Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Br:21][C:22]1[CH:23]=[N:24][N:25]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=1
Reactant: Brc1cn[nH]c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Brc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 85 °C
Yield: 35.6 %

Procedure:
Trityl chloride (9.02 g) was added to a stirred solution of 4-bromopyrazole (4.24 g) and 4-dimethylaminopyridine (0.711 g) in pyridine (90 ml). The reaction mixture was heated to 85° C. for 20 hrs, cooled to room temperature and partitioned between diethyl ether and water. The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. The crude product was recrystallized from hexane/toluene (5/1, 180 ml) to afford the title compound (4.0 g). The remaining solids and the mother liquors were combined and purified by column chromatography on silica gel eluting with pentane/ether (30/1, v/v) to afford a second batch of title compound (3.0 g).
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1)#[N:2].[Cl-].[Ca+2].[Cl-]>[Fe]>[NH2:11][C:6]1[C:7]([CH3:10])=[C:8]([CH3:9])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1c([N+](=O)[O-])cnc(C#N)c1C
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Product: Cc1c(N)cnc(C#N)c1C
Yield: 43.2 %

Procedure:
2-Cyano-3,4-dimethyl-5-nitropyridine (0.15g, 0.85 mmol), calcium chloride (0.05g, 0.42 mmol), and iron powder (0.44g, 7.8 mmol, 325 Mesh) were reacted as described in example 772B. Purification of the crude product by silica gel chomatography using 1:1 ether/CH2Cl2 as the eluent gave compound 773B (0.054g, 50%) as a yellow solid.
Reaction SMILES: Cl.[C:2]([C@:5]12[C@@:12]3([CH3:30])[CH2:13][C@H:14]([OH:29])[C@@:15]4([F:28])[C@H:24]([C@@H:11]3[CH2:10][C@H:9]1[CH2:8][NH:7][CH2:6]2)[CH2:23][C@H:22]([F:25])[C:21]1[C@:16]4([CH3:27])[CH:17]=[CH:18][C:19](=[O:26])[CH:20]=1)(=[O:4])[CH3:3].[CH3:31][C:32]1[O:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.C(O)=O>C(#N)C>[C:2]([C@:5]12[C@@:12]3([CH3:30])[CH2:13][C@H:14]([OH:29])[C@@:15]4([F:28])[C@H:24]([C@@H:11]3[CH2:10][C@H:9]1[CH2:8][N:7]([CH2:36][C:35]1[O:38][C:32]([CH3:31])=[CH:33][CH:34]=1)[CH2:6]2)[CH2:23][C@H:22]([F:25])[C:21]1[C@:16]4([CH3:27])[CH:17]=[CH:18][C:19](=[O:26])[CH:20]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: Cc1ccc(C=O)o1
Agent: Cl
Solvent: O=CO
Solvent: CC#N
Product: CC(=O)[C@@]12CN(Cc3ccc(C)o3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 140 °C
Yield: 68.2 %

Procedure:
In a closed vessel, a mixture of compound 177 (306 mg, 0.692 mmol), 5-methylfurfural (344 μl, 3.46 mmol), TEA (97 μl, 0.692 mmol) and formic acid (266 μl, 6.92 mmol) in acetonitrile (15 ml) is heated under microwave irradiation for 15 minutes at 140° C. LC-MS shows that the reaction is complete. The solution is partitioned between AcOEt and a saturated solution of NaHCO3, the aqueous phase is extracted with AcOEt and the combined organic layers are washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated to give a oil which is purified by silica gel chromatography (eluent AcOEt/petroleum ether 1/1). Trituration with petroleum ether affords the title compound (236 mg, 0.472 mmol, 68.2% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:38])[C:3]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[C:25]([Cl:37])[CH:24]=1)=[O:4].[C:39](Cl)(=[O:42])[CH:40]=[CH2:41].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:37][C:25]1[CH:24]=[C:23]([NH:22][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])=[C:6]([NH:5][C:3]([C@@H:2]([NH:1][C:39](=[O:42])[CH:40]=[CH2:41])[CH3:38])=[O:4])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: COCCCOc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)[C@H](C)N
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)N[C@@H](C)C(=O)Nc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cc1OCCCOC
Yield: 25 %

Procedure:
400 mg of (2S)-2-amino-N-{4-[3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino]-7-(3-methoxypropoxy)-quinazolin-6-yl}-propionamide as a starting material was dissolved in 10 ml of THF and 3 ml of water, and reacted with 0.07 ml of acryloylchloride at room temperature for 1.5 hours after adding 188 mg of sodium bicarbonate. The reacted solution was extracted with a mixture of chloroform and isopropanol after adding water, washed with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-ethylacetate:methanol=15:1) to obtain the title compound (110 mg, 25%).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]=[C:6]2[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc2nccc(O)n2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: COC(=O)c1nc2nccc(Cl)n2n1
Yield: 60.1 %

