Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2OCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1=Cc2cc(-c3ccc(F)cc3)ccc2OCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 85.5 %

Procedure:
To methyl 7-(4-fluorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylate (0.27 g) were added THF (5.0 ml), ethanol (10.0 ml) and 2N sodium hydroxide solution (1.0 ml), and the mixture was stirred at room temperature for 19 hours. Under reduced pressure, the solvent was removed, and the residue was diluted with water (100 ml). The aqueous layer was made acidic with hydrochloric acid, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was dried with anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized and washed with hexane to give 7-(4-fluorophenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.22 g, 86%) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:33]#[N:34])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[C:30]([C:33]#[N:34])=[CH:31][N:32]=[C:20]4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ncc(C#N)n4cc3-c3ccccc3)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-9 (46 mg, 0.1 mmol) in 1 mL of DCM was added TFA (1 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated by evaporation and the residue was purified by prep.HPLC to give the product 4-10.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].F[B-](F)(F)F.[O:25]=[N+:26]=[O:27]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:11]([N+:26]([O-:27])=[O:25])=[C:10]([F:12])[C:9]([C:13]2[C:14]([CH3:19])=[N:15][O:16][C:17]=2[CH3:18])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[N+]=O
Reactant: COC(=O)c1cc(-c2c(C)noc2C)c(F)cc1N
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2c(C)noc2C)c(F)c([N+](=O)[O-])c1N

Procedure:
To a mixture of methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluorobenzoate (14 g, 53 mmol, 1 equiv.) and TFA (100 mL) is slowly added nitronium tetrafluoroborate (9.1 g, 68.9 mmol, 1.3 equiv.). After completion, the mixture was concentrated under reduced pressure. The residue was dissolved and then the residue was dissolved in EtOAc (200 ml) and washed with brine (30 ml×2). The organic solvent was evaporated. Methyl 2-amino-5-(3,5-dimethylisoxazol-4-yl)-4-fluoro-3-nitrobenzoate was used without further purification. 1H NMR (400 MHz, Chloroform-d) δ 6.92 (d, J=5.8 Hz, 1H), 4.24 (s, 4H), 4.07-3.85 (m, 5H), 2.46-2.34 (m, 4H), 2.31-2.22 (m, 5H).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH:4]1[F:27].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][C:10]=2[F:26])[CH2:5][CH:4]1[F:27]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2F)CC1F
Solvent: CC(=O)Cl
Solvent: CSC
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)C3)c(F)c2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 61 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), freshly fused zinc chloride (3.1 mmol), dimethyl sulphide (5.1 mmol), acetyl chloride (3.1 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. The reaction mixture was extracted with ethyl acetate water mixture and the organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 61% yield.
Reaction SMILES: Cl[C:2]1[C:11]([C:12](=[O:23])[C:13](=[CH:19][N:20](C)[CH3:21])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:25])=[C:7]([F:24])[CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:33]=[C:32]([F:34])C=[CH:30][C:28]=1N.C(O)C.N12CCCN=C1CCCCC2>ClC(Cl)Cl>[F:34][C:32]1[CH:33]=[C:27]([F:26])[CH:28]=[CH:30][C:21]=1[N:20]1[C:2]2[N:3]=[C:4]3[CH:5]=[C:6]([F:25])[C:7]([F:24])=[CH:8][C:9]3=[CH:10][C:11]=2[C:12](=[O:23])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19]1
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(F)cc2nc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 80 °C
Yield: 79.4 %

