Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][N:17]=2)=[CH:9][CH:8]=1.[C:18]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:14][C:15]([C:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)([OH:20])[CH3:19])=[CH:16][N:17]=2)=[CH:11][CH:12]=1
Reactant: Fc1ccc(-c2ncco2)cc1
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80336.6 %

Procedure:
To a stirred solution of DIPA (0.13 mL, 0.00092 mmol) in THF (7 mL) at −78° C. was added n-BuLi (0.76 mL, 0.001226 mmol). The mixture was allowed to stir at 0° C. for 30 min, was again cooled to −78° C., and then a solution of 2-(4-fluorophenyl)oxazole (0.1 g, 0.000613 mmol) in THF (2 mL) was added dropwise during 30 min. 4-Acetyl pyridine (0.07 mL, 0.000674 mmol) in THF (2 mL) was then added, the reaction mixture was stirred for an additional 1 hour at −78° C., quenched with saturated ammonium chloride (2 mL), diluted with water (10 mL), and extracted with ethyl acetate (20 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel chromatography (200-400 mesh, 2% of methanol in dichloromethane) to give 1-(2-(4-fluorophenyl)oxazol-5-yl)-1-(pyridin-4-yl)ethanol (0.14 g, 82%) as white solid in 98.5% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, 2H), 7.95-7.91 (m, 2H), 7.45 (d, 2H), 7.32 (t, 2H), 7.14 (d, 1H), 6.38 (s, 1H), 1.81 (s, 3H); LC-MS m/z calculated for [M+H]+ 285.10. found 285.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][Si:12]([CH3:31])([CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[O:13][Si:14]([CH3:24])([CH3:23])[CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH:20]1[CH2:22][O:21]1>C(O)C>[OH:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:22][CH:20]([OH:21])[CH2:19][O:18][CH2:17][CH2:16][CH2:15][Si:14]([CH3:23])([CH3:24])[O:13][Si:12]([CH3:31])([CH3:11])[CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: NCCOCCOCCO
Reactant: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC(O)CNCCOCCOCCO
Temperature: 70 °C

