Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][C:4]=1[B:12]([OH:14])[OH:13].[H-].[Na+].Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][N:11]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:6]2=[CH:5][C:4]=1[B:12]([OH:14])[OH:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1nc2cc[nH]c2cc1B(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc2ccn([Si](C(C)C)(C(C)C)C(C)C)c2cc1B(O)O
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a white suspension of 5-methoxy-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (500 mg, 2.60 mmol) in tetrahydrofuran (25 mL) was added sodium hydride (281 mg, 11.72 mmol) in several portions at 0° C., the resulting light grey suspension was stirred for 30 min, followed by dropwise addition of chlorotriisopropylsilane (2260 mg, 11.72 mmol) through a syringe over 30 sec. under N2. The mixture, as a suspension, was continued stirring at 0° C. for 2 hr, and the conversion was completed as determined by LC/MS. The reaction was carefully quenched with sat. NH4Cl (10 mL), extracted with Et2O (2×50 mL), the combined organic solution was washed with brine (20 mL), dried (Na2SO4), concentrated on rotary vacuo to afford the expected product, 5-methoxy-1-(triisopropylsilyl)-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (900 mg, 99%), as a grey gum. 1H-NMR (500 MHz, CHLOROFORM-D) s ppm 1.11 (d, J=7.63 Hz, 21 H) 1.62-1.72 (m, 3 H) 4.03-4.10 (m, 2 H) 6.67 (d, J=3.36 Hz, 1 H) 7.31 (s, 1 H) 7.43 (d, J=3.05 Hz, 1 H); Mass spec 349.21 (MH+) Calc for C17H29BN2O3Si 348.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:19]([F:22])([F:21])[F:20].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:19]([F:22])([F:20])[F:21]
Reactant: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: OCCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(CCO)cc2)c1
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
To a stirred solution of 3-[3-Methyl-8-(trifluoromethyl)quinolin-4-yl]phenol (0.086 g, 0.28 mmol) and 2-(4-bromomethlyphenyl)ethanol (0.061 g, 0.28 mmol) in CH2Cl2 (5 mL) is added Cs2CO3 (0.365 g, 1.12 mmol). After 1.5 h, additional alkylating agent (0.015 g) is added and the reaction is stirred overnight. The reaction is neutralized with 2N aq HCl, extracted with ethyl acetate and dried (MgSO4). Chromatography eluting with 5:95 ethyl acetate:hexane afforded the title compound (0.092 g, 75%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]=2[CH:17]=1)#[N:2].[Cl-].[NH4+].[N-:20]=[N+:21]=[N-:22].[Na+].CN(C)C=O>O>[C:11]1([C:8]2[C:7]3[CH:17]=[C:3]([C:1]4[NH:22][N:21]=[N:20][N:2]=4)[CH:4]=[CH:5][C:6]=3[O:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1ccc2occ(-c3ccccc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2coc3ccc(-c4nnn[nH]4)cc23)cc1
Temperature: 20 °C

Procedure:
A mixture of 61.4 g. (0.28 mole) of 5-cyano-3-phenylbenzofuran (described in U.S. Pat. No. 4,067,993, Example 1), 16.5 g. (0.31 mole) of ammonium chloride and 20.2 g. (0.31 mole) of sodium azide in 250 ml. of N,N-dimethylformamide is stirred at 110°14 120° C. for 16 hours. The mixture is cooled to about 20° C. and poured into about 1 liter of water. A light brown solid forms which is collected by filtration, washed with water, and then recrystallized from ethanol to provide brown crystals of 3-phenyl-5-(1H-tetrazol-5-yl)benzofuran.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].[F:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32]Cl)[CH:30]=4)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[F:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([CH2:32][N:4]5[C:5](=[O:6])[CH2:7][NH:1][C:2]5=[O:3])[CH:30]=4)[CH2:25][CH2:24]3)[CH2:21][CH2:22]2)=[CH:34][CH:35]=1
Reactant: O=C1CNC(=O)N1
Reactant: Fc1ccc(CCN2CCC(N3CCc4ccc(CCl)cc43)CC2)cc1
Agent: [H-]
Agent: [Na+]
Product: O=C1CNC(=O)N1Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 49.1 %

