Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][Br:6])C.Br.[Br:11][C:12]1[C:13]([NH2:19])=[N:14][C:15](Br)=[CH:16][N:17]=1>CC(O)C>[Br:11][C:12]1[N:17]2[CH:16]=[CH:15][N:14]=[C:4]2[C:5]([Br:6])=[N:19][CH:13]=1
Reactant: Nc1nc(Br)cnc1Br
Reactant: CCOC(CBr)OCC
Agent: Br
Solvent: CC(C)O
Product: Brc1ncc(Br)n2ccnc12

Procedure:
Bromoacetaldehyde diethyl acetal (49 mL, 326 mmol) and 48% hydrobromic acid is heated to reflux for 1.5 h, then poured into propan-2-ol (600 mL) and quenched with NaHCO3. After filtering, 3,6-dibromopyrazin-2-yl amine (41.34 g, 163 mmol) is added to the solution and heated at reflux overnight. The reaction is cooled and solvents removed in vacuo, followed by addition of aq. NaHCO3 and extraction with EtOAc. The organic phase is dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford a brown solid. 1H NMR (250 MHz, CDCl3) δ(ppm) 7.86 (s, 1H), 7.93-7.94 (d, 1H), 7.98-7.99 (d, 1H); m/z (APCI) 278 (M+H)+; m.p 132-135° C.
Reaction SMILES: O=[C:2]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=2[NH:3]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:31].O>C1(C)C=CC=CC=1>[Cl:31][C:2]1[C:11]2[N:12]=[CH:13][N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:16]([O:18][CH3:19])=[O:17])=[CH:5][C:4]=2[N:3]=1
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ncncc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ncncc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
In a vial, methyl 5-oxo-5,6-dihydropyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 151 mg, 0.59 mmol) was mixed in toluene (1 ml) with DIEA (1.5 eq, 155 ul, 0.89 mmol) and POCl3 (5 eq, 270 ul, 3.0 mmol). The mixture was stirred at 120° C. for 1 hour and cooled down to room temperature. After adding ice and water the compound was extracted with CH2Cl2 (4×). The solution was filtered over Na2SO4 and filtered through a pad of celite. After evaporation of the volatiles, the material was triturated in a mixture of ethyl acetate and hexanes, filtered and dried to afford methyl 5-chloropyrimido[4,5-c]quinoline-8-carboxylate as a light brown fluffy solid (115 mg, 71% yield). LCMS (ES): 95% pure, m/z 274 [M+1]+. 1H NMR (DMSO-d6, 400 MHz) δ 3.96 (s, 3H), 8.37 (dd, J=1.6, J=8.4, 1H), 8.60 (d, J=1.6, 1H), 9.15 (d, J=8.8, 1H), 9.74 (s, 1H), 10.61 (s, 1H) ppm
Reaction SMILES: [CH:1]([O:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(C)[CH3:2].[Br:10]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[Br:10][C:7]1[S:6][C:5]([O:4][CH2:1][CH3:2])=[N:9][CH:8]=1
Reactant: CC(C)Oc1nccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a solution of 2-isopropoxythiazole (300 mg, 2.32 mmol) in DMF (2 mL) was added N-bromosuccinimide (620 mg, 3.48 mmol). The mixture was stirred at room temperature for 3 hours then subjected to flash column chromatography using 10% ethyl acetate/hexane to give a colorless oil (440 mg, 91% yield). LCMS (Conditions C): Tr 3.27 min.; (M+H)+: 207.88 (20%), 209.88 (20%), 179.87 (100%), 181.87 (100%).
Reaction SMILES: CON(C)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.[CH3:17][CH:18]([CH3:23])[CH2:19][CH2:20][Mg]Br>C1COCC1>[CH3:17][CH:18]([CH3:23])[CH2:19][CH2:20][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:15]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CCC(=O)c1ccc(C(F)(F)F)cc1
Yield: 77 %