Procedure:
To a suspension of the product obtained in Step 1 (35 g) in 400 ml phosphorus oxychloride 24 g of N,N-dimethylaniline was dropwise added at room temperature. The mixture was refluxed for two hours, excess phosphorus oxychloride was removed by distillation under normal pressure, and the reddish brown oil left was dissolved in 1.5 liters of chloroform. This solution was slowly poured into 800 ml of ice-cooled saturated sodium bicarbonate solution, the chloroform layer was collected after thorough mixing, and the aqueous layer was again extracted with one liter of fresh chloroform. The organic layers were joined together, washed with 500 ml of saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried solution was concentrated under reduced pressure to about 100 ml, and 200 ml of n-hexane was added to this concentrate, giving 20 g of the objective compound as faint yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)=[O:11].Br[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=2)=[O:11])=[N:28][CH:29]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-c2ccc(F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-c2ccc(F)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-(5-fluoropyridin-2-yl)-5-methylphenyl)methanone and 2-bromo-5-chloropyridine. MS (ESI) 453 (M+H).
Reaction SMILES: N.[H][H].[CH3:4][C:5]1[C:15]([CH3:16])=[C:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH:9]=[N:10]O>[Ni].CO>[CH3:4][C:5]1[C:15]([CH3:16])=[C:14]([CH2:17][CH2:18][O:19][CH2:20][CH3:21])[CH:13]=[CH:12][C:6]=1[O:7][CH2:8][CH2:9][NH2:10]
Reactant: [H][H]
Reactant: CCOCCc1ccc(OCC=NO)c(C)c1C
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCc1ccc(OCCN)c(C)c1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 85 %

Procedure:
Into a 20-liter autoclave charged were Raney nickel prepared (50 g as 50% alloy), 10 liters of methanol and 1.5 kg of liquid ammonia. After the hydrogen pressure was adjusted to 20 atm., the mixture was heated to 100° C. with stirring and stirred for one hour Into the mixture of activated Raney nickel thus obtained was charged 820 g of 2-[2,3-dimethyl-4-(2-ethoxyethyl)-phenoxy]-acetaldehyde oxime. Hydrogen was introduced until 20 atm., and the mixture was heated and stirred at 100° C. Absorption of hydrogen began at around 80° C. When the pressure was lowered, hydrogen was introduced to maintain the pressure at 20 atm. After about 0.5 to 2.5 hours, theoretical amount of hydrogen was absorbed, and then after cooling and releasing pressure, the catalyst was removed by filtration through a Nutze having Celite The filtrate was concentrated under reduced pressure to obtain a crude product. Yield 85-93%. The crude product was purified by distillation to obtain 2-[2,3-dimethyl-4-(2-ethoxyethyl)phenoxy]ethylamine (boiling point 170°-175° C./1 mmHg).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9](O)[CH3:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.P(Br)(Br)[Br:21]>C(OCC)C>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]([Br:21])[CH3:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: BrP(Br)Br
Reactant: CC(O)c1ccc(C(C)(C)C)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(Br)c1ccc(C(C)(C)C)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
To 25 ml of ethyl were added 1.78 g of (+)-4-tert.-butyl-α-methylbenzyl alcohol of 100% e.e. and 1.8 g of dry pyridine. The resulting mixed solution was kept at -25° C. and added dropwise with a solution of 3.1 g of phosphorus tribromide dissolved in 18 ml of ethyl ether (at -15° to -25° C.). After completion of addition, the resulting mixture was stirred at -10° C. for one hour and then allowed to stand at 5° C. for 2 days. Ice water was added thereto. The resulting organic layer was washed successively with a saturated aqueous solution of sodium bicarbonate and with ice water, dried with anhydrous Glauber's salt, and freed of solvent by distillation under reduced pressure to give 1.6 g of 4-tert.-butyl-α-methylbenzyl bromide.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:14]([C:16]([CH3:18])=[O:17])[CH3:15]>CCOCC>[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:14]([CH3:15])[C:16](=[O:17])[CH3:18])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: CCC(C)=O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=Cc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
300 g of 32% hydrochloric acid are added dropwise at 15°-20° C. over a period of 1 hour to a mixture of 300 g of p-tert.-butyl-benzaldehyde and 300 g of methyl ethyl ketone and the mixture is left to stir at room temperature for 22 hours. Subsequently, the mixture is taken up in 200 ml of ether, washed with water and saturated sodium bicarbonate solution, dried over sodium sulphate and concentrated. By fractional distillation there is obtained pure 4-(p-tert.butyl-phenyl)-3-methyl-3-buten-2-one of boiling point 120° C./0.03 Torr.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[Cl-].[Li+].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH2:28][NH:27]1.O>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:30]4[CH2:29][CH2:28][NH:27][CH:26]([CH3:25])[CH2:31]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(F)c(F)c(C)c2c1=O
Reactant: CC1CNCCN1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: O
Product: Cc1c(F)c(N2CCNC(C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a suspension of 1.23 g of ethyl 1-cyclopropyl-6,7-difluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate and 254 mg of lithium chloride in acetonitrile was added 1.00 g of 2-methylpiperazine, followed by heating and refluxing for 4 hours. After adding 24 ml of warm water, the reaction mixture was allowed to cool to precipitate crystals and the resulting crystals were filtered and washed with water. The crystals were suspended in 8 ml of isopropyl alcohol and 8 ml of 1N-NaOH, followed by stirring at a temperature in the range of 50° C. to 60° C. for 1 hour. After evaporating the isopropyl alcohol, to the residue were added 40 ml of water and 1.24 ml of concentrated hydrochloric acid, followed by washing with dichloromethane. The aqueous layer was heated at 100° C. for 1 hour to distill off the residual dichloromethane. After the aqueous layer was allowed to cool, 1.04 g of sodium hydrogencarbonate was added and heated with stirring at 60° C. for 1 hour, thereby neutralizing the aqueous layer. The aqueous layer was allowed to cool again, followed by stirring at 0° C. for 1 hour. The resulting crystals were filtered, washed with water and dried at 80° C. for 16 hours to give 1.40 g of 1-cyclopropyl-6-fluoro-7-(3-methyl-1-piperazinyl)-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]1[CH:9]=[CH:8][N:7]=[CH:6]1>>[N:5]1([CH2:3][CH2:2][CH2:1][NH2:4])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: C=CC#N
Reactant: c1c[nH]cn1
Product: NCCCn1ccnc1
Reaction time: 9 h

