Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:26])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1)=[O:4].COCCN(S(F)(F)[F:37])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:37][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:2]([OH:1])([CH3:26])[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=2)=[O:4])=[CH:19][CH:20]=1
Reactant: Cc1cc(NC(=O)C(C)(O)COc2ccc(CO)cc2)ccc1[N+](=O)[O-]
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(CF)cc2)ccc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A solution of 2-hydroxy-3-(4-hydroxymethylphenoxy)-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (prepared in Example 70, 950 mg, 0.002636 mol) in dry CH2Cl2 (6.5 ml) was treated with Deoxo-Fluor® (875 mg, 0.003954 mol) in CH2Cl2 (3 ml) at −76° C. The solution was stirred at −10° C. for 3 hours. The saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography using heptane/ethyl acetate as a gradient eluent (9:1-5:5). Crystallization from dichloromethane/heptane gave the desired compound. 1H NMR (400 MHz, DMSO-d6): 1.44 (3H, s), 2.53 (3H, s), 4.00 (1H, d, 2Jgem=9.7 Hz), 4.24 (1H, d, 2Jgem=9.6 Hz), 5.30 (2H, d, 2JHF=48.6 Hz), 6.21 (1H, s, —OH), 6.95 (2H, d, 3J=8.4 Hz), 7.34 (2H, d, 3J=8.6 Hz), 7.84 (1H, dd, 3J=9.0 Hz, 4J=2.0 Hz), 7.93 (1H, broad s), 8.03 (1H, d, 3J=9.0 Hz), 10.14 (1H, s, —NHCO—).
Reaction SMILES: [N:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:21]([CH2:28][CH2:29][CH3:30])[CH2:22][C:23]([O:25]CC)=[O:24].[O-]CC.[Na+].O>C(O)C>[CH2:11]([NH:10][C:8]([C:7]1[CH:18]=[CH:19][C:4]([N:1]2[C:21]([CH2:28][CH2:29][CH3:30])=[C:22]([C:23]([OH:25])=[O:24])[N:3]=[N:2]2)=[CH:5][CH:6]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
4-Azido-N-benzylbenzamide obtained in Example 58a) and ethyl 3-oxohexanoate (1.08 ml, 6.44 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (487 mg, 6.44 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 10 min, and then at 60° C. for 14 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.71 g, 4.70 mmol, 91.3%).
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1>C1(C)C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:5](=[O:6])[CH:4]=[C:2]([CH3:3])[C:1]2=[O:8])=[N:11][CH:12]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1=CC(=O)OC1=O
Solvent: Cc1ccccc1
Product: CC1=CC(=O)N(c2ccc(Br)cn2)C1=O
Yield: 70.8 %

Procedure:
A mixture of citraconic anhydride (1.00 mL, 11.1 mmol) and 2-amino-5-bromopyridine (1.93 g, 11.2 mmol) in toluene (60 mL) was heated to reflux overnight. The solution was cooled down, filtered. The filtrate was concentrated in vacuo to give a solid (2.10 g, yield: 71%). MS 267 and 269 (M+H).
Reaction SMILES: [OH-].[Na+].[SH:3][CH2:4][CH2:5][OH:6].[CH:7]([N:10]=[N:11][C:12]1(Cl)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])[CH3:8].O>CO>[CH:7]([N:10]=[N:11][C:12]1([S:3][CH2:4][CH2:5][OH:6])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:9])[CH3:8]
Reactant: OCCS
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N=NC1(SCCO)CCCCC1
Temperature: 10 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 4.8 grams (.06 moles) of 50% sodium hydroxide in 60 ml of methanol in a 125 ml erlenmeyer flask was added 5.46 grams (.07 moles) of 2-mercaptoethanol while holding the reaction temperature below 25° C. After the addition was complete, the mixture was stirred for 20 minutes at 10° C and 9.5 grams (.05 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) was added dropwise over 25 minutes while holding the temperature below 15° C. After the addition was complete, the reaction was stirred an additional 60 minutes at 5° to 15° C. A .02 mole portion of 50% sodium hydroxide was added, the reaction stirred an additional 10 minutes, poured into 200 ml of water and the product extracted into 100 ml of pentane. The pentane solution was separated and washed successively with 50 ml portions of 5% HCl, water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid weighing 8.5 grams (74% crude yield). The infrared spectrum was in agreement with the structure of 1-isopropylazo-1-(β-hydroxyethylthio)cyclohexane (absence of carbon-chlorine band at 800 - 825 cm-1 and presence of a strong OH band at 3325 cm-1.)
Reaction SMILES: C([O:8][N:9]1[CH2:15][C:14]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:13][CH2:12][C@@H:11]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:10]1=[O:41])C1C=CC=CC=1.CS(O)(=O)=O>>[Cl:40][C:37]1[CH:36]=[CH:35][C:34]([O:33][C:30]2[CH:31]=[CH:32][C:27]([S:24]([NH:23][C@@H:11]3[CH2:12][CH:13]=[C:14]([CH2:16][N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:15][N:9]([OH:8])[C:10]3=[O:41])(=[O:26])=[O:25])=[CH:28][CH:29]=2)=[CH:39][CH:38]=1
Reactant: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=C(CN2CCOCC2)CN1OCc1ccccc1
Agent: CS(=O)(=O)O
Product: O=C1[C@H](NS(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=C(CN2CCOCC2)CN1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.3 %