Procedure:
Hydantoin (130 mg), 60% sodium hydride (54 mg) and 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-chloromethylindoline (400 mg) were treated as in Example 202 to give the title compound (230 mg) as a white powder (yield: 49%).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](Cl)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19]([N:21]([CH2:29][CH3:30])[CH2:22][C:23]#[C:24][C:25]([NH2:28])([CH3:27])[CH3:26])[CH3:20].[I-].[Na+]>CC(C)=O>[CH2:29]([N:21]([CH2:19][CH3:20])[CH2:22][C:23]#[C:24][C:25]([NH:28][CH:10]1[CH2:11][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9]1)([CH3:26])[CH3:27])[CH3:30]
Reactant: CCN(CC)CC#CC(C)(C)N
Reactant: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCN(CC)CC#CC(C)(C)NC1C=CC(c2ccccc2)(c2ccccc2)C1
Yield: 59.3 %

Procedure:
A mixture of 4,4-diphenyl-2-cyclopentenyl chloride (0.60 g), 4-diethylamino-1,1-dimethyl-2-butynylamine (0.79 g) and a catalytic amount of sodium iodide in acetone (5 ml) was refluxed for 8 hours. After being cooled, the solvent was removed off under reduced pressure and the residue was purified with column chromatography on silica gel with a mixture of chloroform and methanol as an eluent to give N-[4-diethylamino-1,1-dimethyl-2-butynyl]-4,4-diphenyl-2-cyclopentenylamine (0.54 g). The free amine obtained above was dissolved in chloroform, and to the solution was added hydrogen chloride in methanol (0.18 g/ml, 1 ml). The solution was evaporated in vacuo and triturated with a mixture of ethanol and isopropyl alcohol to give its hydrochloride (0.45 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][S:8][C:9]2[C:10](F)=[C:11]([F:27])[C:12]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[C:13]([CH:18]=2)[C:14]([O:16][CH3:17])=[O:15])=[CH:5][CH:4]=1.[N-:31]=[N+:32]=[N-:33].[Na+].O>CN(C=O)C>[N:31]([C:10]1[C:9]([S:8][CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:11]=1[F:27])=[N+:32]=[N-:33]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(F)c(F)c1Nc1ccccc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N=[N+]=[N-])c(F)c1Nc1ccccc1F
Temperature: 90 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of methyl 5-(4-methoxybenzylthio)-3,4-difluoro-2-((2-fluorophenyl)amino)benzoate (12.64 g, 29.2 mmol) in DMF (30 mL) was added NaN3 (2.28 g, 35.0 mmol) at ambient temperature. The mixture was stirred at 90° C. for 3 h. Then water (150 mL) was added. The solution was extracted with ethyl acetate (100 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate, 10:1, v/v) and gave the desired product (white solid, 10.38 g, 78% yield). 1H NMR (400 MHz, CDCl3): δ 8.98 (s, 1H), 7.75 (s, 1H), 7.02-7.28 (m, 6H), 6.83-6.85 (m, 2H), 4.03 (s, 2H), 3.92 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]([O:18]C)=[O:17])=[C:11]2[N:10]=[C:9]([O:20][CH3:21])[C:8]=1[C:22]1[S:23][CH:24]=[CH:25][C:26]=1[CH3:27])[CH:3]([CH3:5])[CH3:4].O1CCOCC1.[OH-].[Na+].Cl>O>[CH3:1][CH:2]([NH:6][C:7]1[N:12]2[N:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[C:11]2[N:10]=[C:9]([O:20][CH3:21])[C:8]=1[C:22]1[S:23][CH:24]=[CH:25][C:26]=1[CH3:27])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)c1cnn2c(NC(C)C(C)C)c(-c3sccc3C)c(OC)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1nc2c(C(=O)O)cnn2c(NC(C)C(C)C)c1-c1sccc1C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
At room temperature, 0.2 g (0.55 mmol) of methyl 7-(1,2-dimethylpropylamino)-5-methoxy-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxylate was mixed with a mixture of 5 ml of 1,4-dioxane and 2.5 ml (2.5 mmol) of a 1 N sodium hydroxide solution. The mixture was then stirred at 22° C. for 16 hours. 5 ml of water and 3 ml of 1 N hydrochloric acid were added to the reaction mixture. The precipitate formed was filtered off, washed with water and dried. This gave 0.2 g of 7-(1,2-dimethylpropylamino)-5-methoxy-6-(3-methylthiophen-2-yl)pyrazolo[1,5-α]-pyrimidine-3-carboxylic acid (logPs=3.65; content according to HPLC: 96%).
Reaction SMILES: [CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[CH:9]=1)[CH3:2].C([Li])CCC.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C>O1CCCC1.CCCCCC>[CH2:1]([S:3][CH2:4][C:5]1[CH:6]=[N:7][N:8]([CH3:10])[C:9]=1[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)[CH3:2]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CCSCc1cnn(C)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCSCc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of 4-[(ethylthio)methyl]-1-methyl-1H-pyrazole (0.81 g, 5.2 mmol) in tetrahydrofuran (3.0 mL) at 0° C. was added 1.6 M n-butyllithium in hexane (6.3 mL, 10. mmol). The solution was stirred at room temperature for 1 h and then cooled down to −78° C. To the solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.06 mL, 10.1 mmol). The reaction was continued at −78° C. for 0.5 h, then warmed up to 0° C. (taking about 0.5 h). The reaction mixture was quenched with brine, adjusted to PH=6-7 with 1 N HCl aqueous solution, extracted with EtOAc (2×). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to give one oil residue which was purified by combi-flash chromatography eluted with EtOAc/hexane (20-100%). The purification gave 1.2 g (86% yield) of the desired product as yellowish oil. LC-MS found: 283.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([NH2:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(OCC)(=O)C>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[C:17]([NH:19][C:20]([NH:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:12]=1)=[O:21])=[O:18]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: Nc1cc(-c2ccc(F)cc2)no1
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1ccccc1Cl)Nc1cc(-c2ccc(F)cc2)no1
Reaction time: 17 h

