Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:19]2[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]2)=[C:16]([F:18])[CH:17]=1)=O)C1C=CC=CC=1.C([Li])CCC.[CH2:30]([O:34][C:35](=[O:39])CCC)[C@@H:31]1[O:33]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.CN1CCCN(C)C1=O.C(OCC)(=O)C>[F:18][C:16]1[CH:17]=[C:12]([N:11]2[CH2:9][C@H:30]([CH2:31][OH:33])[O:34][C:35]2=[O:39])[CH:13]=[CH:14][C:15]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: Cc1cn(-c2ccc(NC(=O)OCc3ccccc3)cc2F)cn1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
5-Benzyloxycarbonylamino-2-(4-methylimidazol-1-yl)fluorobenzene (54 g, 0.166 M) was dissolved in a mixture of dry tetrahydrofuran (600 ml) and 1,3-dimethyl-tetrahydropyrimidin-2-one (100 ml) under nitrogen, cooled to −70°, and treated with a solution of n-butyllithium (1.6M in isohexane, 114 ml), over 30 minutes. After stirring for 30 minutes at −70°, a solution of (R)-glycidylbutyrate (26.35 g, 0.183 M) in dry tetrahydrofuran (50 ml) was added over 15 minutes. Stirring was continued for 16 hours allowing the temperature to rise to ambient. The mixture was treated with aqueous sodium bicarbonate (5%, 500 ml) and ethyl acetate (800 ml), and undissolved solid was removed and washed well with diethyl ether to give title product (16.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.I[C:12]1[C:13]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]2)=[N:14][C:15]([S:20][CH3:21])=[N:16][C:17]=1[O:18][CH3:19].C([O-])([O-])=O.[Cs+].[Cs+]>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.[Cu]I.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:12]3[C:13]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)=[N:14][C:15]([S:20][CH3:21])=[N:16][C:17]=3[O:18][CH3:19])=[N:7][C:6]=2[CH:10]=1
Reactant: Fc1ccc2scnc2c1
Reactant: COc1nc(SC)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1nc(SC)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (4.3 mL) was added to a 125 mL round-bottom flask containing 5-fluorobenzo[d]thiazole (268 mg, 1.749 mmol). Compound 23 (420 mg, 0.874 mmol), Pd(Ph3P)4 (202 mg, 0.175 mmol), Cs2CO3 (1709 mg, 5.25 mmol) and CuI (33.3 mg, 0.175 mmol) were then added. The mixture was degassed placed in an oil bath that was preheated to 100° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water and ethyl acetate and filtered through celite. The organics were then separated and the water layer was washed with ethyl acetate. The organics were combined, washed with brine (×3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a white solid. 1H NMR (CDCl3) δ 10.81-10.78 (m, 1H), 7.79-7.75 (m, 1H), 7.62-7.59 (m, 1H), 7.11-7.07 (m, 1H), 4.41-4.89 (m, 1H), 4.16-4.14 (m, 2H), 3.69-3.44 (m, 2H), 2.00-1.25 (m, 13H), LCMS 3.30 min, 506 (M+H)
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[SH:18].[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]=[C:34]=S)=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[S:18][C:34]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:28][CH:29]=3)=[N:9][C:10]=2[CH:15]=1
Reactant: COc1ccc(S)c(N)c1
Reactant: S=C=Nc1ccc(OCCN2CCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2sc(Nc3ccc(OCCN4CCCC4)cc3)nc2c1

Procedure:
Triethylamine (0.7 ml.) is added to a suspension of 2-amino-4-methoxybenzenethiol hydrochloride (0.96 g.) in toluene (20 ml.) under nitrogen. 4-(2-Pyrrolidin-1-ylethoxy)phenyl isothiocyanate (1.24 g.) is added and the mixture stirred and heated under reflux for 16 hours. Ethyl acetate and 10% sodium hydroxide are added and the organic layer separated, washed with water and dried. The organic layer is passed through a column of silica gel (2 × 20 cm.) and the filtrate rejected. The column is eluted with methanol, which, on concentration gives 5-methoxy-2-[4-(2-pyrrolidin-1-ylethoxy)anilino]benzothiazole, m.p. 167° - 168°C.