Procedure:
In accordance with Method IIB, acrylonitrile (8) and an imidazole (9) are reacted with heat for about 2-4 hours, concentrated to an oil and then hydrogenated with Raney nickel catalyst in methanol and ammonium hydroxide for a period of about 8-10 hours, giving 1H-imidazole-1-propanamine derivatives (10).
Reaction SMILES: O1CCCC1.[C:6]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[C:20]#[N:21])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:22](I)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[C:6]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1([CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:20]#[N:21])(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1CCCCN1C(=O)c1ccccc1
Reactant: ICCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CCc2ccccc2)CCCCN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 ml of tetrahydrofuran containing 140 mmol lithium diisopropylamide was added 15 g of solid 1-benzoyl-2-piperidinecarbonitrile at -78° C. The mixture was stirred for 30 minutes, after which 100 ml of tetrahydrofuran containing 33.2 g of phenethyl iodide was added dropwise at -78° C. After completion of dropwise addition, the temperature of the reaction mixture was gradually increased to 0° C. Then, water was added and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The pooled organic layer was dried over anhydrous magnesium sulfate and filtered and the solvent was then distilled off. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as the eluent. The solution containing the desired compound was distilled under reduced pressure and the resulting solid was recrystallized from ethyl acetate-hexane to provide 17.3 g of colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].C(N(CC)CC)C.[C:23]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:28][CH:29]=1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 73 %

Procedure:
Into 200 mL methylene chloride was dissolved 10.45g (50 mmol) 2-aminoterephthalic acid dimethyl ester. The solution was cooled in an ice bath, and 7.73 mL (55 mmol) triethylamine was added, followed by 10.76 mL 4-tert-butylbenzoyl chloride in 50 mL methylene chloride dropwise. The mixture was allowed to come slowly to room temperature, and after 16 h the mixture was shaken with 200 mL cold dilute HCl and 200 mL satd NaHCO3. The organic layer was dried (MgSO4) and evaporated. The residue was redissolved in a minimum ether, giving 13.5 g (73%) of crystalline desired intermediate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([OH:9])[C:4]=1[OH:10].Br[CH2:12]Cl.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[O:10][CH2:12][O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(O)c1O
Reactant: ClCBr
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1OCO2
Reaction time: 4 h

