Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Br[CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([O:17]C)=[O:16].[OH-].[Na+].Cl>CO.O>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: COc1ccc(O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(OC(C(=O)O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: To the solution of 1,032 g of sodium methoxide in 12,000 ml of methanol 2,361 g of 4-methoxyphenol are added while stirring under nitrogen at 40°. After 30 minutes 4,100 g of methyl α-bromophenylacetate are added during 10 minutes and the mixture is refluxed for 5 hours. It is combined with 14,000 ml of 2 N aqueous sodium hydroxide and refluxing is continued for an additional hour. The mixture is stirred at room temperature overnight, diluted with 14,000 ml of water at 65° and 3,000 ml of concentrated hydrochloric acid are added during 1 hour. Stirring is continued for 2 hours at room temperature, the precipitate formed is filtered off and washed 3 times with 4,000 ml of water, to yield the α-(4-methoxyphenoxy)-phenylacetic acid melting at 108°-110°.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=1)[O:14][CH2:15][C@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35](=[O:39])[N:34]([CH2:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])[C:33]=1[CH3:51]>C(OCC)(=O)C>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][N:34]1[C:33]([CH3:51])=[C:32]([Cl:31])[N:37]=[C:36]([NH:8][CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][CH:30]=2)[O:14][CH2:15][C@H:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[C:35]1=[O:39])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Cc1c(Cl)nc(Cl)c(=O)n1CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc(CCN)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(Cl)nc(NCCc2cccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)c2)c(=O)n1CC(=O)OCc1ccccc1
Yield: 95.7 %

Procedure:
Triethylamine (0.51 ml, 3.67 mmol) was added to a solution of tert-butyl (2R)-2-{[3-(2-aminoethyl)phenoxy]methyl}-1-pyrrolidinecarboxylate (preparation 134) (588 mg, 1.84 mmol) and benzyl 2-[3,5-dichloro-2-methyl-6-oxo-1(6H)-pyrazinyl]acetate (preparation 17) (60 mg, 1.83 mmol) in ethyl acetate (10 ml), and the reaction heated under reflux for 6 hrs. The cooled mixture was partitioned between water and ethyl acetate, and the layers separated. The organic phase was washed with water, then brine, dried over MgSO4 and evaporated under reduced pressure to give the title compound, (1.07 g, 94%).
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]=1>C1CCCC1>[CH2:2]1[CH:1]2[CH:8]3[CH:7]=[CH:6][CH:10]([CH:5]2[CH:4]=[CH:3]1)[CH2:9]3
Reactant: C1=CCCC1
Reactant: C1=CCC=C1
Solvent: C1CCCC1
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
In a process for the production of cyclopentene from dicyclopentadiene which comprises splitting dicyclopentadiene under heat to form cyclopentadiene; partially hydrogenating the cyclopentadiene to form a crude cyclopentene containing an impurities fraction boiling at a higher boiling point than cyclopentene and containing cyclopentane; purifying the crude cyclopentene by distillation in which said impurities fraction is separated from the crude cyclopentene; the improvement which comprises recycling at least part of the separated impurities fraction as the impurities fraction is produced in said distillation to the dicyclopentadiene splitting stage, said separated impurities fraction comprising predominantly cyclopentane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[C:21]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:23])[CH3:22].Br[CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=2)[N:32]=1>O1CCCC1.CCOCC>[CH3:26][C:25]([O:24][C:21](=[O:23])[CH2:22][CH2:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:41][CH3:42])[CH:37]=2)[N:32]=1)([CH3:28])[CH3:27]
Reactant: COc1ccc2nc(CBr)ccc2c1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc2nc(CCC(=O)OC(C)(C)C)ccc2c1
Temperature: 10 °C
Reaction time: 0.2 h
Yield: 33.8 %

Procedure:
To a solution of diisopropylamine (7.4 mL, 52.8 mmol) in 70 mL of tetrahydrofuran cooled to -78° C. was added a solution of 1.6M n-butyllithium in hexanes (31.4 mL, 50.2 mmol). After being stirred for 12 minutes, the resulting solution of lithium diisopropylamide was treated with a solution of t-butyl acetate (4.81 g, 41.4 mmol) in 70 mL of tetrahydrofuran, added slowly through an additional funnel. The reaction mixture was allowed to warm gradually to 10° C. over 3.75 hr, and then recooled to -78° C. whereupon a solution of 2-(bromomethyl)-6-methoxyquinoline from the preceding example (3.46 g, 13.7 mmol) in 40 mL of tetrahydrofuran was added and the reaction was allowed to stir overnight at room temperature. The resuting solution was worked-up with ether in the usual manner. Flash chromatography of the crude product on 360 g of silica gel, eluting with hexane-ethyl acetate (4:1) afforded 1.31 g (33.8 %) of the title compound as an orange oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH:4]([CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:29]#[N:30])[C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])[CH2:5][CH3:6]>CO.[OH-].[Na+]>[C:29]([C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:15]=2)[C:20]([OH:21])=[C:11]([C:9]([NH:8][CH2:7][CH:4]([CH2:5][CH3:6])[C:3]([OH:31])=[O:2])=[O:10])[N:12]=1)#[N:30]
