Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[CH:10]1[CH:14]=[CH:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[OH-].[Na+]>>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:15])[CH2:12][CH2:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1C=CCC1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCC/C=C\C1=CCCC1=O

Procedure:
A solution of 3 g. of crude 2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one (Example 1133) in 100 ml. of 2% sodium hydroxide is stirred at 80° C. under nitrogen for 1.5 hours. The cooled solution is acidified to Congo Red and extracted into ether. The ethereal extracts are dried over sodium sulfate and evaporated at reduced pressure to afford the product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CCOC(=O)CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 96 h
Yield: 60.4 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (10.5 g. 30 mmols), ethyl 5-bromovalerate (10.2 ml, 60 mmols), potassium carbonate (4.2 g, 30 mmols) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 96 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 5-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminovalerate (8.65 g, 60.4%).
Reaction SMILES: Cl.[NH2:2][C:3]1([C:26](=[O:28])[CH3:27])[CH2:20][C:19]2[C:18]([OH:21])=[C:17]3[C:8]([C:9](=[O:23])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]3=[O:22])=[C:7]([OH:24])[C:6]=2[CH:5]([OH:25])[CH2:4]1.C(O[C:33](=[O:35])[CH3:34])(=O)C.Cl>N1C=CC=CC=1>[C:26]([C:3]1([NH:2][C:33]([CH3:34])=[O:35])[CH2:20][C:19]2[C:18]([O:21][C:18](=[O:21])[CH3:17])=[C:17]3[C:8]([C:9](=[O:23])[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]3=[O:22])=[C:7]([O:24][C:16](=[O:22])[CH3:15])[C:6]=2[CH:5]([O:25][C:9](=[O:23])[CH3:8])[CH2:4]1)(=[O:28])[CH3:27]
Reactant: CC(=O)C1(N)Cc2c(O)c3c(c(O)c2C(O)C1)C(=O)c1ccccc1C3=O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NC1(C(C)=O)Cc2c(OC(C)=O)c3c(c(OC(C)=O)c2C(OC(C)=O)C1)C(=O)c1ccccc1C3=O
Temperature: 0 °C

Procedure:
To a mixture of 9-amino-9-acetyl-6,7,11-trihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione hydrochloride (550 mg) and anhydrous pyridine (10 ml), acetic anhydride (3 ml) was added thereto while cooling with ice water. The resultant mixture was heated at a temperature of 60° to 65° C. for 30 minutes. The reaction mixture was poured into 3% hydrochloric acid and extracted with chloroform. The chloroform extract was washed with water, a saturated sodium bicarbonate solution and water in order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography to give 9-acetyl-9-acetamino-6,7,11-triacetoxy-7,8,9,10-tetrahydro-5,12-naphthacenedione. M.P., 276°-278° C.
Reaction SMILES: Cl.CC1(C)[O:7][C@H:6]([CH2:8][N:9]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[C:16]3[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]3=[O:25])=[CH:10]2)[CH2:5][O:4]1.O>C(#N)C>[OH:7][C@@H:6]([CH2:5][OH:4])[CH2:8][N:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:16]2[C:11]([N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH3:26])[C:15]2=[O:25])=[CH:10]1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)n(C[C@@H]3COC(C)(C)O3)cc2n(C)c1=O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(C[C@@H](O)CO)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
HCl (2 M in diethyl ether) (92 ml, 185 mmol) was added dropwise to a solution of (R)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (7.15 g, 18.46 mmol) and water (6.65 g, 369 mmol) in acetonitrile (35.1 mL). The mixture was stirred at room temperature for 30 minutes. Evaporation of the reaction mixture under vacuum afforded the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[C:21]([O:23]C)=[O:22].[ClH:37].[Cl:38]CCl.CO>CO.O>[ClH:38].[ClH:37].[OH:3][CH:4]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1)[CH2:5][CH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][S:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][C@@H:8]1[C:21]([OH:23])=[O:22]
Reactant: ClCCl
Reactant: COC(=O)[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSC4CCCC4)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C