Procedure:
With the similar conditions of Example 29, steps (a) and (c), reaction of N-Methoxy-N-methyl-4-trifluoromethyl-benzamide, compound 31 a, with 3-methyl-1-butyl magnesium bromide, compound 29a, in THF gave the title compound in 77% yield; Calcd MW 244.26. Found MH+ 245.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](OC1C=C2C(C(NCCOC3C=CC=CC=3)=C(N)C=N2)=CC=1)[C:23]1C=CC=CC=1.[C:51](OCC)(OCC)(OCC)CC.C(OC)(OC)(OC)CCCC>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:21]([CH2:22][CH3:23])[N:20]([CH3:51])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCCOc1ccccc1
Reactant: CCOC(CC)(OCC)OCC
Agent: CCCCC(OC)(OC)OC
Product: CCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1C

Procedure:
The general method described in Part A of Example 47 was followed using 6-benzyloxy-N4-methylquinoline-3,4-diamine (7.91 g, 28.3 mmol) in lieu of 7-benzyloxy-N4-(2-phenoxyethyl)quinoline-3,4-diamine and triethyl orthopropionate (12.69 mL, 56.6 mmol) in lieu of trimethyl orthovalerate. The precipitate from the reaction was isolated in two crops to provide 7.56 g of 8-benzyloxy-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinoline as a yellow solid, mp 168.2-169.0° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[CH:16]=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[C:28](Cl)(=[O:32])[C:29](Cl)=[O:30].[N:34]1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:28](=[O:32])[C:29]([NH2:34])=[O:30])=[C:15]([CH2:17][CH3:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1
Reactant: CCc1cc2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(F)c1
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73 %

Procedure:
To a solution of 300 mg (0.770 mmol) of [[2-(methylthio)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester in 5 mL of chloroform was added 0.21 mL of oxalyl chloride followed by 0.09 mL of pyridine. The reaction was stirred for 2 days at ambient temperature then quenched into 4.0 mL of dilute ammonium hydroxide. The product was extracted into 4.0 mL of methylene chloride. The organic phase was washed with water, dried with sodium sulfate and concentrated to 430 mg of tan solid. The residue was purified by flash chromatography (45 g of silica, ethyl acetate) to provide 260 mg (73%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[(3-fluorophenyl)methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid methyl ester as a solid. nmr (300 MHz, dmso-d6) δ1.00 (t, 3H), 2.45 (s, 3H), 2.90 (q, 2H), 3.65 (s, 3H), 4.97 (s, 2H), 5.52 (s, 2H), 6.91 (d, 1H), 7.03 (d, 1H), 7.12 (dt, 1H), 7.47 (dt, 1H), 7.60 (s, 1H), 8.01 (s, 1H)
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]=[CH:10][O:9]1)[CH3:2].C([OH:16])C.[OH-].[Na+].OO>CCCCCC.O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH:8]1[O:9][CH2:10][CH:11]([OH:16])[CH2:12][CH2:13]1)[CH3:2]
Reactant: CCOCCOCC1CCC=CO1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOCCOCC1CCC(O)CO1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
2.5 ml of borane-dimethyl sulfide complex was added drop by drop to a stirred solution of 10.00 g of 5A in 30 ml of hexane under a nitrogen atmosphere at 2°-5° C. After 2 hours at 0°-10° C., 4 ml of ethanol was added. The solvent then was stripped, and the residue was dissolved in 30 ml of tetrahydrofuran. At -2° to +6° C. under a nitrogen atmosphere, 10.72 ml of 10% sodium hydroxide solution was added in portions to the stirred mixture. Then at 15°-40° C., 6.4 ml of 30% hydrogen peroxide solution was added drop by drop. The resulting mixture was warmed to 45° C. and held there for 45 minutes, then stripped of solvent. The residue was slurried with ethyl acetate. The mixture was filtered, and the filtrate was dried (MgSO4) and stripped of solvent. The residue was vacuum distilled to give 6 -((2-ethoxyethoxy)methyl)tetrahydro-2H-pyran-3-ol (5B), b.p.: 110°-112° C., 0.07 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([NH2:12])[N:6]=1)=[O:4].[CH2:13]([O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH3:14].O1CCOC[CH2:22]1>>[Br:11][C:8]1[C:7]([NH:12][C:19]([NH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17])=[S:20])=[N:6][C:5]([C:3]([O:2][CH2:1][CH3:22])=[O:4])=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(Br)c(N)n1
Reactant: CCOC(=O)N=C=S
Reactant: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1nc(C(=O)OCC)ccc1Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (3.3 g, 14.28 mmol) in dry 1,4-dioxane (20 mL) was added ethoxy carbonyl isothiocyanate (1.8 mL, 15.7 mmol) under an argon atmosphere and stirred at room temperature for 16 hours. The solvent was evaporated and the title compound was obtained as yellow solid (4.9 g, 95%).
Reaction SMILES: FC1C=CN=C2C=1CCCN2.Br[C:13]1[C:14]([F:26])=[C:15]2[C:20](=[N:21][CH:22]=1)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]2.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]([C:41]3([OH:47])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH:38]=[N:39][CH:40]=2)O1>>[F:26][C:14]1[C:13]([C:35]2[CH:40]=[N:39][CH:38]=[C:37]([C:41]3([OH:47])[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[CH:36]=2)=[CH:22][N:21]=[C:20]2[C:15]=1[CH2:16][CH2:17][CH2:18][N:19]2[C:23]([NH2:25])=[O:24]
Reactant: NC(=O)N1CCCc2c1ncc(Br)c2F
Reactant: CC1(C)OB(c2cncc(C3(O)CCOCC3)c2)OC1(C)C
Agent: Fc1ccnc2c1CCCN2
Product: NC(=O)N1CCCc2c1ncc(-c1cncc(C3(O)CCOCC3)c1)c2F