Procedure:
2-(2-(2-Amino-ethoxy)-ethoxy)-ethanol (4.25 g) and ethanol (40 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,1,3,3-Tetramethyl-3-(3-oxiranylmethoxy-propyl)-1-(2-trimethylsilanyl-ethyl)-disiloxane (2.0 g) mixed with ethanol (10 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, ethanol was removed under vacuum, and the mixture was vacuum distilled to remove impurities and excess raw material.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[NH:5]1)[CH3:3].[Li]CCCC.CCCCCC.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>C1COCC1>[O:24]=[C:21]([N:5]1[C@@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:8][O:7][C:6]1=[O:9])[CH2:22][CH3:23]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: CCC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
To a cooled solution (-78° C.) of 1.5910 g (12.316 mmole of (+)-(4S)-3-(1-oxopropyl)-4-(1-methylethyl)-2-oxoazolidinone (A) in 20 ml of THF under N2 atmosphere is added 5.80 ml of 2.32M n-BuLi in hexane (13.55 mmole, 1.1 equiv.) to form the conjugate base. The milky slurry is stirred for 1 hour before 1.11 ml (1.1852 g, 12.81 mmoles, 1.04 equiv., mwt 92.53, bp 77°-9° C., d 1.065) of propionyl chloride is added in one portion. The slurry dissolves instantly to a clear orange solution. After stirring an additional 15 min. at -78° C., the reaction is quenched with 20 ml sat. NH4Cl, and the THF is removed in vacuo at RT (room temp). The resultant concentrate is taken up in ether and extracted successively with aq. NaHCO3, water, brine and dried over anh. Na2SO4. Evaporation of the solvent followed by flash chromatography affords 1.82 g (80%) of purified product B as a viscous yellow oil. Proton NMR (200 MHz) in CDCl3 shows: ##STR58## 4.41 (d of t, 1H, J=7.6 Hz, J=3.6 Hz, C3 -H); 4.22 (m, 2H, 2J=5.4 Hz, C4 -H); 2.92 (q of d, 2H, J=7.7 Hz, J=4.0 Hz, C9 -H); 2.35 (m, 1H, J=7.0 Hz, J=3.9 Hz, C2 -H); 1.14 (t, 3H, J=7.7 Hz, C10 -H); 0.89, 0.85 (d, 6H, J=7.0 Hz, C1 -H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH3:18])[N:11]=1)[C:7](=O)[CH3:8]>C(O)C>[CH3:8][C:7]1[N:1]=[C:2]([NH2:4])[S:3][C:6]=1[C:10]1[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH3:18])[N:11]=1
Reactant: NC(N)=S
Reactant: CSc1nc(C)cc(C(Br)C(C)=O)n1
Solvent: CCO
Product: CSc1nc(C)cc(-c2sc(N)nc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thiourea (2.7 g, 35 mmol) is added to a stirred solution of 1-bromo-1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (AC3) in ethanol (100 ml) at 60° C. After 30 minutes the reaction is allowed to cool to room temperature. After standing for 18 hours the hydrobromide salt of the titled compound is removed by filtration and washed with diethyl ether. The product is dissolved in water and 2M sodium hydroxide is added to precipitate the titled compound as the free base.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:26]2[CH2:30][S:29]C(=S)[S:27]2)[CH:17]=[C:18]([O:24][CH3:25])[C:19]=1[O:20][CH2:21][O:22][CH3:23]>C1COCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:26]([SH:27])[CH2:30][SH:29])[CH:17]=[C:18]([O:24][CH3:25])[C:19]=1[O:20][CH2:21][O:22][CH3:23]
Reactant: COCOc1c(OC)cc(C2CSC(=S)S2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1c(OC)cc(C(S)CS)cc1OC
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (0.622 g, 16.38 mmole) is added to 60 ml dry diethyl ether. To this slurry is added dropwise 4-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1,3-dithiolane-2-thione (33) (3.40 g, 10.24 mmole) predissolved in 35 ml dry THF. The reaction is stirred under an N2 atmosphere until the solution becomes colorless (4 hours). The reaction is cooled to 0° C. and the excess hydride destroyed with H2O. The reaction mixture is acidified with 10% HCl and immediately extracted with diethyl ether. The organic layer is washed with H2O, dried over MgSO4, filtered and evaporated to a white solid (2.47 g, 84%). NMR: (CDCl3) 2.33,d,1H;2.90,m,1H;3.10,m,1H; 3.59,s,3H;3.85,s,6H;4.03,m,1H;5.10,s,2H;6.53,s,2H Melting Point: 84°-85° C. C,H,S analysis: (theoretical, actual) C (49.63,49.52); H (6.25,6.28); S (22.08,22.16).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:42])[CH2:15][C@H:16]([C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:43]O.[OH-].[Li+].Cl>C1COCC1.O>[O:39]1[CH:40]=[CH:41][C:37]([C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][C:14]([OH:42])=[O:43])=[N:38]1
Reactant: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of the oxazolidinone 47.2 (58.0 mg, 0.1 mmol) dissolved in THF (5 mL), was added a 30% hydrogen peroxide solution (113 μL, 1 mmol) followed by a 2 M lithium hydroxide solution (250 μL, 0.5 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 47 (23.6 mg). MS ESI (pos.) m/e: 422.0 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.34 (1 H, s), 7.53 (2 H, d, J=8.6 Hz), 7.14 (2 H, d, J=8.6 Hz), 7.00 (2 H, d, J=8.6 Hz), 6.83 (2 H, d, J=8.6 Hz), 6.16 (1 H, d), 4.45 (1 H, t, J=7.8 Hz), 4.25-4.31 (2 H, m), 4.20-4.24 (2 H, m), 3.09 (1 H, dd, J=16.4, 8.2 Hz), 2.84 (1 H, dd, J=16.4, 7.4 Hz).
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH:3]=[CH2:4].[OH-].[Na+].[C:9]([C:14]1[C:15](=[O:30])[CH2:16][CH:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])[CH2:18][C:19]=1[OH:20])(=O)[CH2:10][CH2:11][CH3:12].C(O)C>O>[CH2:2]([O:5][N:6]=[C:9]([C:14]1[C:19](=[O:20])[CH2:18][CH:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])[CH2:16][C:15]=1[OH:30])[CH2:10][CH2:11][CH3:12])[CH:3]=[CH2:4]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Reactant: C=CCON
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCON=C(CCC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Yield: 76.3 %

