Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][N:12]=1)C(OCC)=O)C.O.[OH-].[Li+].Cl>C1COCC1.O>[F:17][C:16]1[C:11]([CH2:5][C:4]([OH:19])=[O:3])=[N:12][CH:13]=[C:14]([F:18])[CH:15]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ncc(F)cc1F
Temperature: 25 °C
Yield: 53 %

Procedure:
To a stirred solution of 2-(3,5-difluoro-pyridin-2-yl)-malonic acid diethyl ester (1 g, 3.56 mmol) (Preparation 264) in THF (15 mL) was added a solution of lithium hydroxide monohydrate (462 mg, 10.4 mmol) in water (4 mL) dropwise at 0° C. and the mixture heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, acidified (pH ˜3) with 2N hydrochloric acid and extracted with 20% isopropanol-dichloromethane (5×20 mL). The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of DCM: MeOH 100:0 to 95:5) to afford the title compound as a solid in 53% yield, 336 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:17])C(=O)C1.O>CN(C=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:17])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminobenzonitrile (14.9 g, 100 mmol) was added a solution of NBS (17.8 g, 100 mmol) in DMF at rt. The mixture was stirred overnight at rt, then water (30 mL) was added and the mixture was extracted with Et2O (3×250 mL). The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC to give compound P36a (19 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[C:25](OC)=[O:26])[N:19]([CH3:29])[C:18]=4[CH:30]=3)[C:10](=[O:31])[CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[Cl-].[Ca+2].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([CH:22]5[CH2:24][CH:23]5[CH2:25][OH:26])[N:19]([CH3:29])[C:18]=4[CH:30]=3)[C:10](=[O:31])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C2CC2CO)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A suspension of methyl(1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylate (200 mg) in THF (1.5 ml) and MeOH (0.750 ml) was added dropwise to a solution of NaBH4 (32.6 mg) and CaCl2 (71.8 mg) in THF (3 ml) and MeOH (2 ml) at 0° C. The mixture was stirred at room temperature under Ar atmosphere overnight. NaBH4 (300 mg) was added to the m resulting mixture at 50° C., and the mixture was stirred at 50° C. overnight. The mixture was neutralized with 1 M HCl at 0° C. and extracted with EtOAc. The organic layer was separated, washed with saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (156 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([C:21](O)=[O:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]([CH2:21][OH:22])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1Cc2ccccc2N(C(=O)OCc2ccccc2)C1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(CO)Cc2ccccc21

Procedure:
14.0 g of N-benzyloxycarbonyl-3(R,S)-carboxy-1,2,3,4-tetrahydroquinoline are stirred in 400 ml of tetrahydrofuran with 9.0 ml of 10M borane-dimethylsulfide complex at 25° C. for 16 h. The reaction mixture is diluted several times with methanol and evaporated. The crude product is recrystallized from ethyl acetate/hexane: mp 62°-4° C.; Rf (X)=0.50; FAB-MS: (M+H)+ =298; anal. calc. for C18H19NO3 : C 72.71%, H 6.44%, N 4.71%; found C 72.84%, H 6.35%, N 4.75%.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([N:13]([CH3:48])[C:14]([N:16]([CH3:47])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]3[O:33][C:32]([CH:34]4[CH2:39][CH2:38][N:37]([C:40](OC(C)(C)C)=[O:41])[CH2:36][CH2:35]4)=[N:31][N:30]=3)[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[CH3:52]C(O)C>>[C:40]([N:37]1[CH2:38][CH2:39][CH:34]([C:32]2[O:33][C:29]([N:19]3[CH2:20][C@@H:21]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[C@H:17]([N:16]([CH3:47])[C:14]([N:13]([C:5]4[CH:4]=[C:3]([C:2]([F:49])([F:1])[F:50])[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=4)[CH3:48])=[O:15])[CH2:18]3)=[N:30][N:31]=2)[CH2:35][CH2:36]1)(=[O:41])[CH3:52]
Reactant: CC(C)O
Reactant: CN(C(=O)N(C)[C@@H]1CN(c2nnc(C3CCN(C(=O)OC(C)(C)C)CC3)o2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CC(=O)N1CCC(c2nnc(N3C[C@@H](N(C)C(=O)N(C)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@H](c4ccc(F)cc4)C3)o2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
A mixture of the compound (0.10 g) obtained in step 1 and 2N hydrogen chloride/2-propanol was stirred at room temperature for 3 days. The mixture was concentrated under reduced pressure, and to the residue were added acetyl chloride (0.016 mL), triethylamine (0.071 mL) and acetonitrile (4.0 mL), and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (0.041 g, 43%) as a pale-brown powder.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([C:13]([O:15]CC)=O)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].C(N(CC)C(C)C)(C)C>CO.[OH-].[Na+].O.CN(C=O)C>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([C:13]([NH:31][CH2:30][CH2:29][C:23]2[C:22]3[C:26](=[CH:27][CH:28]=[C:20]([Cl:19])[CH:21]=3)[NH:25][CH:24]=2)=[O:15])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1noc(Cc2ccccc2)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccccc2)n1
Yield: 43.8 %