Procedure:
5-Fluoro-1,2,3,4-tetrahydro-[1,8]naphthyridine is converted to 6-bromo-5-fluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide according to Step 1 and Step 2 of Example 121. 6-Bromo-5-fluoro-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide is coupled with 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-tetrahydro-pyran-4-ol (which is prepared according to Step 4 of Example 119) to give the titled product using Suzuki Coupling Method VI.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].C(N(CC)CC)C.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]#[CH:23]>COCCOC.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]#[C:23][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7]
Reactant: Cc1ncsc1Br
Reactant: C#Cc1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1ncsc1C#Cc1ccccc1F
Yield: 113.4 %

Procedure:
5-Bromo-4-methyl-1,3-thiazole (500 mg, 2.8 mmol) and CuI (120 mg, 0.63 mmol) were combined in DME (5 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (2.0 mL, 14 mmol) and PdCl2(PPh3)2 (220 mg, 0.32 mmol) were added, followed by the dropwise addition of (2-fluorophenyl)acetylene (1.0 g, 8.3 mmol). The reaction mixture was heated and after 3 h at reflux, allowed to cool, diluted with ethyl acetate (20 mL), and filtered through Celite™. The filter pad was washed thoroughly with ethyl acetate and the combined filtrates were washed with water (20 mL), brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with 95:5 hexane:ethyl acetate to afford 5-[(2-fluorophenyl)ethynyl]-4-methyl-1,3-thiazole (690 mg, 56% yield) as a red oil. 1H NMR (CDCl3, 300 MHz) δ 8.65 (s, 1H), 7.53–7.47 (m, 1H), 7.36–7.26 (m, 1H), 7.17–7.09 (m, 2H), 2.62 (s, 3H). MS (ESI) 217.3 (M+).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:11][C:10]=3[C:23](=[O:25])[O:24][C:4]=2[CH:3]=1.[CH2:26](OS(OCC)(=O)=O)[CH3:27].C([O-])([O-])=O.[K+].[K+].[CH3:41][C:42](C)=O>>[CH2:26]([O:1][C:2]1[C:7]([O:8][CH2:41][CH3:42])=[CH:6][C:5]2[C:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)[CH2:11][C:10]=3[C:23](=[O:25])[O:24][C:4]=2[CH:3]=1)[CH3:27]
Reactant: O=c1oc2cc(O)c(O)cc2c2c1CN(CCN1CCCCC1)CC2
Reactant: CC(C)=O
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1cc2oc(=O)c3c(c2cc1OCC)CCN(CCN1CCCCC1)C3