Procedure:
Allyloxyamine hydrochloride (0.72 g) and then a solution of sodium hydroxide (0.25 g) in water (3 ml) were added to a stirred mixture of 2-butyryl-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.78 g; 5.9 mmole) and 95% ethanol. The progress of the reaction was monitored using thin layer chromatography on silica gel (eluant dichloromethane). On completion of the reaction the ethanol was removed by evaporation using a rotary evaporator and the residue was extracted with dichloromethane. The organic extract was washed with aqueous 5% hydrochloric acid and then with water and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure using a rotary evaporator to give the product, 2-[1-(allyloxyimino)butyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (1.6 g) as an oil.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[N:13]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4])=[CH2:2].[CH3:24][NH:25][CH3:26]>C(O)C.C(O)(=O)C>[CH3:24][N:25]([CH2:2][CH2:1][S:3]([C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH2:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[N:13]2)=[CH:10][CH:11]=1)(=[O:4])=[O:5])[CH3:26]
Reactant: C=CS(=O)(=O)c1ccc(N2CCC(c3ccc(Cl)cc3)=N2)cc1
Reactant: CNC
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCS(=O)(=O)c1ccc(N2CCC(c3ccc(Cl)cc3)=N2)cc1
Temperature: 25 °C

Procedure:
6.9 g of 1-(p-vinylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline are stirred in 5.5 g of a 33% solution of dimethylamine in ethanol and 15 ml of ethanol. The solution is heated gradually over one hour to 78° C. and stirring is continued until the starting material is dissolved and a concentrated sample is soluble in dilute acetic acid. The solution is allowed to cool to room temperature, whereupon a dense precipitate of the reaction product forms. This precipitate is collected by suction filtration, washed with ethanol and dried, affording 6.7 g of 1-(p-dimethylaminoethylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline (formula 103). 1-(p-Diethylaminoethylsulfonylphenyl)-3-(p-chlorophenyl)-2-pyrazoline (m.p. 104°-107° C.) is obtained in analogous manner using diethylamine in isopropanol instead of dimethylamine in ethanol.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:23][CH2:24][CH2:25]O)=[CH:20][C:19]=2[CH:27]=1.[C-:28]#[N:29].[Na+]>>[C:28]([CH2:25][CH2:24][CH2:23][C:21]1[O:22][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])=[CH:27][C:19]=2[CH:20]=1)#[N:29]
Reactant: [C-]#N
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2oc(CCCO)cc2c1
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2oc(CCCC#N)cc2c1
Yield: 80 %