Procedure:
This compound was prepared according to method F with ethyl 5-benzyl-1,2,4-oxadiazole-3-carboxylate (0.1 g; 0.432 mmol) in methanol (6 mL) and sodium hydroxide in water (2M, 6 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.432 mmol), HART (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (6 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.072 g (44%) of 5-benzyl-N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6]Cl)[CH3:2].[C-:35]#[N:36].[Na+].O>CS(C)=O>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([CH2:12][C:13]([NH:15][CH:16]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:14])[CH:9]=[CH:8][C:5]=1[CH2:6][C:35]#[N:36])[CH3:2]
Reactant: [C-]#N
Reactant: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CCl
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1cc(CC(=O)NC(c2ccccc2)c2ccccc2N2CCCCC2)ccc1CC#N
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A solution of 2-ethoxy-4-[N-(α-phenyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzyl chloride (2.6 g, 5.45 mmol) in dimethylsulphoxide (10 ml) is added dropwise at 50-60° C. to sodium cyanide (0.32 g, 6.5 mmol) in dimethylsulphoxide (40 ml). The mixture is then stirred for 5 hours at 60° C., added to water and extracted with chloroform. The extract is concentrated by evaporation in vacuo. The residue is purified by column chromatography on silica gel (toluene/ethyl acetate=5/1).
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:24])[CH:11]=1)=[O:5].ClC([O-])=O>C1COCC1>[C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:24])[CH:11]=1)(=[O:5])[NH:1][NH2:2]
Reactant: NN
Reactant: O=C(Cl)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Product: NNC(=O)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Into a 250 ml 3-neck flask was added 5.4 grams (0.11 mole) of 64% aqueous hydrazine and 50 mls of THF. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and a dropping funnel containing 9.6 grams (0.03 mole) of 2-(3-hydroxy-4-benzoylphenoxy)ethyl chloroformate dissolved in 50 ml of THF. The chloroformate solution was added dropwise to the stirring hydrazine solution over 1/2 hour. The temperature quickly exothermed to 36° C. and slowly subsided after the addition was over. The reaction was stirred an additional 1/2 hour and concentrated to 31 grams. The THF solution was added to 300 ml of water. A sticky solid formed. The solid was filtered off, taken up in methylene chloride, dried over Na2SO4, filtered and the methylene chloride stripped off. The residue was a viscous orange-brown liquid. The crude product was slurried in 150 ml of warm MtBE. Most of the crude product went into solution, leaving a dark brown liquid residue. The yellow MtBE layer was decanted off and the MtBE stripped off on a rotating evaporator, leaving 9.0 grams of a yellow viscous liquid. Liquid chromatography indicated it was about 92% pure. The residue was slurried in warm methanol and upon cooling, a solid formed. The solid was filtered off and after air drying, weighed 6.4 grams (67% yield) and had a melting point of 58°-61° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][O:21][C:22]([C:24]1[S:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27](Br)[CH:28]=1)=[O:23].[CH3:33][C:34]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:38][C:37]([SH:46])=[CH:36][CH:35]=1>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:20][O:21][C:22]([C:24]1[S:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([S:46][C:37]2[CH:38]=[C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]([CH3:33])=[CH:35][CH:36]=2)[CH:28]=1)=[O:23]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: Cc1ccc(S)cc1-c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Sc2ccc(C)c(-c3ccccc3)c2)c([N+](=O)[O-])s1
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of triphenylphosphine (0.67 g, 2.55 mmol), 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 1 g, 3.76 mmol) and 4-(dimethyl)aminopyridine resin (1 eq) in THF was added 6-methyl-biphenyl-3-thiol from above step b. This mixture was stirred for 3 hrs. The reaction mixture was filtered and the solvents were removed in vacuo. The residue was purified via column chromatography (SiO2, 15% ethyl acetate/hexane) to afford a yellow glass (600 mg, 61%), which was used in the following step.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([CH:23]=[C:24]([O:26][CH2:27][CH3:28])[N:25]=2)[C:18]([O:20]CC)=O)C2C=CC=CC=2)C=CC=CC=1.O.[OH-].[Li+].[C:32]1([C:38]2[CH:42]=[C:41]([CH2:43][N:44]3[CH2:49][CH2:48][CH:47]([CH2:50][NH2:51])[CH2:46][CH2:45]3)[O:40][N:39]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.O.ON1C2C=CC=CC=2N=N1>CO.ClCCl.O.O1CCCC1>[NH2:14][C:15]1[CH:16]=[C:17]([CH:23]=[C:24]([O:26][CH2:27][CH3:28])[N:25]=1)[C:18]([NH:51][CH2:50][CH:47]1[CH2:46][CH2:45][N:44]([CH2:43][C:41]2[O:40][N:39]=[C:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:42]=2)[CH2:49][CH2:48]1)=[O:20]
Reactant: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reactant: CCOC(=O)c1cc(N=C(c2ccccc2)c2ccccc2)nc(OCC)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)no3)CC2)cc(N)n1
Reaction time: 48 h
Yield: 22 %

