Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([CH2:7][CH2:8][C:9]2[CH:15]=[C:14](O)C=C[C:10]=2[OH:11])C=CC=CC=1.C1C(N)=CC=C([OH:24])C=1.C([O:28][C:29](=[O:31])[CH3:30])(=O)C>>[C:29]([OH:28])(=[O:31])[C:30]1[CH:7]=[CH:8][C:9]([C:10]([OH:11])=[O:24])=[CH:15][CH:14]=1
Reactant: Oc1ccc(O)c(CCc2ccccc2)c1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(O)cc1
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
17.84 g (83.3 mM) of phenylethylhydroquinone, 1.01 g (9.2 mM) of p-aminophenol and 20 ml of acetic anhydride are fed under a nitrogen stream into a 100 ml flask fitted with a mechanical stirrer, nitrogen inlet tube and distillation head. The temperature is gradually raised to 150° C. This temperature is maintained for 1 hour after which the acetic acid is distilled off for a further hour. The temperature is then lowered to 20° C. over a period of 30 minutes, and after a further 30 minutes is raised to 340° C. over a period of 1 hour distilling off acetic acid. This temperature is maintained for 15 minutes after which the mixture is allowed to cool to ambient temperature. The solid obtained is ground and washed with acetone, hot water and acetone/methanol. After drying under vacuum for 5 hours at 180° C. a polymer is obtained having a melting point of 355° C. and an inherent viscosity of 0.31 dl/g. By heating to 100° C. under high vacuum a polymer is obtained the thermal decomposition of which commences slowly above 400° C. and which shows an inherent viscosity of 4 dl/g.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:14][S:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1.[CH3:24][CH:25]([CH3:35])[CH2:26][N-:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>C(O)C>[ClH:36].[CH3:24][CH:25]([CH3:35])[CH2:26][N:27]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([CH2:14][S:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[NH:23])[NH2:41])=[CH:18][CH:17]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: [NH4+]
Reactant: CCOC(=O)CC[N-]CC(C)C
Reactant: Cn1c(CSc2ccc(C#N)cc2)nc2cc(C(=O)O)ccc21
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CCN(CC(C)C)C(=O)c1ccc2c(c1)nc(CSc1ccc(C(=N)N)cc1)n2C
Yield: 83 %

Procedure:
Prepared analogously to Example 27 from 1-methyl-2-[(4-cyanophenyl)thiomethyl]-benzimidazol-5-yl-carboxylic acid-(N-(2-methylpropyl-N-(2-ethoxycarbonylethyl)-amide, ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 83% of theory, C25H31N6O3S (495.65) Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5): EKA mass spectrum: (M+H)+ =496
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:39](O)[CH3:40].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH:33]=[CH:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([C:19]([O:21][CH2:39][CH3:40])=[O:20])=[CH:18][C:12]=3[N:11]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([N:31]4[CH2:32][CH:33]=[CH:34][CH2:35]4)=[O:30])=[CH:25][CH:24]=3)[C:10](=[O:36])[CH2:9]2)=[O:7])=[CH:37][CH:38]=1
Reactant: CCO
Agent: O=C(O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Reaction time: 8 h

Procedure:
10 mg (0.019 mmol) of 4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-diazepine-8-carboxylic acid was dissolved in 2 ml of dichloromethane. 0.022 ml (0.38 mmol) of ethanol, 4 mg (0.023 mmol) of 2-chloro-1,3-dimethylimidazonium chloride and 0.005 ml (0.038 mmol) of triethylamine were added to the obtained solution, and they were stirred overnight. The solvent was evaporated and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3]C[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].CCCCCCCCCCCC>C(OCOCC)C>[CH2:2]=[C:1]=[O:3].[CH2:10]=[C:9]1[O:8][C:6](=[O:7])[CH2:5]1
Reactant: CCOCCC(=O)OCC
Solvent: CCCCCCCCCCCC
Solvent: CCOCOCC
Product: C=C1CC(=O)O1
Product: C=C=O

