Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:20](=[O:23])[CH2:21][CH3:22])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O1CCOCC1.[Rh]>[CH:1]1([C:7]2([C:20](=[O:23])[CH2:21][CH3:22])[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Rh]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCC(=O)C1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
The following are introduced into a Parr bomb: 582 mg (1.83 mmol) of tert-butyl 4-phenyl-4-propionylpiperidine-1-carboxylate, 300 mg of rhodium on alumina and 0.5 mL of acetic acid in 15 mL of dioxane. The reaction mixture is placed under a hydrogen pressure of 6 bar and stirred at 80° C. for 16 hours. The reaction is stopped, filtered through Celite and washed with dichloromethane. The solvents are evaporated off and the residue is then chromatographed on silica gel (eluent: 95/5 heptane/ethyl acetate). 549 mg of tert-butyl 4-cyclohexyl-4-propionylpiperidine-1-carboxylate in the form of a colourless oil are obtained in a yield of 93%.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Cu][C:11]#[N:12].[C-]#N.[Na+].CN(C)C=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[N:4][C:3]=1[CH3:9]
Reactant: N#C[Cu]
Reactant: Cc1nc(Br)ccc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nc(C#N)ccc1Br
Temperature: 95 °C
Reaction time: 48 h
Yield: 66.4 %

Procedure:
A 1-L, three-neck, round-bottom flask equipped with a mechanical stirrer and a nitrogen inlet was charged with 3,6-dibromo-2-methylpyridine (150 g, 0.59 mol), copper (I) cyanide (42.8 g, 0.47 mol) and sodium cyanide (23 g, 0.47 mol). To the mixture was added N,N-dimethylformamide (300 mL). The mixture was heated to 95° C. and stirred for 48 h. The reaction mixture was cooled to ambient temperature and poured into ethanol (3 L) while stirring. The mixture was filtered through a pad of Celite, the filtrate was concentrated under reduced pressure and partitioned between water (3 L) and ethyl acetate (3 L). The organic layer was separated and washed with brine (2×600 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel plug purification (0-5% ethyl acetate in hexanes) to afford the product (61.5 g, 45% yield) as a white solid. In addition, 19.32 g (14%) of the mixture of the starting material and the product was isolated.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15]C)=[O:14])=[CH:9][C:8]=1[C:17]([O:19]C)=[O:18])(=O)C.[OH-].[Na+]>C1COCC1.O>[SH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:8]=1[C:17]([OH:19])=[O:18]
Reactant: COC(=O)c1ccc(CCSC(C)=O)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCS)c(C(=O)O)c1
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a degassed solution of dimethyl 4-[2-(acetylthio) ethyl]-1,3-benzenedicarboxylate (0.130 g, 0.44 mmol) in THF (5 mL) was added a degassed solution of 5 N NaOH (5 mL). The reaction mixture was stirred under nitrogen overnight. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAC (10 mL). The organic layer was dried over MgSO4 and concentrated to give 0.045 g of white solid (45% yield): 1H NMR (DMSO) δ 2.67 (t, 2H) 3.21 (t, 2H), 7.37 (d, 1H), 7.98 (d, 1H), 8.46 (s, 1H). 13C NMR (DMSO) δ 26.64, 40.60, 130.87, 132.05, 133.46, 133.81, 134.13, 148.53, 169.22, 170.20. Elemental analysis calculated for C10H10SO4: C, 53.09; H, 4.45; S, 14.47. Found: C, 53.37; H, 4.87; S, 12.84. MS(FAB): 225.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH3:12][CH2:13][O:14][C:15](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:14][C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[CH:23][CH:24]=1)[CH3:12]
Reactant: Cc1nc(C)c(CBr)nc1C
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)cc1
Temperature: 90 °C
Yield: 76.7 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (2.15 g, 0.01 mol), p-hydroxyl ethyl cinnamate (2.30 g, 0.012 mol), anhydrous potassium carbonate (2.76 g, 0.02 mol), and DMF (50 mL) into a 100 mL three-necked bottle in turn, heating to 90° C., stifling to react for 10 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.5), filtering to obtain filtrate, adding 40 mL water, extracting with chloroform (3×40 mL), incorporating the chloroform layer and wishing with water (2×30 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain 2.5 g white crystalloid of (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-phenyl)acrylic acid ethyl ester, a yield is 76.7%, m.p. 90-92° C.
Reaction SMILES: O1CCC[CH2:2]1.C[Mg]Br.[C:9]([CH:12]1[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10]>C(OCC)C>[CH3:10][C:9]([CH3:2])([CH:12]1[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH2:17]1)[OH:11]
Reactant: CC(=O)C1CCC=C(C)C1
Reactant: C1CCOC1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC1=CCCC(C(C)(C)O)C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To 90 ml of dry tetrahydrofuran maintained in an inert atmosphere at -60° C. was added 45.3 ml of a 3.0M solution of methylmagnesium bromide in diethyl ether followed by dropwise addition of 15.6 g of 5-acetyl-1-methylcyclohexene in a solution of 50 ml dry tetrahydrofuran. The reaction mixture was warmed to -20° C. and stirred for two hours. The resulting reaction mixture was poured into 150 ml of chilled, saturated ammonium chloride solution and extracted three times with 300 ml portions of diethyl ether. The combined extracts were washed successively with 300 ml of water and 300 ml of saturated sodium chloride, dried (MgSO4) and concentrated in vacuo to leave 17.1 g of a pale yellow oil. Distillation of the oil gave 10.7 g of the desired product as a colorless oil, b.p. 63°-65° C. (0.65 mm).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[CH:16]1([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1.[CH:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C(O)(=O)C>[CH2:31]([N:17]1[CH2:18][CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C1NCCc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1c2ccccc2CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.7 %