Procedure:
A mixture of 3-methoxy-benzene-1,2-diol (1.161 g, 8.28 mmol) in DMF (10 mL) was added to bromo-chloro-methane (611 ul, 1.1 equivalents) and stirred at 90 degrees Celsius for 4 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was poured thru a phase separator cartridge and concentrated to dryness. The crude product is a yellow liquid. The liquid was purified by column chromatography yielding 1.21 g, (96%). 1H-NMR (DMSO, 500 MHz) 6.7 (t, 1H), 6.63 (d, 1H), 6.58 (d, 1H), 5.97 (s, 2H), 3.83 (s, 3H)HPLC (method A) 2.86 min.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19].Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.C1CCN2C(=NCCC2)CC1.[OH-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][C:28]3[CH2:29][NH:30][CH2:31][C:24]=3[CH2:25]2)=[C:4]([F:20])[CH:5]=[C:6]2[C:11]=1[N:10]([C@@H:12]1[CH2:14][C@@H:13]1[F:15])[CH:9]=[C:8]([C:16]([OH:18])=[O:17])[C:7]2=[O:19]
Reactant: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn([C@@H]2C[C@@H]2F)c2c(Cl)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Yield: 10.7 %

Procedure:
A solution of 318 mg of 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 544 mg of 3,7-diazabicyclo[3.3.0]oct-1(5) -ene dihydrobromide (JP-A-3-193779) and 2 ml of DBU in 20 ml of acetonitrile was heated under reflux for 15 hours. To the mixture was added 1N sodium hydroxide, and an insoluble material was removed by filtration. To the filtrate, was added hydrochloric acid till pH became 7.4, and the mixture was extracted by five 50 ml portions of chloroform. A combined organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was recrystallized from a mixture of ethanol and ammonia water to yield 43.7 mg of the titled compound.
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(Cl)([Cl:31])=O>ClCCl>[CH2:1]([C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21]([Cl:31])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)O)c1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCc1cccc(OC(CC)C(=O)Cl)c1

Procedure:
2-(3-Pentadecylphenoxy)butanoic acid (7.8 g, 0.02 mol) (CAS Registry Number 14230-52-5) and thionyl chloride (50 ml) were heated under reflux on a steam-bath for 1 h. The resulting yellow solution was allowed to cool before being distilled under reduced pressure to leave a yellow oil. The oil was dissolved in dichloromethane (50 ml) and the solution was distilled under reduced pressure to remove volatiles. The residual 2-(3-pentadecylphenoxy)butanoyl chloride was used without further purification.
Reaction SMILES: [H-].[Na+].CN1CCCC1=O.[CH2:10]([S:12][C:13]1[NH:14][CH:15]=[CH:16][N:17]=1)[CH3:11].Cl[C:19]1[N:31]([CH3:32])[C:22]2=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=[C:21]2[N:20]=1>O>[CH2:10]([S:12][C:13]1[N:17]([C:19]2[N:31]([CH3:32])[C:22]3=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]3[N:20]=2)[CH:16]=[CH:15][N:14]=1)[CH3:11]
Reactant: CCSc1ncc[nH]1
Reactant: Cn1c(Cl)nc2cc(C(F)(F)F)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCSc1nccn1-c1nc2cc(C(F)(F)F)cnc2n1C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
41 mg of sodium hydride (60% oil-based) was suspended into 4 ml of 1-methyl-2-pyrrolidone (NMP), and 0.13 g of 2-ethylthioimidazol was added under ice cooling. After stirring the mixture for 10 minutes, 0.2 g of 2-chloro-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine was added, and the mixture was stirred under room temperature for 3 hours. Water was poured, and the deposited precipitate was obtained by filtration and was applied to a silica gel column chromatography to obtain 0.28 g of 2-(2-ethylthio-3H-imidazol-3-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5,b]pyridine (Compound of Present Invention (1)).
Reaction SMILES: C(O[K])(C)(C)C.F[C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([OH:30])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.O>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([O:30][C:8]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=2[CH:10]=[O:11])[CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: O=Cc1ccc(F)cc1F
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)ccc2C=O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 18.3 %

Procedure:
tBuOK (434 mg; 3.87 mmol; 1.1 eq.) was added to a solution of 2,4-difluoro-benzaldehyde (500 mg; 3.52 mmol; 1 eq.) and (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (779 mg; 3.87 mmol; 1.1 eq.) in 1,4-dioxane (3 mL) and reaction mixture was stirred at room temperature for 15 minutes. The solution was diluted with water and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (heptanes/EA) afforded the title compound (208 mg, 18%) as white solid. HPLC (max plot) 92.8%; Rt 4.46 min.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[N:9]=1.[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][C:47](O)=[O:48])[CH:42]=[CH:43][C:44]=1[Cl:45]>>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:31]=1)[CH2:6][CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:20])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:47](=[O:48])[CH2:46][C:41]3[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([Cl:38])[CH:40]=3)=[CH:24][CH:23]=2)[N:9]=1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)cc1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)Nc1ccc(Cn2nc(CCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n(Cc3ccccc3)c2=O)cc1

Procedure:
Prepared as for Example 7 using the compound of Example 5 and 3,4-dichlorophenylacetic acid.