Procedure:
A 100 ml three-necked round bottom flask equipped with a dry ice condenser, magnetic stirrer, gas inlet and thermometer was charged with 40 ml of diethoxymethane, 5.0 g of ethyl 3-ethoxypropionate and 1.00 g dodecane (an internal standard for gas-liquid chromatography analysis), and the flask was placed in a 30° C. water bath. Ketene gas, produced by cracking diketene in a 550° C. furnace, was added until the solution became saturated. A portion (0.1143 g) of the catalyst prepared as described above and stored for one week at room temperature, was added on the tip of the thermometer. An exothermic reaction ensued, briefly raising the pot temperature to 80° C. The mixture was kept saturated with ketene for 30 minutes. The mixture was then analyzed by gas-liquid chromatography, and it was found that the 0.1143 g of catalyst had produced 17.3 g of ethyl 3-ethoxypropionate, not including the 5 grams added at the start. This catalyst was thus capable of producing 156 g of ethyl 3-ethoxypropionate for each gram of catalyst.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[S:39]([C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1)(=[O:41])=[O:40]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:39]([C:42]2[CH:43]=[CH:44][C:45]([C:46]([OH:48])=[O:47])=[CH:49][CH:50]=2)(=[O:41])=[O:40])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1CN(S(=O)(=O)c2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 6 h
Yield: 385 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (80 mg, 0.0189 mmol) and diisopropylethylamine (122 mg, 0.942 mmol) in CH2Cl2 (6 mL) was added p-(chlorosulfonyl)benzoic acid (70.0 mg, 0.283 mmol, Eastman) and the reaction mixture was stirred at room temp. for 6 hrs. The resulting mixture was diluted with EtOAc, washed with aqueous Na2CO3, 1N HCl and brine, and concentrated to dryness to give rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-sulfonyl]-benzoic acid (44.2 mg, 38%) as a white solid. HRMS (ES+) m/z Calcd for C29H26Cl2F2N2O4S H [(M+H)+]: 607.1031; Found: 607.1032.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22](O)=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1.C(N(C(C)C)C(C)C)C.[NH2:44][CH2:45][C:46]([CH3:49])([OH:48])[CH3:47].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10](/[CH:13]=[C:14]2/[C:15]([NH:20][CH2:21][C:22]([NH:44][CH2:45][C:46]([OH:48])([CH3:49])[CH3:47])=[O:23])=[N:16][C:17](=[O:19])[S:18]/2)[CH2:9][CH2:8]1
Reactant: CC(C)(O)CN
Reactant: O=C(O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)CNC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of N-[(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]piperidin-4-yl}methylidene)-2-oxo-2,5-dihydro-1,3-thiazol-4-yl]glycine hydrochloride (1.2 g), N-ethyl-N-(1-methylethyl)propan-2-amine (0.79 mL) and 1-amino-2-methylpropan-2-ol (0.40 g) in DMF (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.03 g), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and the obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (294 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[CH:3]=1.[Li]CCCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CSc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of 1,3-difluoro-5-(methylthio)benzene (0.800 g, 4.99 mmol) in dry THF (25 mL) under nitrogen at −78° C., n-BuLi in THF (1.6 M; 3.28 mL, 5.24 mmol) was added slowly while keeping the internal temperature below −65° C. The reaction mixture was stirred at −78° C. for 2 h. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.07 g, 5.74 mmol) was then added. The reaction mixture was allowed to warm to room temperature for 2 h, and then quenched with aq. NaHCO3 and extracted with EtOAc. The organic extracts were washed with brine, dried, filtered and concentrated under reduced pressure to yield the crude sub-title compound (1.42 g, 99%) as a viscous liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([NH:5][C:6]1[S:7][CH:8]=[C:9](/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[N:10]=1)=[O:4].C(O)(=O)C.CO>[Pd].O1CCCC1>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH3:22])[S:7][CH:8]=2)=[CH:14][CH:15]=1
Reactant: CC(C)C(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)cs1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)C(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
A mixture of 2-methyl-N-{4-[(E)-2-(4-nitrophenyl)ethenyl]-1,3-thiazol-2-yl}propanamide (333 mg), palladium on carbon (33 mg), acetic acid (1 ml), methanol (2 ml) and tetrahydrofuran (2 ml) was stirred under hydrogen atmosphere (4 atm) at ambient temperature for 5 hours. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 5% methanol/ethyl acetate as an eluent. The solid residue was collected and washed with diisopropyl ether to give N-{4-[2-(4-aminophenyl)ethyl]-1,3-thiazol-2-yl}-2-methylpropanamide (260 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(#N)C>[CH3:13][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(N)ccc1C
Reactant: O=C(Cl)c1ccc(CCl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCOC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.4 %