Procedure:
In an ice bath, sodium triacetoxyborohydride (6.11 g) was added to a solution of ethyl 1,2,3,4-tetrahydroisoquinoline-1-carboxylate hydrochloride (4.98 g) and benzaldehyde (2.72 g) in acetic acid (50 mL). The mixture was stirred at room temperature for 15 hours. A 1 M aqueous NaOH solution was added to the reaction liquid which was then extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain ethyl 2-benzyl-1,2,3,4-tetrahydroisoquinoline-1-carboxylate (1.99 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[O:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[F:26][C:24]([F:25])([F:27])[C:20]1[CH:21]=[C:22]2[N:23]=[C:15]([C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[OH:8])[O:16][C:17]2=[N:18][CH:19]=1
Reactant: FC(F)(F)c1cnc2oc(-c3ccncc3OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Yield: 77.7 %

Procedure:
A mixture of 1.7 g of 2-[3-(benzyloxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine, 40 ml of ethyl acetate and 10% palladium on carbon was reacted under the conditions of 40 bar and 40° C. for two hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.0 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol (hereinafter, referred to as “active compound 159”).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]([F:32])([F:31])[C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:30]=[CH:29][C:13]([O:14][CH:15]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:9]=1.Cl>O1CCCC1>[F:32][C:4]([F:3])([F:31])[C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH:15]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:29][CH:30]=2)[CH:9]=1
Reactant: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
Lithium hydroxide (1.0 mL, 1N in water, 1.0 mmol) was added to a room temperature solution of methyl 4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoate (95 mg, 0.23 mmol) in tetrahydrofuran (2 mL). The solution was stirred at ambient temperature for 18 hours, then at reflux for 2 hours. The mixture was cooled to room temperature and acidified to pH=2 with 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give (+/−)-4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoic acid (80 mg, 87%). 1H NMR (400 MHz, CDCl3, δ): 8.09-8.04 (m, 2H), 7.71 (s, 1H), 7.46-7.41 (m, 3H), 7.20-7.14 (m, 2H), 6.92-6.87 (m, 2H), 5.20-5.14 (m, 1H), 2.08-1.95 (m, 1H), 1.88-1.76 (m, 1H), 1.62-1.36 (m, 2H), 1.01-0.92 (m, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.O[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cccnc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (500 mg, 2.67 mmol) in anhydrous THF (13 mL) under nitrogen were added 3-hydroxypyridine (508 mg, 5.34 mmol) and triphenylphosphine (1.40 g, 5.34 mmol). The reaction mixture was cooled to 0° C. and DEAD (775 μL, 4.27 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 then concentrated. The residue was purified on column chromatography (eluent: pentane/acetone 9/1 to 7/3) to give the title compound (606 mg, 86%) as a wax.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:17])=[C:12](F)[C:13]=2[F:15])[C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6]1)[CH3:4].[NH2:24][CH:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>C(#N)C>[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:12]2[C:13]([F:15])=[C:14]3[C:9]([C:8](=[O:18])[C:7]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][N:5]3[CH:3]([CH3:4])[CH2:2][Cl:1])=[CH:10][C:11]=2[F:17])[CH2:26]1
Reactant: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(F)c(F)cc2c1=O
Reactant: NC1CCNC1
Solvent: CC#N
Product: CCOC(=O)c1cn(C(C)CCl)c2c(F)c(N3CCC(N)C3)c(F)cc2c1=O
Yield: 83.1 %