Procedure:
The compound prepared in Example 230 (0.090 g) and lithium hydroxide hydrate (0.011 g) were combined in methanol (1 mL), tetrahydrofuran (1 mL) and water (0.1 mL) and allowed to stir for 48 hours. The reaction was concentrated, pumped to dryness and used without further purification. The crude acid was combined with the compound prepared in Example 9 (0.11 g, 0.31 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.069 g, 0.36 mmol), diisopropylethylamine (0.16 g, 1.2 mmol) and 1-hydroxybenzotriazole hydrate (0.049 g, 0.36 mmol) in dichloromethane (2.5 mL). The reaction was sonicated briefly to aid dissolution and then stirred for 24 hours. The crude reaction was concentrated and then dissolved in methanol and treated with 2N hydrochloric acid. After stirring for 15 minutes, this solution was concentrated and then partitioned between ethyl acetate and sodium hydrogen carbonate aqueous solution. The organic phase was dried over magnesium sulfate, filtered, concentrated and purified by column chromatography using an eluant of 4% methanol/dichloromethane to provide the title compound (0.023 g) with the following physical data.
Reaction SMILES: [CH3:1][C@@H:2]1[N:23]2[C:6]3[C:7]([C:19]([C:21]([C:24]([OH:26])=[O:25])=[CH:22]2)=[O:20])=[CH:8][C:9]([F:18])=[C:10]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[C:5]=3[O:4][CH2:3]1.[O:27]=C1O[C@H]([C@H](CO)O)C(O)=C1O>CCCCO>[CH3:1][C@@H:2]1[N:23]2[CH:22]=[C:21]([C:24]([OH:26])=[O:25])[C:19]([C:7]3=[CH:8][C:9]([F:18])=[C:10]([N:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)[C:5](=[C:6]23)[O:4][CH2:3]1)=[O:20].[CH3:1][C@@H:2]1[N:23]2[CH:22]=[C:21]([C:24]([OH:26])=[O:25])[C:19]([C:7]3=[CH:8][C:9]([F:18])=[C:10]([N:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)[C:5](=[C:6]23)[O:4][CH2:3]1)=[O:20].[OH2:27]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: C[C@H]1COc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CCCCO
Product: O
Temperature: 25 °C