Procedure:
To 251 mg of N-(1-Benzyloxy-6-morpholin-4-ylmethyl-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-(4-chloro-phenoxy)-benzenesulfonamide was added 8 mL of methanesulfonic acid. The reaction was stirred at room temperature for 20 hours, and then the solution was poured over ice. After the ice melted, the aqueous layer was extracted with ethyl ether. The aqueous layer was then neutralized with NaHCO3(s). The aqueous layers were then extracted with dichloromethane three times. The organic layers were then washed with NaCl(aq.) solution, and dried over Na2SO4(s). Filtration and solvent removal was followed by filtration over silica gel and elution with an ethyl acetate methanol mixture (4:1). Solvent removal, dilution with ethyl ether, filtration of the solids and drying gave 105 mg of a beige solid. MS: 1037 (2M+Na), 530 (M+Na), 508 (M+H).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:15]([C:18]1[CH:19]=[C:20]([C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16]
Reactant: Brc1ccc2sc3ccccc3c2c1
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-c2ccc3sc4ccccc4c3c2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
15.0 g of 2-bromodibenzothiophene (57.0 mmol) and 14.3 g of 2-nitrophenylboronic acid (85.5 mmol) are dissolved in 400 ml of toluene and degassed. 370 ml of a degassed 2 M K2CO3 and 1.6 g of Pd(PPh3)4 (1.4 mmol) are added. The reaction mixture is stirred at 80° C. for 48 h under a protective-gas atmosphere. Further toluene is added to the cooled solution, which is washed a number of times with water, dried and evaporated. The residue in the form of a yellowish oil is employed in the subsequent reaction without further purification. The yield is 16.9 g (55.4 mmol, 89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]2[C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=[C:4]2[CH:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]3[C:9](=[O:23])[N:10]([CH2:12][C:13]4[CH:14]=[N:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=4)[N:11]=[C:4]3[CH:3]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc(Cl)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a stirred solution of 7-chloro-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (2.0 g, 5.8 mmol), 4-chlorophenylboronic acid (1.2 g, 7.58 mmol), and tetrakis(triphenylphosphine)palladium (0.67 g, 0.58 mmol) in toluene (25 mL) at room temperature under argon was added aqueous Na2CO3 solution (2 M, 5.8 mL, 11.6 mmol). The resulting reaction mixture was stirred at 100° C. under argon overnight, after which time analysis by HPLC/MS indicated that the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The resulting mixture was extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous NaCl, then dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by triturating with MeOH (15 mL) to obtain 1.95 g of the title compound as an off-white solid. HPLC/MS: retention time=3.85 min, [M+H]30 =420.
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[O:8])=[O:2]>[Pd].C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C=Cc1ccc(OC)cc1C=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1ccc(OC)cc1CO
Reaction time: 18 h

Procedure:
A mixture of methyl 2-formyl-4-methoxycinnamate (15.9 g) and 10% palladium on carbon (2.0 g) in ethyl acetate (200 ml) is shaken under a hydrogen pressure of 45 psi for about 18 hours. The mixture is filtered, concentrated in vacuo, and the residue purified by HPLC, eluting with hexanes/ethyl acetate (3:2), to give the desired product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([N:19]=[C:20]=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: CCCCCCCN=C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCNC(=O)Oc1ccc2ncccc2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A mixture of quinolin-6-ol (0.58 g., 4 mmol), heptyl isocyanate (0.77 ml, 4.8 mmol), potassium carbonate (0.56 g., 4 mmol) and sodium iodide (0.60 g., 4 mmol) in dry dimethylformamide (2 ml) was stirred at 50° C. for 12 hours. The reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and chromatographed on silica gel with chloroform as an eluant to give (1b), yield: 0.50 g. (43.7%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.C(O[C:13]([C:15]1[CH:19]=[CH:18][NH:17][C:16]=1[CH3:20])=[O:14])C.Cl>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([N:3]([CH2:4][CH3:5])[C:13]([C:15]1[CH:19]=[CH:18][NH:17][C:16]=1[CH3:20])=[O:14])[CH3:2]
Reactant: CCNCC
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCN(CC)C(=O)c1cc[nH]c1C
Reaction time: 0.33 h