Procedure:
A mixtue of 0.01 m of 1,2,3,4-tetrahydro-8,9-dihydroxy-3-(2-piperidinoethyl)-5H-[1]benzopyrano[3,4-c]-pyridin-5-one, 0.022 m of diethylsulfate and 0.1 m K2CO3 in 250 cc of acetone was refluxed for 20 hr and filtered hot. After evaporation, the residue was crystallized twice from EtOAc affording 0.6 g of product; mp 144°-146°C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Mg+2].[S:27]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28]1>C(N(CC)CC)C>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH:3]([NH:2][CH2:32][C:29]2[CH:30]=[CH:31][S:27][CH:28]=2)[C:4]([O:6][CH3:7])=[O:5])=[CH:13][CH:12]=1
Reactant: O=Cc1ccsc1
Reactant: COC(=O)[C@H](N)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(NCc1ccsc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of methyl(R)-amino-(4-hydroxyphenyl)acetate hydrochloride and 100 mL of anhydrous ethyl acetate (thick suspension) are introduced at ambient temperature into a 500 mL Woulff bottle equipped with a nitrogen intake, a magnetic stirrer and a condenser. 3.1 mL of triethylamine, some magnesium sulphate and 3 g of thiophene-3-carbaldehyde are added. After 4 hours under reflux, the white solid is filtered, washed with ethyl acetate and dried under vacuum. The product is taken up in 100 mL of anhydrous dichloromethane. 14 g of sodium triacetoxy borohydride are added and the mixture is stirred at ambient temperature for 2 hours. 100 mL of methanol are added then the reaction mixture is concentrated. The product is extracted with ethyl acetate. It is washed with water then the organic phases are dried over magnesium sulphate. The mixture is concentrated, and the residue is purified over a silica column with 50/50 heptane/ethyl acetate. After concentration and crystallisation in isopropanol, a white solid is obtained (2.35 g; Yd=37%).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>C1COCC1>[CH2:24]([O:26][NH:27][C:3]([C:5]1[N:6]=[CH:7][C:8]2[N:9]([CH:20]=[N:21][CH:22]=2)[C:10]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[F:19])=[O:4])[CH3:25]
Reactant: CCON
Reactant: COC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCONC(=O)c1ncc2cncn2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
To a solution of 5-(2-fluoro-4-iodo-phenylamino)-imidazo[1,5-a]pyrazine-6-carboxylic acid methyl ester (165.0 mg, 0.40 mmol) and O-ethylhydroxylamine hydrochloride (78.1 mg, 0.80 mmol, 2.0 eq) in anhydrous THF (9.4 mL) at 0° C. was added lithium hexamethyldisilazide (1M in THF, 1.2 mL, 1.2 mmol, 3.0 eq). After stirring at room temperature for 16 h, additional O-ethylhydroxylamine hydrochloride (234.3 mg, 2.40 mmol, 3.0 eq) and lithium hexamethyldisilazide (1M in THF, 3.6 mL, 3.6 mmol, 9.0 eq) were added at 0° C., and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate (5 mL) and diluted with ethyl acetate (50 mL). The organic layer was isolated and washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 45% to 100%, ethyl acetate in hexane, followed by gradient 0 to 15% methanol in ethyl acetate) to give an oil. Crystallization from DCM—ether—hexane afforded the title compound as a yellow solid (33.7 mg, 19.1%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.86 (s, 1H), 10.38 (s, 1H), 8.82 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (d, J=10.4 Hz, 1H), 7.44 (d, 8.4 Hz, 1H), 6.57 (t, J=8.4 Hz, 1H), 3.90 (q, J=7.2 Hz, 2H), 1.18 (t, J=6.8 Hz, 3H); LCMS (method D2): RT=1.24 min, [M+H]+=442.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[N:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=1)=[N+:24]=[N-:25].CCN(C(C)C)C(C)C.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C.CCOC(C)=O>[N:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:32])=[CH:33][CH:34]=1)=[N+:24]=[N-:25]
Reactant: C1COCCN1
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
TBTU (1.28 g; 3.98 mmol; 1.3 eq.) was added to a cooled (0° C.) solution of 4-azidobenzoic acid (500 mg; 3.06 mmol; 1.0 eq.) and DIEA (1.2 mL; 7.05 mmol; 2.3 eq.) in DMF (10 mL). After 15 min, morpholine (324 μl; 3.68 mmol; 1.2 eq.) was added and the reaction mixture was stirred at RT for 3 hours. The reaction mixture was diluted with EtOAc and washed twice with an aqueous saturated solution of NaHCO3 then with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound as a beige solid (710 mg, 100%). 1H NMR (300 MHz, DMSO-d6) δ 7.46 (d, J=8.6 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 3.59-3.47 (m, 8H). HPLC (Condition A): Rt 2.21 min (purity 98.2%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[N:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:29]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:30])[C:17]=2[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[N:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCCN)CCCC3
Product: COCCc1nc2c(N)nc3c(c2n1CCCNC(=O)N1CCOCC1)CCCC3
Yield: 44.4 %