Procedure:
174 mg (0.5 mmol) of ethyl 1-(1-chloroprop-2-yl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was dissolved into 20 ml of acetonitrile. To this was added 215 mg (2.5 mmol) of 3-aminopyrrolidine and the mixture was reacted with heating under refluxing for 7 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1-20:1) to obtain 172 mg of light yellow crystals of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(1-chloroprop-2-yl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (Compound No. 1).
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].C(N)CCC.[C:15]([C@:17]1([O:35][Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[CH2:18][C:19]2([C:24]3[C:25](/[C:29]/1=[CH:30]\[C:31]([O:33][CH3:34])=[O:32])=[CH:26][O:27][N:28]=3)[O:23][CH2:22][CH2:21][O:20]2)#[CH:16]>C1C=CC=CC=1.[Cl-].[Na+].O.[Cu]I>[CH2:41]([Si:36]([CH2:37][CH3:38])([CH2:39][CH3:40])[O:35][C@@:17]1([C:15]#[C:16]/[CH:2]=[CH:3]\[C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7])[CH2:18][C:19]2([C:24]3[C:25](/[C:29]/1=[CH:30]\[C:31]([O:33][CH3:34])=[O:32])=[CH:26][O:27][N:28]=3)[O:23][CH2:22][CH2:21][O:20]2)[CH3:42]
Reactant: C[Si](C)(C)C#C/C=C\Cl
Reactant: C#C[C@]1(O[Si](CC)(CC)CC)CC2(OCCO2)c2nocc2/C1=C\C(=O)OC
Agent: [Cu]I
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCN
Solvent: c1ccccc1
Solvent: O
Product: CC[Si](CC)(CC)O[C@@]1(C#C/C=C\C#C[Si](C)(C)C)CC2(OCCO2)c2nocc2/C1=C\C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
(Z)-(4-chloro-3-buten-1-ynyl)trimethylsilane (1.41 mL, 8.16 mmol) and n-butylamine (0.81 mL, 8.16 mmol) were added to a solution of Pd(Ph3)4 (628 mg, 0.54 mmol) in benzene (25 mL). The solution was stirred at 25° C. for 15 minutes and then added to a mixture of Compound 61 (2.204 g, 5.44 mmol) and CuI (207 mg, 1.09 mmol) in benzene (25 mL) at zero degrees C. The solution was stirred two hours at zero degrees C, poured into brine (100 mL) and extracted with dichloromethane (3×100 mL). The organic extracts were dried (Na2SO4), concentrated and purified by flash chromatography (10 percent Et2O in petroleum ether) to give Compound 62 (2.606 g, 91 percent) as a colorless oil; Rf =0.46 (30% Et20 in petroleum ether); [a]D25 =+17.4° (c .2.7 , CH2Cl2); IR (thin film) νmax 1720 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 9.50 (s, 1 H, C=CH--O), 6.65 (s, 1 H, C=CH--CO2), 5.86 (ABq, J =11.0 Hz, Dn =30 Hz, 2 H, CH=CH), 4.38-4.29 (m, 2 H, ethylene ketal), 4.15-4.09 (m, 2 H, ethylene ketal), 3.74 (s, 3 H, CO2Me), 2.67 (ABq, J =14.1 Hz, Dn =61 Hz, 2 H, CH2), 0.89 (t, J =7.3 Hz, 9 H, Si(CH2CH3)3), 0.66 (m, 6 H, Si(CH2CH3)3), 0.17 (s, 9 H, SiMe3); 13C NMR (125 MHz, CDCl3) δ 166.6, 161.2, 161.0, 143.7, 121.2, 118.6, 114.9, 112.0, 103.5, 101.3, 100.7, 95.5, 85.7, 72.1, 65.0, 64.6, 51.5, 50.0, 6.8, 5.9, -0.4; FAB HRMS (NBA/CsI) m/e 660.1213, M+Cs+ calcd for C27H37NO6Si2 660.1214.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH3:25])[CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(O)C.Cl.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]([CH3:25])[CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(CCOc1ccccc1)c1cccc(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(CCOc1ccccc1)c1cccc(O)c1
Reaction time: 2 h