Procedure:
Ethyl 1-(2,4-difluorophenyl)-7-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylate was obtained under the conditions of Example 13, but from 3.68 g of ethyl 3-(2-chloro-6,7-difluoro-3-quinolyl)-2-dimethylaminomethylene-3-oxopropionate and 3.87 g of 2,4-difluoroaniline in 40 cm3 of trichloromethane. 50 cm3 of ethanol and 1.5 cm3 of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to the mixture, which was heated at a temperature around 80° C. for approximately 1 hour. After cooling to a temperature around 10° C., the product was filtered off and washed 2 times with 50 cm3 of ethanol and 2 times with 50 cm3 of isopropyl ether. 3.3 g of ethyl 1-(2,4-difluorophenyl)-7,8-difluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylate were obtained in the form of a yellow solid melting at approximately 300° C., which solid was used without additional purification in the subsequent stages.
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([SH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C:3](=[O:10])[CH2:2][S:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=1)[CH3:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)CSc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-chloroacetoacetate (32.6 g, 0.188 mol), 3-methoxythiophenol (25.1 g, 0.179 mol) and DMF (700 mL) are combined and degassed by bubbling nitrogen through the stirred mixture for about 10 min, then potassium carbonate (50 g, 0.36 mol) is added to the stirred mixture in one batch. This mixture is stirred under nitrogen at room temperature for 2 h, the mixture is filtered to remove potassium carbonate, then diluted with ethyl acetate. The resulting solution is washed with water, then 5% aq. NaCl. The combined organics are washed with brine, dried over Na2SO4. Concentration yields the title compound as yellow liquid. This material is used without purification.
Reaction SMILES: [SH:1][C:2]1[C:3]([C:12]#[N:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.Cl[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17].[OH-].[K+].C(OCC)(=O)C>CN(C)C=O.O>[NH2:13][C:12]1[C:3]2[CH:4]=[C:5]3[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:11][C:2]=2[S:1][C:15]=1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])=[O:17]
Reactant: N#Cc1cc2c(cc1S)CCCC2
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)sc2cc3c(cc12)CCCC3
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
To a solution of crude 3-mercapto-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (121 mg, 0.64 mmol) and 2,2′,4′-trichloroacetophenone (143 mg, 0.64 mmol, 1.0 eq) in anhydrous N,N-dimethylformamide (5 mL) was added powdered potassium hydroxide (177 mg, 1.28 mmol, 2.0 eq). The reaction mixture was stirred under argon at 80° C. for 16 h. The brown reaction mixture was cooled and poured into ethyl acetate and water. The organic layer was washed with water, brine, and dried over magnesium sulfate. The solvent was removed at reduced pressure, and the crude product was purified on the MPLC (Biotage), eluted with 30% ethyl acetate-hexane. Trituration from hexane afforded 92.4 mg (38.4%) of the benzothiophene. 1H-NMR (Acetone-d6) δ 7.88 (broad, s, 3H), 7.62 (d, J=1.5 Hz, 1H), 7.53 (m, 2H), 7.42 (s, 1H), 2.85 (m, 4H), 1.83 (m, 4H); MS ES (MH+=376/378); Rf=0.60 (30% ethyl acetate-hexane).
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:29]([O:31]CC)=[O:30])[CH2:20][C:19]2[C:14](=[C:15]([O:27][CH3:28])[C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[C:18]=2[O:21][CH3:22])[CH2:13]1>C(O)C>[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:29]([OH:31])=[O:30])[CH2:20][C:19]2[C:14](=[C:15]([O:27][CH3:28])[C:16]([O:25][CH3:26])=[C:17]([O:23][CH3:24])[C:18]=2[O:21][CH3:22])[CH2:13]1
Reactant: CCOC(=O)C1(CCCCCCCCO)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)(C(=O)O)C2
Yield: 50.7 %

Procedure:
An aqueous sodium hydroxide solution (3N, 1.07 ml, 3.22 mmols) was added to an ethanol (10 ml) solution of ethyl 2-(8-hydroxyoctyl)-4,5,6,7-tetramethoxy-2-indancarboxylate (708 mg, 1.61 mmols). The reaction mixture was heated under reflux for 6 hours, and then concentrated in vacuo, which was made acidic with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:2) to obtain the entitled compound (335 mg) as an oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1.[CH3:22][NH2:23]>CCOCC.O>[C:15]1([C:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([NH:23][CH3:22])=[O:2])[O:14][N:13]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN
Reactant: COC(=O)c1ccccc1-c1nc(-c2ccccc2)no1
Solvent: O
Solvent: CCOCC
Product: CNC(=O)c1ccccc1-c1nc(-c2ccccc2)no1
Reaction time: 19 h

Procedure:
A solution of 6.16 g. (0.022 mole) o-(3-phenyl-1,2,4-oxadiazol-5-yl)-benzoic acid methyl ester in 150 milliliters ether is treated with 150 milliliters 40 percent methyl amine in water. The resulting two-phase system is stirred vigorously for 19 hours. The ether is evaporated, and the resulting mixture extracted with methylene chloride. The organic phase is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The resulting solid is triturated with ether and filtered to give o-(3-phenyl-1,2,4-oxadiazol-5-yl)-N-methyl benzamide, m.p. 145°-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:18])[CH2:14][O:13][CH2:12][CH:11]3[CH2:15][N:16]=[CH:17][N:10]23)=[CH:5][CH:4]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:18])[CH2:14][O:13][CH2:12][C:11]3=[CH:15][N:16]=[CH:17][N:10]23)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)COCC3CN=CN32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1ccc(C2(C)COCc3cncn32)cc1
Temperature: 25 °C