Procedure:
Using the general method of Example 167, 1-(3-aminopropyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 6.59 mmol) was reacted with 4-morpholinecarbonyl chloride (1.08 g, 7.25 mmol) to provide 1.22 g of N-{3-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]propyl}morpholine-4-carboxamide as a white powder, m.p. 171.8–173.2° C. Analysis: Calculated for C21H32N6O3: % C, 60.56; % H, 7.74; % N, 20.18; Found: % C, 60.30; % H, 7.72; % N, 20.11.
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[C:7]=1[OH:13])=[O:4].C([O-])([O-])=O.[K+].[K+].O.C(OCC)(=O)C>CN(C=O)C>[Br:12][C:8]1[C:7]2[O:13][C:2]([CH3:15])([CH3:14])[C:3](=[O:4])[NH:5][C:6]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(Br)C(=O)Nc1cccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2c(Br)cccc2NC1=O
Temperature: 150 °C
Yield: 84.6 %

Procedure:
The 2-bromo-N-(3-bromo-2-hydroxy-phenyl)-2-methyl-propionamide of step 1 was dissolved in DMF (200 ml), and to the DMF solution was added to K2CO3 (6.3 g, 45.58 mmol). The mixture was heated overnight at 150° C., then cooled and poured into a mixture of water/ethyl acetate. The organic fraction was washed with brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 8-bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one as a white solid (84.6%). MS: (M−H)− 256.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)N3CCOCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
Morpholine (0.106 g, 1.225 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.352 g, 1.838 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenoxy)benzoic acid (0.250 g, 0.613 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.173 g, 0.341 mmol, 51%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]([N:23]=[C:24]=[O:25])=[CH:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[C:17]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][C:24]([NH:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]2[N:4]([CH3:7])[N:5]=[CH:6][C:2]=2[Br:1])[CH:9]=1)=[O:25]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccccc1-c1ccccc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccccc2-c2ccccc2)cc1-c1c(Br)cnn1C
Yield: 46.2 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.036 g, 0.13 mmol) was treated with 2-biphenylyl isocyanate (0.027 g, 24.0 μL, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 22 (0.031 g, 0.06 mmol, 51%) as a white powder. LCMS m/z (%)=477 (M+H79Br, 100), 479 (M+H81Br, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.41 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.60 (d, J=2.7, 9.0 Hz, 1H), 7.43-7.51 (m, 3H), 7.37-7.43 (m, 3H), 7.29-7.37 (m, 2H), 7.24 (s, 1H), 7.20 (dd, J=1.6, 7.6 Hz, 1H), 7.11 (dd, J=1.0, 7.4 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 3.80 (s, 3H), 3.66 (s, 3H).