Procedure:
2 cm3 of 5N aqueous sodium hydroxide solution were added, with stirring and under an inert atmosphere, to a solution of 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylate in 10 cm3 of methanol. After heating the mixture for 16 hours at a temperature in the region of 60° C., the reaction mass was evaporated under reduced pressure (2.9 kPa) at a temperature in the region of 60° C. and the residue obtained was taken up in 4.3 cm3 of distilled water to which had been added 4.3 cm3 of 28% hydrochloric acid. The remaining insoluble material was filtered off and then the filtrate was evaporated under the same conditions as above. The residue obtained was stirred in a dichloromethane/methanol (90/10 by volume) mixture. The resulting precipitate was filtered off and washed with 3 times 2.5 cm3 of the same mixture. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid dihydrochloride was obtained in the form of a foam with a green color melting with softening at a temperature in the region of 156° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.CCN(C(C)C)C(C)C.[CH:30]1([C:33]([CH:42]2[CH2:44][CH2:43]2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([SH:41])[CH:36]=2)[OH:34])[CH2:32][CH2:31]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:42]1([C:33]([CH:30]2[CH2:31][CH2:32]2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([S:41][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]3[C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[N:13][N:14]=[C:7]3[CH:6]=[CH:5]4)[CH:36]=2)[OH:34])[CH2:44][CH2:43]1
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccc4)n32)c1
Reactant: OC(c1cccc(S)c1)(C1CC1)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OC(c1cccc(Sc2ccc3c(ccc4nnc(-c5ccccc5)n43)c2)c1)(C1CC1)C1CC1
Temperature: 100 °C

Procedure:
To 7-iodo-1-phenyl-[1,2,4]triazolo[4,3-a]quinoline (10j, 176 mg, 0.47 μmmol) in 1,4-dioxane (4.5 mL) was added iPr2NEt (0.16 mL, 0.94 mmol), and the reaction was degassed with N2 for 5 minutes. 10i (174 mg, 0.47 mmol) was added, followed by Pd2dba3 (22 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (28 mg, 0.05 mmol). The reaction was sealed and heated at 100° C. for 6 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (60-80% EtOAc in hexanes) to give the desired product, 10k.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:16]1[CH2:21][CH2:20][CH:19]([N:22]2[CH2:27][CH2:26][CH2:25][NH:24][C:23]2=[O:28])[CH2:18][CH2:17]1>C(O)C>[C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]([OH:13])[CH2:12][N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:27][CH2:26][CH2:25][NH:24][C:23]3=[O:28])[CH2:18][CH2:17]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(OCC2CO2)cc1
Reactant: O=C1NCCCN1C1CCNCC1
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(O)CN2CCC(N3CCCNC3=O)CC2)cc1