Procedure:
A mixture of 1.9 mmol of 5-(4-methoxyphenyl)-5-methyl-5,6,8,8a-tetrahydro-1H-imidazo[5,1-c][1,4]oxazine and 3 g of manganese dioxide in 50 ml of toluene is heated to reflux for 3.5 hours. The reaction mixture is cooled to room temperature, the solid is filtered off through Hyflo, and the filtrate is evaporated. The crude title compound is obtained as a yellow oil from the residue and is employed without further purification in the next stage. Rf=0.31 (dichloromethane-methanol-25% aqueous ammonia solution 200:10:1), Rt=2.66 (gradient I)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[N:10][C:11]=2[NH2:15].[CH2:24]([O:26][P:27]([O-:31])[O:28][CH2:29][CH3:30])[CH3:25].C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[NH2:15][C:11]1[N:10]=[C:9]([O:16][CH2:17][CH2:18][O:19][CH3:20])[N:8]=[C:7]2[C:12]=1[N:13]=[CH:14][N:6]2[CH2:5][C:4]1[CH:3]=[C:2]([P:27](=[O:31])([O:28][CH2:29][CH3:30])[O:26][CH2:24][CH3:25])[CH:23]=[CH:22][CH:21]=1
Reactant: COCCOc1nc(N)c2ncn(Cc3cccc(Br)c3)c2n1
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cccc(Cn2cnc3c(N)nc(OCCOC)nc32)c1
Temperature: 130 °C

Procedure:
9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine (29) (500 mg, 1.32 mmol) was suspended in DMF (5 mL). Diethylphosphite (0.26 mL, 2.0 mmol), triethylamine (0.28 mL, 2.0 mmol) and (1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), complex with CH2Cl2 (106 mg, 0.13 mmol) was added and the mixture was heated at 130° C. for 5 min in a microwave reactor. Then the reaction mixture was diluted with ethyl acetate (150 mL) and washed with water and brine. The organic solution was dried with sodium sulfate and the solvent was removed under vacuum. The residue was redissolved in ethyl acetate (10 mL) and adsorbed on a short column of silica gel. The product was eluted with dichloromethane/methanol 1:0 to 1:1 giving diethyl 3-((6-amino-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)phenylphosphonate (30) (400 mg, 70%) as a dark brown oil after evaporation of the solvent. MS: 436 (MH+).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:32][C:29]2[CH:28]=[CH:27][C:26]([O:25][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:31][CH:30]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCOc1ccc(O)cc1
Reactant: CCCCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCCCCC)cc2)cc1
Reaction time: 8 h
Yield: 50.4 %

Procedure:
In tetrahydrofuran were dissolved 1.0 g of p-octyloxybenzoic acid chloride and 800 mg of p-hexyloxyphenol, and 500 mg of triethylamine was added to the solution and reaction was carried out with stirring overnight. The precipitate was removed by filtration, and the filtrate was concentrated, purified by using a silica gel column and recrystallized from ethanol to obtain 800 mg of 4-hexyloxyphenyl 4-octyloxybenzoate. The phase transition temperatures of the so-obtained compounds are as follows. ##STR142##
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[CH2:10][CH:9]([F:11])[CH2:8][N:7]1C(OCC1C=CC=CC=1)=O)=[O:5])[CH3:2]>CO.[C].[Pd]>[CH2:1]([NH:3][C:4](=[O:5])[C@@H:6]1[CH2:10][CH:9]([F:11])[CH2:8][NH:7]1)[CH3:2]
Reactant: CCNC(=O)[C@@H]1CC(F)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCNC(=O)[C@@H]1CC(F)CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.2 %

Procedure:
A suspension of 1.80 g of the compound obtained in step 8-1 and 360 mg of 10% palladium-carbon in 36 mL of methanol was stirred for 3 hours at room temperature and under hydrogen atmosphere. The insolubles were filtered off and the reaction mixture was concentrated under reduced pressure to obtain 1.07 g of the titled compound. This compound was used in the following reaction without being purified.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[C:14]([F:24])=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[F-].[K+].Cl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH:31]([CH3:35])[C:30]1=[O:36]>CN1C(=O)CCC1>[F:24][C:14]1[C:13]([CH:11]([C:8]2[N:6]3[N:7]=[C:2]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[C:30](=[O:36])[CH:31]4[CH3:35])[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH3:12])=[C:22]([F:23])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2
Reactant: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(Cl)nn12
Reactant: CC1NCCN(C)C1=O
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(c1c(F)cc2ncccc2c1F)c1cnc2ccc(N3CCN(C)C(=O)C3C)nn12
Temperature: 180 °C
Reaction time: 20 h

Procedure:
(rac)-6-[1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-ethyl]-5,7-difluoro-quinoline (Intermediate C, 50 mg, 0.145 mmol), KF (84 mg, 1.450 mmol), 1,3-dimethylpiperazin-2-one HCl salt (75 mg, 0.435 mmol) were suspended in NMP (483 μL). The RM was stirred at 180° C. for 20 h. The mixture was purified by preparative UPLC with acetonitrile and water (+0.1% TFA) The fractions were collected and acetonitrile was removed. It was taken up with MeOH and passed through an SPE cartridge of PL-HCO3 MP from polymer lab. The solvent was removed and a brown solid was obtained (tR 0.9 min (conditions 4), MH+=437).
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3]>ClCCl>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:3](=[O:4])[CH2:5][CH3:9])[CH:9]=1)=[O:4]
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reaction time: 2 h