Procedure:
3-(4-Fluorophenyl)-5-aminoisoxazole (250 g.) was combined with 300 g. of 2-chlorobenzoyl isocyanate in 50 ml. of ethyl acetate. The reaction mixture was stirred overnight (about 17 hours) and the resulting solid was filtered, washed with ethanol, ether, and then dried, m.p., 200°-202° C.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.Cl.[CH3:33][C:34]1[CH:35]=[C:36]([CH:48]=[CH:49][CH:50]=1)[CH2:37][C:38]1([C:44]([O:46][CH3:47])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(C(C)C)CC)(C)C>ClCCl>[C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:41]3[CH2:42][CH2:43][C:38]([CH2:37][C:36]4[CH:48]=[CH:49][CH:50]=[C:34]([CH3:33])[CH:35]=4)([C:44]([O:46][CH3:47])=[O:45])[CH2:39][CH2:40]3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncc2CO)cc1
Reactant: COC(=O)C1(Cc2cccc(C)c2)CCNCC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1(Cc2cccc(C)c2)CCN(Cc2cncn2Cc2ccc(C#N)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a cold (−78° C.) solution of 3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl alcohol (184 mg, 0.81 mmol) and dilsopropylethylarnine (155 μL, 0.89 mmol) in dichloromethane (3.8 mL), trifluoromethanesulfonic anhydride (143 μL, 0.85 mmol) was added. The resulting mixture was stirred at −78° C. for 20 min., and was treated with a solution of methyl 4-(3-methylbenzyl)piperidine-4-carboxylate hydrochloride salt (276 mg, 0.97 mmol; Example 61, Step B) and diisopropylethylamine (186 μL, 1.07 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at −78° C. for one h., and at room temp. for two h. The resultant solution was concentrated under vacuum, and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was subjected to high pressure liquid column chromatography on C-18 reverse phase stationary phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[C:14]1([C:20]2[O:24][N:23]=[CH:22][C:21]=2[CH2:25][CH2:26][C:27](O)=[O:28])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][C:4]1[S:3][C:2]([NH:1][C:27](=[O:28])[CH2:26][CH2:25][C:21]2[CH:22]=[N:23][O:24][C:20]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1sc(N)nc1-c1ccccc1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(NC(=O)CCc2cnoc2-c2ccccc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
A mixture of 2-amino-5-methyl-4-phenylthiazole (0.95 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.01 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.78 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.97 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(5-methyl-4-phenyl-2-thiazolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.74 g, yield 96%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 150–151° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:15][CH2:16]C3C=CC=CC=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]1([C:7]2[C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH2:15][CH2:16][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1c(-c2ccccc2)noc1CCc1ccccc1
Product: O=C(O)c1c(-c2ccccc2)noc1CCCc1ccccc1
Yield: 72 %