Procedure:
A solution of 19.35 g of 1-(p-acetamido-phenoxy)-2,3-epoxy-propane and 9.15 g of 1-(4-piperidyl)-2-oxo-hexahydropyrimidine in 10 ml of abs. ethanol is heated to 95° C. The reaction product crystallises out at boiling heat after about 5 minutes. The crystal broth is diluted with 10 ml of abs. ethanol and heated for a further 5 hours. When the reaction is terminated the batch is evaporated in vacuo and the residue is recrystallised from abs. ethanol/ether to yield the 1-[3-(p-acetamido-phenoxy)-2-hydroxypropyl]-4-(2-oxo-hexahydro-1-pyrimidinyl)-piperidine, which melts at 218°-221° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])O1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[C:31]3[CH:37]=[CH:36][NH:35][C:32]3=[N:33][CH:34]=2)=[C:25]([F:38])[CH:24]=1>>[F:38][C:25]1[CH:24]=[C:23]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]([CH2:19][CH3:20])(=[O:17])=[O:18])[CH:28]=[CH:27][C:26]=1[C:29]1[N:30]=[C:31]2[CH:37]=[CH:36][NH:35][C:32]2=[N:33][CH:34]=1
Reactant: Fc1cc(Br)ccc1-c1cnc2[nH]ccc2n1
Reactant: CCS(=O)(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc3[nH]ccc3n2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 490 using N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanesulfonamide and 2-(4-bromo-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine. MS (ESI): mass calcd. for C20H17FN4O2S, 396.11; m/z found, 397.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 8.78 (d, J=2.6, 1H), 8.20-8.11 (m, 2H), 7.75-7.66 (m, 2H), 7.47-7.37 (m, 1H), 7.36-7.28 (m, 2H), 7.27-7.20 (m, 1H), 6.87-6.79 (m, 1H), 6.59 (s, 1H), 3.11 (q, J=7.4, 2H), 1.33-1.18 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C@H:10]2[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26]I.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][N:11]2[C:12](=[O:23])[C:13]3[C:18]([C:10]2([CH3:26])[CH2:9]1)=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cccc3C(F)(F)F)[C@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(C(F)(F)F)cccc3C2(C)C1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(S)-1,3,4,10b-tetrahydro-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (150 mg, 0.4 mmol) and methyl iodide (125 mg, 0.9 mmol) in dry DMF (6 mL) was added sodium hydride (15 mg, 0.6 mmol). The reaction was stirred for 3 h and then quenched with brine. The reaction was extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0-50% EtOAc in hexanes) to yield 59 mg of the desired product as a white solid. MS (ESI) 371 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:16]O)[C:12]([O:14][CH3:15])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.CS(Cl)(=O)=O>C(N(CC)CC)C>[CH2:1]([O:8][C:9]([C:11](=[CH2:16])[C:12]([O:14][CH3:15])=[O:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(CO)C(=O)OCc1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C(=O)OC)C(=O)OCc1ccccc1
Temperature: 20 °C
Yield: 92 %

Procedure:
To a flame dried three neck round bottom flask, was added methyl 2-(benzyloxycarbonyl)-3-hydroxypropanoate (129 g, 509 mmol), anhydrous methylene chloride (2 L), and methanesulfonyl chloride (49.3 mL, 636 mmol). The mixture was cooled to −15° C.→20° C. for 20 min while stirring with a mechanical stirrer. Triethylamine (213 mL, 1527 mmol) was added dropwise ensuring the inner temperature of the reaction mixture did not exceed 0° C. (the addition of the first equivalent of triethylamine was exothermic). After the addition of triethylamine, the mixture was stirred at 0° C. for 30 min, then the cooling bath was removed and the mixture was stirred at room temperature for 1.5 h. Methanol (21 mL) was added to quench excess methanesulfonyl chloride. The mixture was washed portionwise with 0.5% aq. potassium hydrogen sulfate to pH 5, then sat. sodium bicarbonate/brine (1:2 by volume) and brine. The methylene chloride solution was dried over anhydrous sodium sulfate. After filtration, the solvents were removed and the residue was subjected to column chromatography on silica gel using 1:9 ethyl acetate/hexanes as eluent to afford the title compound as a colorless very viscous oil, which recrystalized upon standing at room temperature, 0° C. and −15° C. (111 g, 92% yield). 1H-NMR (DMSO-d6) δ 8.96 (s, 1H), 7.39-7.35 (m, 5H), 5.76 (s, 1H), 5.60 (s, 1H), 5.10 (s, 2H), 3.71 (s, 3H); 13C-NMR (DMSO-d6) δ 163.7, 153.5, 136.3, 133.3, 128.8, 128.3, 128.1, 127.8, 65.9, 52.3.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])([O-])=O.O.O.[Sn](Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)Cn1ccc2c([N+](=O)[O-])cccc21
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Cn1ccc2c(N)cccc21