Procedure:
1.5 g of levofloxacin crude and 36 mg of ascorbic acid were put in suspension in 9.5 ml of n-BuOH under inert atmosphere. The mixture was heated to reflux temperature and a hot filtration was performed. The solution was then evaporated to dryness and n-BuOH (10 ml) was added. The mixture was heated to reflux until complete dissolution and then cooled to RT over a period of 1.5 hour. The precipitate was filtrated under vacuum, washed with n-BuOH (4 ml) and dried at 60° C. in a vacuum oven to give 840 mg (56%) of purified levofloxacin hemihydrate.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([S:14][C:15]1[C:16]([C:21]2[N:33]([CH3:34])[C:24]3=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=[C:23]3[N:22]=2)=[N:17][CH:18]=[CH:19][N:20]=1)[CH3:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:12]([S:14]([C:15]1[C:16]([C:21]2[N:33]([CH3:34])[C:24]3=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=[C:23]3[N:22]=2)=[N:17][CH:18]=[CH:19][N:20]=1)=[O:6])[CH3:13]
Reactant: CCSc1nccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)c1nccnc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
467 mg of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 425 mg of 2-(3-ethylsulfanylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine and 8 ml of chloroform under ice cooling. The mixture was heated to room temperature and stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 205 mg of 2-(3-ethylsulfinylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 7) and 230 mg of 2-(3-ethylsulfonylpyrazin-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound of Present Invention 8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:30]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[C:23](=[O:29])[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
N,N'-Carbonyldiimidazole (1.13 g) is added to a solution of 2-methoxyphenylacetic acid (1.16 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 15 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.28 g) and triethylamine (1.96 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The meringue obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (80 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)-acetyl]-4-perhydroisoindolone (2 g) is obtained in the form of white crystals melting at 158° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]=[CH:3]1.[Li+].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.IC>O1CCCC1>[CH3:1][C:2]1([CH3:9])[CH2:7][CH:6]([CH3:11])[C:5](=[O:8])[CH:4]=[CH:3]1
Reactant: CC1(C)C=CC(=O)CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(C)(C)C=CC1=O
Temperature: 23 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of 4,4-dimethyl-cyclohex-2-en-1-one (5.00 g, 40.3 mmol, 1 equiv) in tetrahydrofuran (130 mL) was added to a solution of LHMDS (1 M in tetrahydrofuran, 58.4 mL, 58.4 mmol, 1.45 equiv) in tetrahydrofuran (60 mL) at −78° C. After stirring for 1 h, iodomethane (5.02 mL, 80.6 mmol, 2.0 equiv) was added dropwise to the flask. The cooling bath was immediately removed and the reaction mixture was allowed to warm to room temperature (23° C.). After stirring 11 h, saturated aqueous ammonium chloride solution (50 mL) and distilled water (10 mL) were added to the flask. The layers were separated and the aqueous layer was extracted with three 50-mL portions of ether. The combined organic layers were washed once with brine (10 mL) and dried over sodium sulfate (15 min). Following filtration, volatiles were removed in vacuo, leaving a brown residue which was distilled at 22 torr furnishing 4,4,6-trimethyl-cyclohex-2-en-1-one (10, 3.93 g, 72%) as a clear oil, bp 82-86° C. (Torri, J.; Azzaro, M. Bull. Soc. Chem. Fr. 1978, 283; incorporated herein by reference).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:19][CH2:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(C)cc1-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1-c1ccc(F)cc1

Procedure:
A solution of methyl 2-(4-fluorophenyl)-4-methylbenzoate (54.18 g; 0.22 mol), N-bromosuccinimide (39.6 g; 0.22 mol), 2,2′-azobis(2′-methylproprionitrile) (0.25 g; 1.5 mmol) and benzoylperoxide (0.25 g; 1 mmol) in tetrachloromethane (550 ml) was heated at reflux for 6 hours. The solid was filtered and the filtrate evaporated to give methyl 4-bromomethyl-2-(4-fluorophenyl)benzoate as an oil (79.7 g; 79%) which was used in the next step without purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:18]([OH:19])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:21]([N:24]([CH2:29][CH2:30][CH3:31])[C:25](=[O:28])[CH2:26]Cl)[CH2:22][CH3:23].O>CC(C)=O>[Br:7][C:8]1[C:18]([O:19][CH2:26][C:25]([N:24]([CH2:29][CH2:30][CH3:31])[CH2:21][CH2:22][CH3:23])=[O:28])=[C:17]([Br:20])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(Br)c(O)c1Br
Reactant: CCCN(CCC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCCN(CCC)C(=O)COc1c(Br)ccc(C(=O)OCC)c1Br

Procedure:
0.853 g of K2CO3, 0.154 g of KI and 1.000 g of ethyl 2,4-dibromo-3-hydroxybenzoate were introduced in 10 ml of acetone. At RT 0.783 g of N,N-di-n-propylchloroacetamide was added. The mixture was then heated at reflux for 4 hours. It was subsequently poured into water and extracted with diisopropyl ether. The organic phases were washed with water, dried over Na2SO4 and concentrated. Chromatography on silica gel (eluent: n-heptane/ethyl acetate) gave ethyl 2,4-dibromo-3-(N,N-di-n-propylaminocarbonylmethoxy)benzoate as brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[C:9](=[O:18])[NH:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>C(O)C.C(N(CC)CC)C.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10]2[CH:12]=[CH:13][O:18][C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(=O)c(C#C[Si](C)(C)C)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2occc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6Oxo-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester described in Preparation Example P-3 (545 mg, 2.07 mmol) and copper(I)iodide (5.9 mg, 31 μmol) were suspended in ethanol (7 mL) and triethylamine (3 mL), and the mixture was stirred at 75° C. for 20 hours. The reaction mixture was cooled to room temperature, then, potassium carbonate (572 mg, 4.14 mmol) was added to the reaction mixture, which was further stirred at 75° C. for 5 hours. The reaction mixture was cooled to 0° C., then, water was added, the precipitated solid was filtered, and the title compound (303 mg) was obtained as a brown solid. In addition, ethyl acetate was added to the mother liquor for extraction, the organic layer was washed with brine, then, dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (33 mg, 0.17 mmol) was obtained as a white solid.