Procedure:
In a dry flask, 3-proprionyl chloride (1 equivalent) was combined with 2-trichloroacetyl pyrrole (1 equivalent) in a minimum amount of dichloromethane (DCM). To the resulting solution, at ambient temperature, was added aluminum trichloride (1 equivalent). After 2 hours, the reaction mixture was applied directly onto a silica gel column. Gradient elution with 10% ethyl acetate to 50% ethyl acetate in hexanes provided compound 3.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].[F:18][C:19]([F:38])([F:37])[C:20]1[CH:21]=[C:22]([C:30]2[O:34][N:33]=[C:32]([CH2:35]Cl)[N:31]=2)[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>>[F:38][C:19]([F:18])([F:37])[C:20]1[CH:21]=[C:22]([C:30]2[O:34][N:33]=[C:32]([CH2:35][N:4]3[C:5]4[C:10](=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH2:1][CH3:2])[N:31]=2)[CH:23]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:25]=1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole: MS (ESI): m/z 533 (M+1).
Reaction SMILES: C([Li])CCC.[CH:6]([NH:9]C(C)C)(C)[CH3:7].[F:13][C:14]([F:20])([F:19])[C:15](OC)=[O:16].C(#N)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCC>[F:13][C:14]([F:20])([F:19])[C:15](=[O:16])[CH2:7][C:6]#[N:9]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Li]CCCC
Solvent: CC#N
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
A solution of n-butyllithium in n-hexane (280 ml, 0.44 mole) was added to dry diisopropylamine (64 ml, 0.46 mole) dissolved in dry tetrahydrofuran (400 ml), while maintaining the mixture below 0° C. After stirring at 0° C. for 30 minutes, the mixture was cooled below -72° C. A solution of methyl trifluoroacetate (25.61 g, 0.200 mole), acetonitrile (16.42 g, 0.40 mole) in dry tetrahydrofuran (200 ml) were added dropwise, while maintaining the mixture below -72° C. and after maintaining the mixture at the same temperature for additional 45 minutes, it was warmed to room temperature over 1 hour. Ice-water (700 ml) was added to the mixture and tetrahydrofuran and n-hexane were then evaporated under reduced pressure at a bath temperature of 40° C. The residue was extracted with diethyl ether to remove neutral and basic components, adjusted to pH 1 with 36% HCl and then extracted with methylene chloride to remove by-products such as acetoacetonitrile, etc. The solution was extracted with diethyl ether. After the extract was dried with anhydrous sodium sulfate, p-toluenesulfonic acid (40 mg, 0.0002 mole) was added to the extract. The extract was distilled under the atmospheric pressure and then distilled under reduced pressure to give 26.82 g (crude yield 97.8%) of a cured product. This product was further distilled under reduced pressure to give 16.78 g (61.2%) of the title compound, b.p. 37° C./2.4 mmHg-43° C./2.5 mmHg. When the resulting compound was dissolved in d6 -acetone and its NMR was measured, the ratio of the keto form/the enol form was found to be 17/83.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[C:25](Cl)(=O)[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(NC1C=CC(N2C(=O)CC(=O)NC3C4C(C=CC2=3)=CC=CC=4)=CC=1)(=O)C1C=CC=CC=1>>[C:28]1([CH2:27][CH:26]=[CH:25][NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Agent: O=C1CC(=O)N(c2ccc(NC(=O)c3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(NC=CCc3ccccc3)cc2)c2ccc3ccccc3c2N1
Yield: 908.1 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (50 mg, 0.158 mmol) obtained in Example 1, (3), and cinnamoyl chloride (32 mg, 0.19 mmol), the title compound (622 mg, yield 31%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=2)=O)[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.S(=O)(=O)(O)O.[Pd]>[C:27]([C:21]1[CH:20]=[C:19]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[C:9]([CH3:12])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:24]=[C:23]([CH3:25])[C:22]=1[OH:26])([CH3:30])([CH3:29])[CH3:28]
Reactant: [H][H]
Reactant: Cc1cc(C(=O)CCCC(=O)c2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCCc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 12 h
Yield: 68.1 %

Procedure:
8.17 g (19 mmol) of 1,5-di(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)-1,5-pentanedione in 80 ml of ethyl acetate and 3-5 drops of concentrated sulfuric acid are hydrogenated over 1.6 g of Pd/C (5%) at room temperature under atmospheric pressure. After 12 hours, the uptake of hydrogen has ended. The catalyst is filtered over Celite and the resulting colourless solution is concentrated on a rotary evaporator. Chromatography of the liquid residue (SiO2, hexane/ethyl acetate 19:1) gives 5.13 g (67% of theory) of 1,5-bis(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)pentane as a viscous oil.