Procedure:
To a solution of 1.6 ml of diethylamine in 30 ml of toluene was added 7.5 ml of 2M trimethylaluminum in hexane, and the mixture stirred for 20 minutes. To this mixture was added 1.53 g of 2-methylpyrrole-3-carboxylic acid ethyl ester, and the reaction mixture refluxed overnight. The mixture was cooled, acidified with aqueous 2N hydrochloric acid and extracted twice with ethyl acetate and three times with methylene chloride. Solvent was removed from the combined extracts under reduced pressure, and the residue was flash chromatographed on silica gel, eluting with 75% ethyl acetate/hexane, giving 1.5 g of 2-methylpyrrole-3-carboxylic acid diethylamide, m.p. 120°-121° C., the compound of formula (b).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]([O:29]C)=[O:28])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]1[C:20]([N:21]3[CH2:25][CH2:24][CH2:23][C@@H:22]3[CH3:26])=[N:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:27]([OH:29])=[O:28])[CH:17]=3)[N:12]=1)=[CH:6][CH:5]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2cc(-c3nc4ccc(C(=O)O)cc4nc3N3CCC[C@@H]3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
To a solution of methyl 2-(2-methyl-1H-indol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate (140 mg, 0.35 mmol) in methanol (30 mL) and water (2 mL) was added sodium hydroxide (56 mg, 1.40 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (30 mL) and adjusted to pH 5 with acetic acid. The solids were collected by filtration to afford 2-(2-methyl-1H-indol-5-yl)-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nccnc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1nccnc1Cl
Temperature: 140 °C
Reaction time: 0.58 h
Yield: 85.9 %

Procedure:
2.42 g of diethyl (3-chloro-2-pyrazinyl)malonate and 15 ml of dimethyl sulfoxide were mixed. To the mixture was added 0.62 g of sodium chloride and 0.32 g of water. The mixture was stirred for about 35 minutes at an inner temperature of 127 to 153° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 1.53 g of ethyl (3-chloro-2-pyrazinyl)acetate.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=O)[C:3](=[C:4]23)[CH:2]=1)=[O:22].[CH:26]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.N1C=CN=C1>>[CH:26]1([N:33]2[C:21](=[O:22])[C:5]3[C:4]4[C:19]5[C:8](=[CH:7][CH:6]=3)[C:9]3[C:20]6[C:13]([CH:12]=[CH:11][CH:10]=3)=[CH:14][CH:15]=[CH:16][C:17]=6[C:18]=5[CH:1]=[CH:2][C:3]=4[C:24]2=[O:23])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: NC1CCCCCC1
Agent: c1c[nH]cn1
Product: O=C1c2ccc3c4cccc5cccc(c6ccc(c2c36)C(=O)N1C1CCCCCC1)c54
Temperature: 150 °C

Procedure:
0.30 g (0.93 mmol) of perylene-3,4-dicarboxylic anhydride is mixed with 0.32 g (2.83 mmol) of cycloheptylamine and 3 g of imidazole, and the mixture is heated under argon at 150° C. for 4 h. The reaction product is removed from the flask by washing with ethanol, treated with 200 ml of 10% hydrochloric acid and filtered off with suction. The residue is boiled in potassium carbonate solution, filtered off with suction and washed with hot dist. water until the filtrate run-off is colourless. The product thus obtained is dried in a drying cabinet at 120° C. and then recrystallized by extraction with methanol. Yield 0.24 g (62%) of orange crystals showing a red solid fluorescence, m.p. 354°-355° C., Rf (CHCl3 /silica gel)=0.79. UV (CHCl3): λmax (ε)=505 (30370), 483 (30967), 353 (3170), 336 (3170), 295 (3460), 264 (29047). Fluorescence (CHCl3): λmax (Irel)=529 (1), 568 (0.48).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[O:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38]>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:35]3[CH2:36][CH2:37][O:33][C:34]3=[O:38])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Reactant: O=C1NCCO1
Product: CC(=O)N1CCN(c2cc(N3CCOC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 10.2 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (221.5 mg) described in Preparation Example 126 and oxazolidin-2-one (42.3 mg), the title compound (25.2 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20](OCC)=[O:21])=[N:16][N:15]4[C:25]=3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3]1.[NH3:32]>CO>[NH2:1][C:2]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:13]=[C:14]4[CH:19]=[CH:18][C:17]([C:20]([NH2:32])=[O:21])=[N:16][N:15]4[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:10][CH:11]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: N
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Solvent: CO
Product: NC(=O)c1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 130 °C
Yield: 72 %