Procedure:
A solution of 3-(3-benzyloxyphenyl)-1-phenoxybutane (11.2 g., 33.5 mM) in a mixture of ethyl acetate (110 ml.), ethanol (110 ml.) and concentrated hydrochloric acid (0.7 ml.) is hydrogenated for 2 hours under 60 p.s.i. hydrogen in the presence of 10% palladium-on-carbon (1.5 g.). Removal of the catalyst by filtration and concentration of the filtrate gives an oil. The oil is purified by chromatography on silica gel (100 g.) and eluting with benzene-ethyl acetate consisting of 0-10% ethyl acetate. The middle fractions are combined and concentrated to give the title product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=O)[CH:11]([CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:21][OH:22].Cl.CCN(CC)CC.O>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)/[C:12](=[N:21]\[OH:22])/[CH:11]([CH3:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2C1=O
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC1C[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc2/C1=N\O
Reaction time: 1 h

Procedure:
To a solution of (4S)-4-(3,4-dichlorophenyl)-2-methyl-3,4-dihydronaphthalen-1(2H)-one (55) (1.2 g, 3.92 mmol) in CH2Cl2 (30 mL) and MeOH (20 mL) was added NH2OH.HCl (0.41 g, 5.92 mmol) and Et3N (1.19 g, 11.84 mmol). The reaction mixture was heated at reflux. After 1 h, H2O (10 mL0 was added and the resultant mixture was heated at reflux for 5 h before being concentrated. The residue was purified by silica gel column chromatography (ethyl acetatelhexane=1:7 to 1:5). Oxime 57, eluted from the column first (0.51 g, 41%) followed by the oxime 58 (0.49, 39%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1.[C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1)#[N:21].NC(N)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=2)=[O:30])[CH:5]=1
Reactant: COC(=O)c1cccc(CNCc2ccccc2)c1
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: NC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN(Cc2ccccc2)C(=O)Nc2ccc(C#N)cc2)c1
Yield: 34.4 %