Reactant: CCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-{[(1-Cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-methyl}-butyric acid methyl ester (55 mg, 0.13 mmol) was dissolved in MeOH (3 mL) and 2 N NaOH (3 mL). After stirring for 16 hours at room temperature, the solvent was partially removed (until 3-4 mL left). H2O (15 mL) and 1 N hydrochloric acid were added until pH was 1. The resulting suspension was filtered. The solid was washed with H2O and dried to give the title compound in 35 mg. MS: (−) m/z 404.32 (M−1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([OH:24])=O)=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=2)[C:35]([O:37]C)=[O:36])[CH2:28][CH2:27]1.ON1C2C=CC=CC=2N=N1.N=C=N.C(=O)([O-])[O-].[N-]=C=O>CN(C=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[C:3]([C:22]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=3)[C:35]([OH:37])=[O:36])[CH2:28][CH2:27]2)=[O:24])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)O
Reactant: COC(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Agent: N=C=N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCC(c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
To a mixture of 8.2 mg of 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid, 7.7 mg of methyl 3-piperidin-4-yl-benzoate monohydrochloride, 3.4 mg of 1-hydroxybenzotriazole, 7.0 μL of triethylamine, and 1.0 mL of DMF was added 100 mg of PS-Carbodiimide (Biotage), followed by stirring at room temperature overnight. To the reaction mixture were added 75 mg of MP-Carbonate (Biotage), 50 mg of PS-Isocyanate (Biotage), and 0.5 mL of DMF at room temperature, followed by stirring for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. To the obtained residue were added 0.5 mL of methanol, 0.5 mL of tetrahydrofuran, and 0.5 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. To the reaction mixture was added 0.5 mL of 1 M hydrochloric acid and the solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 5.8 mg of 3-(1-{[7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-8-yl]carbonyl}piperidin-4-yl)benzoic acid.
Reaction SMILES: [OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([O:24]C)=[O:23].[OH-].[Na+].CCCCC>O1CCOCC1.C(OC(C)C)(C)C>[OH:1][CH:2]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=2)[N:29]=[CH:28][CH:27]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]#[C:13][C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])[CH2:7][C@@H:6]1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)[C@H]1CN(CC#Cc2c(F)cccc2F)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCCCC
Solvent: CC(C)OC(C)C
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CC#Cc4c(F)cccc4F)C[C@@H]3C(=O)O)c2c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 56.7 %

Procedure:
A solution of 0.531 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,6-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylate in 5.3 cm3 of dioxane to which had been added 0.84 cm3 of 5N aqueous sodium hydroxide solution was stirred for 15 hours at a temperature in the region of 60° C. After cooling to a temperature in the region of 20° C., the reaction mixture was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 50 kPa on a column of silica gel (particle size 20-45 μm; diameter 3 cm; 20 g), elution was carried out with a dichloromethane/methanol (90/10 by volume) mixture, and first a fraction of 100 cm3 was collected, followed by 25-cm3 fractions. Fractions 1 to 12 were combined and then concentrated as above. A foam was obtained, which product was taken up with stirring in 15 cm3 of diisopropyl ether for 15 minutes. After adding 15 cm3 of pentane and stirring for an additional 10 minutes, the crystallized product formed was filtered off, washed with 2 times 10 cm3 of a diisopropyl ether/pentane (50/50 by volume) mixture, and then 3 times 20 cm3 of pentane, and dried in the air. 0.293 g of (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[3-(2,6-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid was obtained in the form of a solid with a cream color melting at 107° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:25][O:26][C:27]1[CH:49]=[CH:48][C:30]([CH2:31][O:32][C:33]2[CH:34]=[N:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][O:32][C:33]2[CH:38]=[C:37]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:36]=[N:35][CH:34]=2)=[CH:48][CH:49]=1
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ccc(COc2cncc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Product: COc1ccc(COc2cncc(-c3nc(N4CCOCC4)c4sc(CN5CCN(C)CC5)cc4n3)c2)cc1

Procedure:
2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 3-(4-methoxy-benzyloxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine in General Procedure A. Purification on silica yielded 2-[5-(4-methoxy-benzyloxy)-pyridin-3-yl]-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. This was then reacted with trifluoroacetic acid in dichloromethane to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]1>C(OCC)(=O)C.CO.C(=O)([O-])O.[Na+]>[NH2:9][C:7]1[CH:6]=[CH:5][C:4]([N:12]2[CH:16]=[C:15]([CH2:17][OH:18])[N:14]=[CH:13]2)=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cnc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N)ccc1-n1cnc(CO)c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
[1-(2-Methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]methanol (500 mg, 2.0 mmol) and stannous chloride dehydrate (2.35 g, 10.4 mmol) were suspended in a mixture of 40 ml of ethyl acetate and 20 ml of methanol. The reaction mixture was refluxed for 1 hour, cooled to room temperature and diluted with acquous sodium hydrogencarbonate solution. Extraction with ethyl acetate gives the title compound (311 mg, 71%) as a yellowish viscous oil.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[O:45]([CH2:52][CH2:53][CH2:54]Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.O>[OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:54][CH2:53][CH2:52][O:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=1
Reactant: BrCCCOc1ccccc1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(OCCCOc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (400 mg, 0.755 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (313 mg, 2.27 mmol) and 3-phenoxy-1-bromopropane (487 mg, 2.27 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (245 mg, 50%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH2:34][OH:35])[CH2:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18].CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]([CH2:33][CH:34]=[O:35])[CH2:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: O=C(CC(CCO)c1ccc(Cl)c(Cl)c1)N1CCc2ccccc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CCC(CC(=O)N1CCc2ccccc2C1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
A solution of oxalyl chloride (0.460 mL) in CH2Cl2 (20 mL) was cooled to -78° C. whereupon DMSO (0.749 mL) was added dropwise over 15 mins. This mixture was stirred for 15 minutes. Whereupon a CH2Cl2 (10 mL) solution of 2-[3-(3,4-dichlorophenyl)-5-hydroxy-1-oxopentyl]-1,2,3,4-tetrahydroisoquinoline (1.0 g) was added over 20 minutes. The mixture was stirred for 30 minutes and then treated with Et3N (3 mL) and stirred for an additional 30 minutes at -78° C., followed by 1.5 hours at room temperature. The reaction mixture was quenched with water and diluted with CH2Cl2 (100 mL). The organic fraction was separated, washed sequentially with 1N HCl (1×50 mL), sat. NaHCO3 (1×50 mL) and brine (1×50 mL), dried over MgSO4, filtered and concentrated under reduced pressure to yield an oil. Silica gel chromatography eluting with 5-15% EtOAc/Hex gave the title compound (800 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1c[n+]([O-])ccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a mixture of 0.20 g of 2-(3-methylpyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 4 ml of chloroform, 0.30 g of 65% m-chloroperbenzoic acid was added while ice-cooling. The reaction mixture was stirred at room temperature for three hours, then diluted with ethyl acetate, and washed with 5% aqueous solution of sodium hydroxide and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.17 g of 3-methyl-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 24”).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].CO[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=2)=[CH:17][C:16]=1[CH:30]1[C:43]2[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=2[O:37][C:36]2[CH2:35][C:34]([CH3:48])([CH3:47])[CH2:33][C:32](=[O:49])[C:31]1=2.[BH4-].[Na+].[Cl-].[NH4+]>C1COCC1.O>[OH:28][CH2:27][C:25]1[N:26]=[C:21]([C:18]2[C:17]([O:2][CH3:1])=[C:16]([CH:30]3[C:43]4[C:42](=[O:44])[CH2:41][C:40]([CH3:46])([CH3:45])[CH2:39][C:38]=4[O:37][C:36]4[CH2:35][C:34]([CH3:47])([CH3:48])[CH2:33][C:32](=[O:49])[C:31]3=4)[CH:15]=[CH:20][CH:19]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2cccc(C(=O)O)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(-c2cccc(CO)n2)cccc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
1,1′-Carbonyldiimidazole (38.8 mg, 0.239 mol) was added to a solution of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylic acid obtained in Example 1-2 (100 mg, 0.199 mmol) in THF (1.0 mL) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 30 minutes. Subsequently, the reaction solution was cooled to 0° C., sodium borohydride (7.5 mg, 0.199 mmol) and water (0.1 mL) were then added thereto, and the mixture thus obtained was then stirred at the same temperature as above for 30 minutes. Thereafter, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate twice. The organic layer thus obtained was washed with brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to 3:7, v/v), and was then solidified with a mixed solution of diethyl ether-hexane to obtain the title compound (76.3 mg, yield: 78%).