Procedure:
To a solution of ethyl 5-amino-2-methylbenzoate (500 mg, 2.79 mmol) and TEA (0.78 mL, 5.58 mmol) in dried THF (9 mL) was added 4-(chloromethyl)-3-(trifluoromethyl)benzoyl chloride (714 mg, 2.79 mmol). The reaction mixture was stirred for 5 hours at room temperature after which, it was concentrated under reduced pressure. To a solution of the reaction mixture in acetonitrile (10 mL) were added methyl piperazine (558 mg, 5.58 mmol) and K2CO3 (1.1 g, 8.38 mmol). The reaction mixture was stirred for 8 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, celite filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography using (3% to 7% Methanol/CH2C12) as a solvent to afford title compound (820 mg, 63% yield). MS m/z: 464 [M+1].
Reaction SMILES: FF.[N+:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[C-:4].[H-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[N:20]=[C:21](\Cl)/[C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[C:21]([C:22]([F:23])([F:24])[F:25])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[CH:4]2)=[CH:18][CH:19]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: FC(F)(F)/C(Cl)=N/c1ccc(Cl)cc1
Agent: FF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.4 %

Procedure:
The synthetic intermediate imine (Z)—N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride (a pale yellow oil) was prepared as described in Huang et al., J. Fluorine Chem., 74:279-282 (1995) and used without distillation. To ethyl isocyanoacetate (0.467 g, 4.13 mmol) in dry THF (50 mL) was added NaH (170 mg, 4.13 mmol, 60% dispersed in oil) at 0° C. and after 5 minutes, (Z)—N-(4-chlorophenyl)-2,2,2-trifluoroacetimidoyl chloride (1.0 g, 4.13 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was purified using an 80 g SiO2 column and a 10-100% EtOAc/hexanes gradient. Obtained 900 mg (68% yield) of ethyl 1-(4-chlorophenyl)-5-(trifluoromethyl)-1H-imidazole-4-carboxylate as a pale yellow solid. This compound matched the 1H NMR found in the J. Fluorine Chem. reference.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.[Cl:8][C:9]1[C:10]([CH3:16])=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.Cl.[NH2:26][OH:27]>O>[Cl:8][C:9]1[C:10]([CH3:16])=[C:11]([NH:12][C:3](=[O:5])[CH:2]=[N:26][OH:27])[CH:13]=[CH:14][CH:15]=1
Reactant: NO
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1c(N)cccc1Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1c(Cl)cccc1NC(=O)C=NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.6 %

Procedure:
A mixture of 4.62 g of chloral hydrate, 3.5 g of 3-chloro-2-methylaniline, 30 g of anhydrous sodium sulfate, 120 ml of water and 2 ml of 2N hydrochloric acid was stirred at room temperature for 2 hours. Then, to the resulting mixture, 1.8 g of hydroxylamine hydrochloride was added, and the mixture was heated to reflux for 30 minutes. The reaction mixture was ice-cooled, and a deposited precipitate was collected by filtration to obtain 2.5 g of N-(3-chloro-2-methylphenyl)-2-(hydroxyimino)acetamide of the formula:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[C:27]([CH3:44])=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:43])([CH3:42])[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[C:27]([CH3:44])=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:43])[C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1Cl
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 58.7 %

Procedure:
1.40 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.636 g of isopropyl 2-(6-chloro-7-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 190-200° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected to yield 0.737 g of isopropyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-7-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 6 ml of ethanol; 3.15 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 7 hours. After cooling, the mixture was concentrated under reduced pressure; under ice cooling conditions, 1.89 ml of 1 N hydrochloric acid was added; the residue was washed with ethyl acetate. To the water layer, 1.89 ml of 1 N hydrochloric acid was added to saturate with sodium chloride, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; 1.89 ml of 1 N hydrochloric acid was added to the residue, followed by concentration to dryness under reduced pressure; the residue was crystallized by the addition of ethyl ether, collected by filtration, washed with ethyl ether and dried to yield 0.445 g of the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])=[O:6])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[CH:1]([O:4][C:5]([O:7][C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([Cl:19])=[O:11])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Oc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.8 %