Procedure:
In the same manner as in Example 13, 3-[5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]propanol was mesylated and then reacted with sodium cyanide to yield 2-(3-cyanopropyl)-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (yield 80%), which was then recrystallized from acetone-isopropyl ether to yield colorless prisms having a melting point of 114° to 115° C.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:42][C@@H:43](O)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C@@H:43]([CH3:42])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(-c2ccc(O)cc2)cc1)c1ccccc1
Reactant: CCCCCC[C@@H](C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC[C@H](C)Oc1ccc(-c2ccc(OC(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To an argon-flushed flask containing 2.32 g (8 mmol) of 4'-hydroxy-4-biphenylyl benzoate and 1.25 eq of triphenylphosphine in 200 ml of dry THF was added a solution of 1.052 g (8.08 mmol) of (R)-2-octanol dissolved in 15 ml of dry THF via syringe. Then 1.2 eq of diethyl azodicarboxylate in 30 ml of dry THF was added dropwise over 30 min. The reaction mixture was stirred at room temperature for 20 h and then 5 drops of water was added and stirring was continued for an additional 1 h. The solvent was evaporated and the crude product was triturated for 1 h in a mixture of hexanes/ethyl acetate [70/30]. The solution was filtered through a short silica gel pad and the solvent evaporated. Flash chromatography on silica gel using hexanes/ethyl acetate [98/2] as eluent afforded 2.42 g (75%) of (S) -4'-(1-methylheptyloxy)-4-biphenylyl benzoate (Compound 39, Scheme VIII, R2 =(S)--OCH(CH3)C6H13) as a white solid (top. 84° C.); Rf [hexanes/ethyl acetate 95/5]: 0.34; 1H NMR (300 MHz, CDCl3): δ 0.89(t, 3 H, J=6.8 Hz), 1.14-1.68(m, 9 H), 1.32(d, 3 H, J=6.1 Hz), 1.75(m, 1 H), 4.39(m, 1 H), 6.95(d, 2 H, J=9 Hz), 7.25(d,2 H, J=8.4 Hz), 7.46-7.68(m, 7 H), 8.22(dd, 2 H, J=1.2 Hz J=6.9 Hz); 13C NMR (300 MHz, CDCl3): δ 14.02, 19.73, 22.55, 25.50, 29.24, 31.75, 36.48, 73.96, 116.10, 121.88, 127.72, 128.58, 129.61, 130.21, 132.64, 133.59, 138.79, 149.87, 157.94, 165.30; IR (CHCl3): 3020, 2930, 2850, 1745, 1600, 1500, 1260, 1240, 1170, 1190, 1070, 1000, 840, 820 cm-1 ; Mass spectrum, m/z(rel.intensity): 402(M+ 16), 290(14), 105(100), 77(16), 43(6).
Reaction SMILES: [CH2:1]([C:8]#[N:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:10]([CH2:12]N)[OH:11]>O.O.C([O-])(=O)C.[Cd+2].C([O-])(=O)C>[CH2:1]([C:8]1[O:11][CH2:10][CH2:12][N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: NCCO
Reactant: CCCCCCCC#N
Agent: CC(=O)[O-]
Agent: [Cd+2]
Solvent: O
Product: CCCCCCCC1=NCCO1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A mixture of about 100.0 grams (0.774 mole) of heptylcyanide, about 47.3 grams (0.774 mole) ethanolamine, and about 4.8 grams (0.019 mole) cadmium acetate dihydrate is heated to about 120 degrees C. to about 130 degrees C. for about 2 days. The mixture is distilled under vacuum and the fraction boiling at about 109 degrees C. to about 116 degrees C. at about 28 mmHg is collected for later use.
Reaction SMILES: [I:1]I.[CH2:3]([N:10]1[CH2:18][C:17]2([C:19]([O:21][CH3:22])=[O:20])[CH:12]([C:13](=NN)[CH2:14][CH2:15][CH:16]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCCC1>[CH2:3]([N:10]1[CH2:18][C:17]2([C:19]([O:21][CH3:22])=[O:20])[CH:12]([C:13]([I:1])=[CH:14][CH2:15][CH:16]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Reactant: II
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1OC
Yield: 48.5 %

Procedure:
106.1 g (0.418 mol) of iodine in 1.1 dm3 of tetrahydrofuran were added dropwise to a solution of 85 g (0.209 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate in 2 dm3 of tetrahydrofuran. After addition of 2 dm3 of ethyl acetate, the organic phases were washed with two times 1 dm3 of a saturated aqueous sodium hydrogencarbonate solution, washed with two times 1 dm3 of a saturated aqueous sodium thiosulphate solution, then dried over magnesium sulphate and concentrated under reduced pressure. After purification by chromatography on silica gel (230-400 mesh), elution being carried out with a cyclohexane/ethyl acetate (95/05 by volume) mixture, 51 g (48%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-(2-methoxyphenyl)-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate were obtained in the form of a brown oil, the characteristics of which were as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[CH:25]=[N:24]2)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:27]2[CH2:28][CH2:29][CH2:30][C:31]3[N:23]([C:20]4[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=4)[N:24]=[CH:25][C:26]2=3)=[O:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Cc1ccc(Cl)c(C(F)(F)F)c1)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 41 %