Procedure:
A mixture of ethyl 2-[4-(1-aminocyclobutyl)phenyl]-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate that was prepared in a manner analgous to that described for Example 4, (1.00 g, 93% purity) and ammonia (17.3 mL of a 7M solution in methanol) was heated at 130° C. under microwave irradiation for 5 hours. The volatile components were removed by distillation under reduced pressure. Crystallization from methanol/diisopropyl ether gave the title compound (672 mg, 72% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16](O)=[O:17])[CH:9]=2)=[CH:4][C:3]=1[F:19].S(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH2:15][C:16]([Cl:22])=[O:17])[CH:9]=2)=[CH:4][C:3]=1[F:19]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)O
Product: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1CC(=O)Cl
Temperature: 80 °C
Reaction time: 1 h

Procedure:
10.00 g (35.88 mmol) of (4′-chloro-3′-fluoro-4-methylbiphenyl-3-yl)acetic acid (Example 1A) were dissolved in 24.33 g (204.51 mmol) of thionyl chloride. The reaction mixture was stirred at 80° C. for one hour and then concentrated under reduced pressure. Drying under fine vacuum gave 10.54 g (99% of theory) of the title compound as a brownish oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[O:14]=[C:11]1[NH:10][C:9]2[CH:15]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[O:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1COc2ccc(C(=O)O)cc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 260.6 %

Procedure:
To a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester (3.13 g, 15.1 mmol) in THF/H2O (3:1; 76 mL) was added a LiOH (4 M in H2O; 19.0 mL, 75.5 mmol), and the solution was stirred at RT for 24 h. The solution was concentrated, diluted with H2O (50 mL), and acidified to pH<1 with conc. HCl. The resulting precipitate was collected by filtration afforded 7.6 g of the title compound contaminated with excess HCl and H2O. MS (ESI): exact mass calculated for C9H7NO4, 193.04; m/z found, 194.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): 10.85 (br s, 1H), 7.50-7.47 (m, 2H), 6.99 (d, J=8.3, 1H), 4.63 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:23]#[N:24])=[C:11]([NH:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1.B.C1COCC1.Cl>C1COCC1.O1CCOCC1.CO>[NH2:24][CH2:23][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:14][N:13]2[CH:15]=[CH:16][N:17]=[C:12]2[C:11]=1[NH:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CNc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Agent: B
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CNc1c(CN)c(-c2ccc(Cl)cc2Cl)cn2ccnc12
Temperature: 40 °C
Reaction time: 1 h
Yield: 24.5 %

Procedure:
In a sealed flask, a solution of 6-(2,4-dichloro-phenyl)-8-isobutylamino-imidazo[1,2-a]pyridine-7-carbonitrile (19.1 mg, 0.053 mmol) in THF (0.5 mL) was cooled to 0° C. (ice bath), treated with BH3.THF complex (1.0 M solution in THF, 0.48 mL, 0.48 mmol) and heated at 40° C. After 1 h, the reaction was not complete according to HPLC. 4.0 M HCl in dioxane (2 drops) and additional BH3.THF complex (1.0 M solution in THF, 0.16 mL, 0.16 mmol) were added, then the reaction mixture was heated at 40° C. for 14 h, cooled to 0° C., and diluted in MeOH (large excess). The resulting mixture was concentrated under vacuum, and the remaining residue was dissolved in TFA. After evaporation to dryness, the remaining residue was purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 7.6 mg, 0.013 mmol, 24%). MS: 363 [M+1]+; HPLC: AtRet=1.47.
Reaction SMILES: [C:1]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH2:50]>C(Cl)Cl>[CH3:42][C:43]1([CH3:51])[CH2:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH:44]1[NH:50][C:15]([C:12]1([NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:13][CH2:14]1)=[O:17]
Reactant: CC1(C)CCC(C)(C)C1N
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)C1NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Reaction time: 48 h

Procedure:
To a stirred solution of N-Cbz-1-aminocyclopropanecarboxylic acid in dry CH2Cl2 containing dicyclohexylcarbodiimide and dimethylaminopyridine (DMAP), all at 0° C., is added, via an addition funnel, 2,2,5,5-tetramethyl-1-cyclopentyl amine dissolved in CH2Cl2. After stirring for 48 hours, the mixture is filtered, and the filtrate is washed with 5% HCl (1×50 ml), saturated NaHCO3 (1×50 ml), and water (2×50 ml). The organic layer is separated, dried over MgSO4 and evaporated to yield N-Cbz-1-aminocyclopropanecarboxylic acid 2,2,5,5-tetramethylcyclopentyl amide.