6-(morpholinomethyl)pyridin-3-yl)benzamide (0.089 g, 53% yield). LCMS: 558.35 (M+1)+; HPLC: 96.52% (@254 nm) (Rt; 4.375; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.75 (s, 1H), 8.18 (t, 1H), 8.01 (d, 1H, J=6.8 Hz), 7.49 (d, 1H, J=8 Hz), 7.33 (s, 1H), 7.18 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=3.6 Hz), 3.59-3.61 (m, 6H), 2.75 (m, 1H), 2.65 (s, 3H), 2.43 (bs, 4H), 2.21 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.70 (bs, 4H), 1.53-1.56 (m, 1H), 1.42-1.44 (m, 1H), 1.09-1.23 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])[CH:6]([CH3:8])[CH3:7])C.Cl.[NH2:21]O.C[O-].[Na+]>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:9]1[O:18][N:21]=[C:4]([OH:3])[C:5]=1[CH:6]([CH3:8])[CH3:7]
Reactant: NO
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1F)C(C)C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)c1c(O)noc1-c1ccc(F)cc1F
Yield: 39.2 %

Procedure:
2-(2,4-Difluorobenzoyl)isovaleric acid ethyl ester (1.7 g), hydroxylamine hydrochloride (0.9 g) and sodium methoxide (28% methanol solution, 7.5 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 8(b) to obtain the title compound (0.59 g, 39%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[C:11](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1Cl
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1nccnc1Cl
Reaction time: 48 h

Procedure:
To a suspension of 3-chloropyrazine-2-carboxylic acid (10 g, 63 mmol) and cesium carbonate (31 g, 95 mmol) in DMF was added iodomethane (5.9 ml, 95 mmol). The solution was stirred for 48 hours. After that time, the reaction was removed from stirring, acidified to pH 5 with 1.0 N HCl and extracted five times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated, affording to target material as an orange oil. MS (ESI, pos. ion) m/z: 173.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:29]([Cl:39])[CH:28]=1)=[N:7]2>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:29]([Cl:39])[CH:28]=1)=[N:7]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Nc4ccc(N5CCOCC5)c(Cl)c4)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc(Nc2ncc3c(Br)ccc(OC4CCNCC4)c3n2)ccc1N1CCOCC1
Yield: 50 %

Procedure:
A solution of tert-butyl 4-(5-bromo-2-(3-chloro-4-morpholinophenylamino) quinazolin-8-yloxy)piperidine-1-carboxylate in 30% TFA/DCM was stirred at room temperature for 30 min. The solvent was evaporated and crude was purified by semi-prep HPLC to provide 5-bromo-N-(3-chloro-4-morpholinophenyl)-8-(piperidine-4-yloxy) quinazolin-2-amine in 50% yield. ES/MS m/z 518.0 (MH+).
Reaction SMILES: [CH2:1](O)[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10].S(Cl)([Cl:14])=O.N1C=CC=CC=1>O1CCCC1>[CH2:1]([Cl:14])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COCCOCCOCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCCOCCOCCCl
Yield: 90 %

Procedure:
101.16 g (≈0.6 mole) of 3,6,9-trioxadecanol are reacted with 44.6 ml (≈0.6 mole) of thionyl chloride and 51.7 ml (≈0.64 mole) of pyridine in a tetrahydrofuran solution by refluxing for 12 hours to give 3,6,9-trioxadecyl chloride ##STR19## The mixture is cooled and then extracted several times with methyl ethyl ketone (MEK), and the MEK phase is then neutralized with NaHCO3 and dried over Na2SO4. After the MEK has been removed, the residue is distilled under 30 Pa and at 30°-37° C. Yield: 90%.