Procedure:
The title compound was prepared as described for Compound 28A but substituting 2-phenylethylbromide for benzyl bromide. The crude was purified by flash chromatography (ethyl acetate-petroleum ether-acetic acid 1:1:0.01 mL) to afford the title compound (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:10](=[O:17])[N:11]([CH2:13][C:14](O)=[O:15])[CH:12]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:39](=[O:53])([O:41][CH2:42][CH:43]([NH2:52])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46](Cl)[C:45]=1Cl)[NH2:40].Cl>CN(C=O)C>[C:39](=[O:53])([O:41][CH2:42][CH:43]([NH:52][C:14](=[O:15])[CH2:13][N:11]1[CH:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([CH2:18][CH:19]([OH:24])[C:20]([F:23])([F:22])[F:21])[C:10]1=[O:17])[C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([C:20]([F:23])([F:22])[F:21])[CH:45]=1)[NH2:40]
Reactant: NC(=O)OCC(N)c1cccc(Cl)c1Cl
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NC(=O)OCC(NC(=O)Cn1cc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A quantity of 58 mg (0.11 mmol) of [4-(4-chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetic acid from Example 184A was dissolved in 2 ml of DMF, and the solution was admixed with 28 mg (0.15 mmol) of EDC and with 20 mg (0.15 mmol) of HOBt and subsequently stirred at room temperature for 20 minutes. Then 42 mg (0.12 mmol) of the compound from Example 183A were added and the mixture was left with stirring at room temperature for 16 h. For work-up, 100 μl of 1N hydrochloric acid were added and the crude product was purified directly by preparative HPLC [Method 19]. This gave 13 mg (18% of theory) of the target compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:30]1[S:34][C:33]([CH:35]=[O:36])=[N:32][CH:31]=1)[CH2:27][O:28][CH3:29].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:35]([C:33]3[S:34][C:30]([CH:26]([OH:25])[CH2:27][O:28][CH3:29])=[CH:31][N:32]=3)=[O:36])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: COCC(O)c1cnc(C=O)s1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(O)c1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1
Yield: 95 %

Procedure:
A mixture of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (1.00 g), 5-(1-hydroxy-2-methoxyethyl)-1,3-thiazole-2-carbaldehyde (0.56 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (77 mg), triethylamine (0.16 mL), tetrahydrofuran (6 mL) and ethanol (6 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, the residue was subjected to basic silica gel column chromatography, and eluted with ethyl acetate, and the fraction was concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.46 g, yield 95%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (9:1, volume ratio). MS: 536 (MH+).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][NH:17][CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.C1C2C(COC([N:58]=[C:59]=[S:60])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)(Cl)Cl>[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C@H:13]2[CH2:18][N:17]([C:59](=[S:60])[NH2:58])[CH2:16][CH2:15][N:14]2[S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[O:12])=[CH:32][CH:33]=1)([CH3:4])[CH3:3]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)c1ccc(CNC(=O)[C@H]2CNCCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(CNC(=O)[C@H]2CN(C(N)=S)CCN2S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of the compound (506 mg) obtained in Example 1 in chloroform (5 ml) was added, with stirring at room temperature, triethylamine (167 μl), and 9-fluorenylmethoxycarbonyl isothiocyanate (281 mg) was added. After stirring overnight at room temperature, piperidine (198 μl) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (3% methanol/chloroform) to give the title compound (442 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([OH:18])[C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[H-].[Na+].Cl[C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][CH3:31])[N:23]=1.Cl.[Cl-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])=[C:6]([O:18][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:30][CH3:31])[N:23]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1c(O)cccc1Cl
Reactant: COc1nc(Cl)nc(OC)n1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 18.7 %

Procedure:
A solution of 2.0 grams (0.008 mole) of phenylmethyl 6-chlorosalicylate (prepared in Steps A-D) in 25 grams of dimethylformamide was stirred, and 0.3 gram (0.008 mole) of 60% sodium hydride in mineral oil was added. The addition caused the reaction mixture temperature to rise to 32° C. The reaction mixture was allowed to cool to ambient temperature, at which 1.3 grams (0.008 mole) of 2-chloro-4,6-dimethoxy-1,3,5-triazine was added in one portion. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 4 hours. After this time an aliquot of the reaction mixture was subjected to thin layer chromatography, which indicated the reaction mixture had not gone to completion. The reaction mixture was warmed to 80°-85° C. where it was stirred for about 18 hours. After this time the reaction mixture was cooled to ambient temperature and then was poured into a mixture of 100 mL of aqueous 3N hydrochloric acid and 100 mL of an aqueous solution saturated with sodium chloride. The mixture was o extracted with two 300 mL portions of diethyl ether. The combined extracts were washed with one 250 mL portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a point where a solid residue appeared. The residue was slurried in 5 mL of diethyl ether and filtered to yield 0.6 gram of phenylmethyl 6-chloro-2-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate. The nmr spectrum was consistent with the proposed structure.