Procedure:
To a solution of crude methyl 2-(4-nitro-1H-indol-1-yl)acetate (obtained as reported in Example 15, Step 1, theoretical amount 3.08 mmol) in THF (15 ml), tin(II) chloride dihydrate (6.243 g, 27.7 mmol) was added, and the mixture was reacted at 50° C. for 5 hours and at room temperature overnight. A saturated solution of NaHCO3 (120 ml) was added to the cooled reaction mixture, and the resulting precipitate was filtered off on a celite pad. The filtrate was extracted with ethyl acetate (3×20 ml) and the combined organic layers were dried over sodium sulfate. After evaporation of the solvent, crude methyl 2-(4-amino-1H-indol-1-yl)acetate was obtained and used in the next step without any additional purification (810 mg). MS/ESI+ 205.0 [MH]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-aminopyridine-5-boronic acid pinacol ester (Aldrich, Buchs, Switzerland, 26 mg, 0.125 mmol) to give the title compound as a white solid. (HPLC: tR 2.02 min (Method A); M+H=386 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.16-8.10 (m, 1H), 8.07-7.98 (m, 2H), 7.86-7.78 (m, 1H), 7.54-7.46 (m, 1H), 7.42-7.36 (m, 1H), 6.54-6.46 (m, 1H), 6.20 (s, br, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(OC1C=[CH:51][C:50]([NH:53][C:54]2[N:59]=CN=[C:56]([O:60][C:61]3[CH:66]=[CH:65][C:64]([NH:67]C(=O)CC(NC4C=CC(F)=CC=4)=O)=[CH:63][C:62]=3[F:81])[CH:55]=2)=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:59][C:54]1[CH:55]=[C:56]([O:60][C:61]2[CH:66]=[CH:65][C:64]([NH:67][C:8]([C:7]3[C:2](=[O:1])[N:3]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:4]=[CH:5][CH:6]=3)=[O:10])=[CH:63][C:62]=2[F:81])[CH:51]=[CH:50][N:53]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Reactant: O=C(O)c1cccn(-c2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc(NC(=O)c3cccn(-c4ccccc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (36 mg, 0.17 mmol) and HOBt (18 mg) in DMF (3 mL) at rt was added EDCI.HCl (45 mg, 0.23 mmol) followed by 4-(4-amino-2-fluorophenoxy)pyridine-2-amine (Compound B of Example 24, 36 mg, 0.17 mmol), and the reaction mixture was stirred at rt overnight. Purification of the reaction mixture by preparative HPLC afforded the title compound (32 mg, 36%) as a beige colored solid (TFA salt). 1H NMR (DMSO-d6) δ 13.35 (br s, 1H), 12.11 (s, 1H), 8.52 (dd, 1H, J=7.3, 2.1 Hz), 8.08 (dd, 1H, J=6.6, 2.1 Hz), 8.03 (d, 1H, J=2.3 Hz), 7.89 (d, 1H, J=7.2 Hz), 7.81 (s, 1H), 7.54-7.36 (m, 6H), 6.69-6.63 (m, 2H), 6.08 (d, 1H, J=2.4 Hz), 3.55 (br s, 1H); MS (ESI+) m/z 417.2 (M+H)+.
Reaction SMILES: Cl[CH:2]([CH3:27])[C:3]([NH:5][C:6]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:4].[CH3:28][NH2:29]>>[CH3:28][NH:29][CH:2]([CH3:27])[C:3]([NH:5][C:6]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:4]
Reactant: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)C(C)Cl)c1OC
Reactant: CN
Product: CNC(C)C(=O)Nc1c(Cc2nccc3ccccc23)ccc(OC)c1OC