Procedure:
The compound was prepared from 4-chloro-3-trifluoromethylphenylacetic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with brine and 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 54 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 8.44 (s, 0.8H), 7.59 (m, 1H), 7.57 (s, 0.2H), 7.41-7.51 (m, 4H), 7.17 (m, 2H), 4.03 (s, 0.3H), 3.95 (m, 0.3H), 3.91 (s, 1.7H), 3.78 (m, 1.7H), 2.82-2.85 (m, 2H), 2.05 (m, 2H); MS: (ES) m/z calculated for C21H17ClF4N3O [M+H]+ 438.1, found 438.1.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:8]([C:9](=[O:11])[CH:10]=1)[C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[N:5]2[CH3:16].[I:17]I>C(#N)C>[I:17][C:10]1[C:9](=[O:11])[N:8]2[C:4]([N:5]([CH3:16])[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=32)=[N:3][C:2]=1[CH3:1]
Reactant: II
Reactant: Cc1cc(=O)n2c3ccccc3n(C)c2n1
Solvent: CC#N
Product: Cc1nc2n(C)c3ccccc3n2c(=O)c1I

Procedure:
To a solution of Step 2 intermediate (1.2 g, 5.620 mmol) in acetonitrile (15 ml) was added ceric ammonium nitrate (1.53 g, 2.812 mmol) followed by iodine (0.857 g, 3.325 mmol) and refluxed for 2.0 h. After completion of the reaction, the solvent was evaporated and the residue dissolved in ethyl acetate. Combined organic layer was washed with water, saturated NaHSO3 solution, brine and dried and purified to afford the desired compound: 1H NMR (300 MHz, DMSO-d6) δ 2.61 (s, 3H), 3.75 (s, 3H), 7.39-7.42 (s, 1H), 7.52-7.58 (m, 1H), 7.68-7.70 (m, 1H), 8.38-8.41 (s, 1H); ESI-MS (m/z) 340.48 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH:15]=O)[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(OCC)=O)C.CN(C)C=O>O>[CH2:3]([N:10]1[CH:14]=[C:13](/[CH:15]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Sodium hydride (60%, oily, 1.94 g) was added to a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), ethyl diethylphosphonoacetate (9.60 ml), and N,N-dimethylformamide (200 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield ethyl(E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.50 g, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 88–89° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](SC)=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:16].O.[NH2:18][NH2:19]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:18][NH2:19])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:16]
Reactant: CSc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1ncc(-c2ccc(Br)c(F)c2)nn1
Temperature: 90 °C
Yield: 77.7 %

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-3-(methylthio)-1,2,4-triazine (1.15 g, 0.00383 mol) and hydrazine hydrate (0.74 mL, 0.015 mol) in ethanol (50 mL) was heated at 90° C. for 20 h. After cooling, the formed precipitate was collected by filtration, and dried in-vacuo to afford the desired product (0.845 g, 77.6%).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1)[CH:15]=[CH2:14]
Reactant: COc1cc2nc(C)oc2cc1Br
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=CCc1cc2oc(C)nc2cc1OC

Procedure:
400 mg of 6-bromo-5-methoxy-2-methylbenzoxazole was dissolved in 5 ml of toluene. Thereafter, 769 μl of allyl tributyl tin and 57 mg of tetrakis(triphenylphosphine)palladium were successively added to the reaction solution. Thereafter, the reaction solution was heated to reflux under nitrogen atmosphere. Approximately 14 hours later, the reaction solution was stood to cool and then filtered through celite, followed by concentration under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 202 mg of the subject compound.