Procedure:
Dissolved 3-(benzylamino-methyl)-benzoic acid methyl ester (197 mg, 0.77 mmol) in 5 mL of DMF. To this was added 4-cyanophenyl isocyanate (112 mg, 0.78 mmol). The mixture stirred for 48. LC-MS analysis indicated the desired urea. The mixture was diluted with 100 mL EtOAc, washed with 3×50 mL of H2O and 1×20 mL of brine. The organic phase was dried with MgSO4, filtered and concentrated. The resulting residue was applied to a SiO2 prep plate and eluted with 50% EtOAc/hexanes to give two fractions-one clear band and a tail. LC-MS analysis indicated both band and tail were composed of the product. Both fractions were combined to give 105.7 mg of 3-[1-benzyl-3-(4-cyano-phenyl)-ureidomethyl]-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH3:20][O:21][CH2:22][C:23]([NH:25][NH2:26])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][O:21][CH3:20])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: COCC(=O)NN
Solvent: CCCCO
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 8-chloro-1-(methoxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:23]=[CH:22][C:9]([O:10][CH2:11][C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2B(O)O)=[CH:8][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1.[CH3:38][O:39][C:40](=[O:46])/[C:41](/I)=[CH:42]\[O:43][CH3:44]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C.O>[CH3:38][O:39][C:40](=[O:46])/[C:41](/[C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[CH2:11][O:10][C:9]1[CH:22]=[CH:23][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=1)=[CH:42]/[O:43][CH3:44]
Reactant: CO/C=C(/I)C(=O)OC
Reactant: COCCOc1ccc(OCc2cc(Cl)ccc2B(O)O)cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CO/C=C(/C(=O)OC)c1ccc(Cl)cc1COc1ccc(OCCOC)cc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 71.3 %

Procedure:
1.1 g (3.3 mmol) of the compound obtained in Step 3, 0.17 g (0.15 mmol) of tetrakis(triphenylphosphine) palladium and 1.96 g (9.0 mmol) of K3PO4 were placed in a flask, and 5 ml of dioxane and 1 ml of water were added thereto. After adding 0.73 g (3.0 mmol) of (E)-methyl-2-iodo-3-methoxy-2-propenoate thereto, the resulting mixture was stirred at 90° C. for 22 hours. The mixture was cooled to room temperature, and 10 ml of ethyl acetate was added thereto. The water layer was separated and extracted twice with 10 ml of ethyl acetate, and the organic layers were combined, washed with 20 ml of water and then with 20 ml of a brine solution, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was subjected to column chromatography using 20% ethyl acetate/hexane as an eluent to obtain 0.87 g (yield 71%) of (E)-methyl-2-(2-((4-(2-methoxyethoxy)phenoxy)methyl)-4-chlorophenyl)-3-methoxyacrylate.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CCCCCC.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1.ICCCC>O.O1CCCC1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH:22]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:20])=[O:21])=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: [Li]CCCC
Solvent: O
Solvent: CCCCI
Solvent: CCCCCC
Product: CCCCC(c1ccncc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
At −78° C., butyl lithium (a 1.57M hexane solution; 0.29 ml, 0.448 mmol) was added dropwise to a tetrahydrofuran (5 ml) solution of 4-(4-chlorophenylsulfonylmethyl)pyridine (100 mg, 0.374 mmol). At −78° C., the resulting mixture was stirred for 10 minutes. Iodobutane (51 μl, 0.448 mmol) was then added thereto. The temperature of the reaction mixture was gradually elevated to room temperature, at which stirring was performed for 16 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column. The fraction obtained from the hexane:ethyl acetate (=2:1) eluate was concentrated under reduced pressure to give the title compound (76 mg, 63%) as a white solid. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1>C(OCC)(=O)C>[F:23][C:14]([F:13])([F:22])[C:15]1[CH:19]=[C:18]([CH:20]=[O:21])[O:17][N:16]=1
Reactant: OCc1cc(C(F)(F)F)no1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Product: O=Cc1cc(C(F)(F)F)no1
Temperature: 80 °C
Reaction time: 4 h
Yield: 113.6 %

Procedure:
2-Iodoxybenzoic acid (74) (804 mg, 2.87 mmol, Aldrich) was added to a solution of (3-(trifluoromethyl)isoxazol-5-yl)methanol (73) (300 mg, 1.44 mmol) in ethyl acetate (3 ml) at room temperature and stirred at 80° C. for 4 hours. After cooling to 0° C., insoluble materials were filtered off and the filtrate was concentrated in vacuo to give a crude product of 3-(trifluoromethyl)isoxazole-5-carbaldehyde (75) (270 mg, 57) as a pale-yellow solid.