Procedure:
Following the procedure of Example 1, but reacting 1-(2-[2-chloro-propionyl] amino-3,4-dimethoxybenzyl) isoquinoline with methylamine, there is obtained 1-(2-[2-methylamino-propionyl] amino-3,4-dimethoxybenzyl)isoquinoline.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][C:21]=1[O:22]C(=O)C)[C:8]([NH:10][N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]1=[O:18])=[O:9])(=O)C.[OH-].[K+].Cl>CO.O>[OH:4][C:5]1[CH:6]=[C:7]([C:8]([NH:10][N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]2=[O:18])=[O:9])[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: CC(=O)Oc1ccc(C(=O)NN2CCNC(=O)C2=O)cc1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1NCCN(NC(=O)c2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 12.13 g (34.7 mmol) of 3,4-bis(acetyloxy)-N-(2,3-dioxo-1-piperazinyl)benzamide in 290 ml of methanol and 80 ml of water was added 29 ml of 25N potassium hydroxide solution (72.9 mmol), and the mixture was stirred for 1 hour at room temperature. The pH of the solution was brought to 6.9 with dilute hydrochloric acid, the solution was then concentrated to 100 ml and the precipitate filtered off, washed with water and dried in vacuo (60°-70° C.); yield: 7.85 g, melting point 294° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1.[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH:1]1([Br:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[O:2]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(Br)c2ccccc21
Temperature: 25 °C

Procedure:
1H-Isobenzofuran-3-one (40.2 g, 0.3 moles), N-bromosuccinimide (53.4 g., 0.03 moles) and azo-bisisobutyronitrile (1g) were combined in 500 mL of CCl4 and refluxed under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered and the filtrate concentrated in vacuo to a solid residue. The latter was crystallized from cyclohexane to yield title product, 34.5 g., m.p. 78°-80° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Cl[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH2:23][O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[N:21][N:22]=2)[N:19]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].O>>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34]([C:25]([O:24][CH2:23][C:20]3[N:18]4[N:19]=[C:14]([C:6]5[CH:5]=[CH:4][C:3]([N:2]([CH3:12])[CH3:1])=[N:8][CH:7]=5)[CH:15]=[CH:16][C:17]4=[N:22][N:21]=3)=[CH:26][CH:27]=[N:28]2)=[CH:33][CH:32]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: COc1ccc2c(OCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(N(C)C)nc5)nn34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A 48 mL tube was charged with 6-(dimethylamino)pyridin-3-ylboronic acid (0.109 g, 0.658 mmol), 4-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methoxy)-7-methoxyquinoline (0.150 g, 0.439 mmol), and DMF (3.00 ml, 38.6 mmol), and stirred for 10 minutes. A solution of potassium carbonate (0.182 g, 1.32 mmol) and water (0.696 ml, 38.6 mmol) was added, followed by PdCl2(dppf)-CH2Cl2Adduct (0.0358 g, 0.0439 mmol). The tube was flushed with argon, sealed, and heated in a 80° C. oil bath for 5 hours. The mixture was concentrated, and the residue was triturated with water to give a brown solid which was purified by MPLC using a 40 g column, eluting with 1-5% MeOH/DCM over 40 minutes to give 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N,N-dimethylpyridin-2-amine as a dark green solid. MS (ESI pos. ion) m/z: 428 (MH+). Calc'd exact mass for C23H18FN5O2: 427.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:29])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:25](=[CH:26][CH:27]=1)[O:24][C:13]1([CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1)[CH2:12][C:11]2=[O:28].Cl>O.O1CCOCC1>[C:20]([O:19][C:17]([N:15]1[CH2:14][C:13]2([CH2:12][C:11](=[O:28])[C:10]3[C:25](=[CH:26][CH:27]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:29])=[O:4])[CH:9]=3)[O:24]2)[CH2:16]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
1 M NaOH (1.60 ml) was added to a solution of (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (Intermediate 4, Step B, 450 mg, 1.20 mmol) in water (11 ml) and dioxane (22 ml). The mixture was stirred at RT for 5 h. Aqueous HCl 10% was added until reaching pH 7, dioxane was removed under vacuum and the residue was diluted with water. The aqueous layer was acidified to pH 5 with 10% aqueous HCl and the product was extracted with DCM (3×30 ml). The collected organic phases were dried over Na2SO4 and concentrated to give (E)-3-[1′-tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (430 mg) as a yellow solid.