Procedure:
5 g (22 mmol) of 2-(isopropoxycarbonyloxy)benzoic acid are dissolved in 50 ml of dichloromethane with a few drops of pyridine. 1.95 ml (27 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. 5.7 g of 2-(isopropoxycarbonyloxy)benzoyl chloride are obtained with a quantitative yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].[CH3:9]O>>[CH3:9][O:7][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CO
Reactant: O=C(O)c1ccco1
Product: COC(=O)c1ccco1
Temperature: 80 °C
Yield: 91 %

Procedure:
With reference to the chemical reaction formula 6, 2-furan carboxylic acid (20 g, 178 mmol) and 0.5M of HCI/methanol (400 mL) are put in one after another to be dissolved in an 1 L round-bottom flask and are refluxed at 80° C. for 2 hours to be reacted. After the solvent is removed by vacuum drying, the residue from which is diluted in EtOAc to be moved to a separatory funnel, and washed in turn with ice water and 5% of sodium bicarbonate (NaHCO3) aqueous solution, with pH checked at 7˜8 at the end. After moisture in the funnel is removed by MgSO4, the residue having been filtered and vacuum evaporated is separated by flash chromatography (hexanes: EtOAc=10:1) to obtain a 2-furan carboxylic acid methyl ester (20.53 g, 162 mmol, 91% of yield), in the form of light yellow oil. The data of1H and 13C-NMR referring to that is as below.
Reaction SMILES: [CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C=O.[C:11](O)(=O)[CH2:12][C:13]([OH:15])=[O:14].S(=O)(=O)(O)O>N1C=CC=CC=1>[CH3:1][CH:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:11]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CC(=O)O
Reactant: CC(C)CCCCCC=O
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: CC(C)CCCCCC=CC(=O)O
Reaction time: 3 h

Procedure:
In a similar reaction as in 1 above, 100 ml toluene, sodium (39.5 g, 1.72 mole), 7-methyl-octanoate (52 g, 0.29 mole), and 260 ml anhydrous methanol reacted to yield 7-methyl-1-octanol (44.3 g, yield rate 85%); 7-methyl-1-octanol (44.3 g, 0.31 mole) reacted with chloro-chromic pyridine (100 g, 0.465 mole) to yield 7-methyl-octanaldehyde (31 g, yield rate 70%); and finally, 7-methyl-octanaldehyde (20 g, 0.14 mole), malonic acid (15 g, 0.14 mole), and 15 ml pyridine were added together and refluxed with heating for 3 hours. After cooling down 15 ml 30% sulfuric acid was added and the reaction mixture was stirred for 3 hours under ice bath and then extracted by diethyl ether. Diethyl ether was removed by evaporation and product was subject to vacuum fractional distillation and 122° C./1.5 mmHg fraction was collected as 9-methyl-2-decenoic acid (16 g, yield rate 80%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH:6]=[CH:5]2.C([Li])CCC.CCCCCC.Cl.[C:35](=O)(O)[O-:36].[Na+]>O1CCCC1.CN(C)C=O>[C:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([O:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:35]=[O:36])[CH:3]=3)[N:8]=2)[CH2:14][CH2:15]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3n2)CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 6-Bromo-2-(trans-4-tert-butyl-cyclohexyloxy)-quinoline (1.0933 g, 3.0176 mmol) in Tetrahydrofuran (24 mL) was added 1.6 M of n-Butyllithium in hexane (5.6 mL, 9.0 mmol) at −78° C. and the reaction was stirred for 15 min. N,N-Dimethylformamide (1.2 mL) was added and the reaction was stirred for 30 minutes. 1 M HCl was added and the reaction allowed to warm to RT. Saturated sodium bicarbonate solution was added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using hexanes/ethyl acetate (0-50%) as eluent to give product in 603 mg yield (64%). ESI-MS(M+H+): 312.20.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=O.[F:25][C:26]([F:34])([F:33])[C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[F:25][C:26]([F:34])([F:33])[C:27]([C:28]1[C:29]([CH3:30])=[N:1][C:2]2[C:3]([C:13]=1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[CH:4][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:7]=2)=[O:32]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C(=O)c2cc(OC(F)(F)F)ccc2N)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2ccc(S(C)(=O)=O)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 45 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(4-methanesulfonyl-phenyl)-methanone [example A 13] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 45%; MS: m/z=477 (M).