Reaction SMILES: N[C:2]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:11]#[N:12].C(I)[I:14].C(ON=O)CC(C)C>C(Cl)(Cl)Cl>[I:14][C:2]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH:5]=[N:4][C:3]=1[C:11]#[N:12]
Reactant: ICI
Reactant: CC(C)Cn1cnc(C#N)c1N
Agent: CC(C)CCON=O
Solvent: ClC(Cl)Cl
Product: CC(C)Cn1cnc(C#N)c1I
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 5-amino-1-isobutyl-1H-imidazole-4-carbonitrile S10 (410 mg, 2.5 mmol, 1 equiv) and CH2I2 (2 mL) in CHCl3 (25 mL) at 80° C. was added a solution of isoamylnitrite (1.36 mL, 10.2 mmol, 4.0 equiv) in CHCl3 (5.0 mL) over 20 min. The reaction was heated for additional 30 min, then cooled to 25° C. and concentrated in vacuo. Purification by silica gel column chromatography (1/9 EtOAc/hexanes-7/3 EtOAc/hexanes, gradient) afforded the title compound (536 mg, 78%) as an orange solid: 1H NMR (CDCl3, 600 Hz) δ 0.92 (d, J=7.2 Hz, 6H), 2.12 (non, J=10.2 Hz, 1H), 3.76 (d, J=7.8 Hz, 2H), 7.62 (s, 1H); 13C NMR (CDCl3, 150 Hz) δ 19.6, 29.5, 56.1, 82.7, 114.6, 122.5, 141.3; LRMS (APCI+): calcd C8H111N3 [M+H]+ 276.1. found 276.0.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=O)(=O)C.[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[OH:4])=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NC(=O)c2ccccc2O)cc1

Procedure:
This compound was obtained as a white solid starting from acetylsalicyclic acid and 4isopropylaniline using the same procedure described in example 5.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:14]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[N:12][CH:11]=1)(C(C)(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:8][CH2:9][C:10]1[N:14]([CH:15]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[N:12][CH:11]=1
Reactant: COC(=O)CC(c1ccc(C#N)cc1)n1cncc1CO[Si](C)(C)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)CC(c1ccc(C#N)cc1)n1cncc1CO

Procedure:
The title A compound, methyl 3-[5-(t-butyl-dimethylsilanyloxymethyl)-imidazole-1-yl]-3-(4-cyanophenyl)-propionate (0.98 g, 2.46 mmol) and p-toluenesulfonic acid (0.55 g, 2.9 mmol) are stirred in MeOH (10 mL) at RT for 24 h. The reaction mixture is evaporated to an oil and partitioned between EtOAc and aqueous saturated sodium bicarbonate. The combined organic phases are dried over anhydrous sodium sulfate and removal of the solvent in vacuo yields methyl 3-[5-(hydroxymethyl)-imidazol-1-yl]-3-(4-cyano-phenyl)-propionate as an oil: 1H-NMR (CDCl3) δ 7.65 (2H, d, J=8.4), 7.62 (1H, s), 7.31 (2H, d, J=8.4), 6.98 (1H, s), 6.05 (1H, dd, J=9.2, 6.2), 4.62 (1H, d, J=13.5), 4.47 (1H, d, J=13.5), 3.67 (3H, s), 3.36 (1H, dd, J=16.5, 9.2), 3.21 (1H, dd, J=16.5, 6.2); e/z (ES) 286 (M+1, 100%).
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: NC(CC(=O)O)c1ccc(OCc2ccccc2)cc1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)CC(N)c1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(4-benzyloxy phenyl)propionic acid.