Reaction SMILES: [CH:1]1([CH:7]=[C:8]([CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO>[CH3:13][O:12][CH:11]([O:14][CH3:15])[CH:8]([C:9]#[N:10])[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(OC)C(C#N)=CC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(OC)C(C#N)CC1CCCCC1
Yield: 100 %

Procedure:
3-Cyclohexyl-2-dimethoxymethylacrylonitrile, obtained from Example 3 (8.3 g, 0.04 mol), methanol (100 mL) and 10% palladium on carbon (0.3 g) were shaken together in a Parr bottle under 50 psig hydrogen pressure for 30 minutes. The catalyst was removed by filtration and the methanol was evaporated in vacuo to give the product as a pale-yellow oil (8.3 g, 100%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16](I)=[CH:15][N:14]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[N:51][N:52]([CH2:54][C:55]3[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=3)[CH:53]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:58]1[CH:59]=[CH:60][C:55]([CH2:54][N:52]2[CH:53]=[C:49]([C:16]3[C:10]4[C:11](=[N:12][CH:13]=[C:8]([C:6]5[CH:7]=[CH:2][C:3]([CH:28]6[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]6)=[CH:4][CH:5]=5)[CH:9]=4)[N:14]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=4)(=[O:20])=[O:19])[CH:15]=3)[CH:50]=[N:51]2)=[CH:56][CH:57]=1
Reactant: CC1(C)OB(c2cnn(Cc3ccncc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccncc4)c3)c3cc(-c4ccc(C5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (Intermediate 67B) (150 mg, 0.52 mmol) was coupled with 4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine (intermediate 64G) (180 mg, 0.63 mmol) using sodium carbonate (165 mg, 1.56 mmol) and Pd(dppf)Cl2 (18 mg, 0.026 mmol) in toluene/ethanol/water (10/10/2 mL) to afford 142 mg (crude) of the titled compound. MS: m/z=589.4 (M-Boc+1).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5]C=C.C(OCC)=O.S(=O)(=O)(O)O.[CH3:18][CH:19]1[O:23][CH2:22][CH2:21][CH2:20]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:5]([CH:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[OH:23])[CH:4]=[CH2:3]
Reactant: C=CCCCBr
Reactant: CC1CCCO1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Solvent: CCOC=O
Product: C=CCC1CCCC1O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a reaction vessel was added magnesium turnings (2.45 equivalents) and MeTHF (8 volumes). The flask was then sparged with nitrogen and 5-bromo-1-pentene (2.4 equivalents) was added to the addition funnel. The mixture was heated to about 60° C. and 0.05 volumes of 5-bromo-1-pentene were dripped into the mixture to initiate the reaction. Once the reaction initiated, the remaining portion of 5-bromo-1-pentene was slowly added into the flask over about 3 hours. After the addition, the reaction was allowed to stir at about 60° C. for about 1 hour after which Grignard L was cooled to room temperature. In a separate flask was added ethyl formate (1.0 equivalent) and titanium isopropoxide (0.5 equivalents) in MeTHF (2 volumes) under nitrogen. The mixture was cooled to about 0° C. and slowly the Grignard L was added into the flask over 3 hours. Upon complete addition, the reaction mixture was allowed to warm to room temperature and the reaction was stirred for about 12 hours. The mixture was then cooled to about 0° C. and 4M sulfuric acid (10 volumes) was added slowly. The slurry was stirred for 30 minutes after which the salts were dissolved. The mixture was then polished filtered. The biphasic mixture was separated and the organic layer was then washed twice with 10 wt. % sodium bicarbonate (10 volumes) and once with water (10 volumes). The organic layer is concentrated under reduced pressure at about 0° C. to obtain crude 2-allylcyclopentanol M. 1H NMR (400 MHz, CDCl3): δ 5.53-5.43 (m, 1H), 4.76-4.70 (m, 1H), 4.65-4.59 (m, 1H), 2.90-2.86 (m, 1H), 1.75 (br s, 1H), 1.65-1.51 (m, 2H), 0.69-0.59 (m, 1H), 0.40-0.35 (m, 1H), 0.05-0.01 (m, 1H).
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:35])([CH3:34])[N:31]([OH:36])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=[C:19]([NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH:44]3[CH2:49][C:48]([CH3:51])([CH3:50])[N:47]([OH:52])[C:46]([CH3:54])([CH3:53])[CH2:45]3)[N:18]=2)[CH2:6][C:5]1([CH3:56])[CH3:55].S([O-])([O-])=O.[Na+].[Na+].[C:63]([OH:67])([CH3:66])([CH3:65])[CH3:64]>O.C(OCC)(=O)C>[OH:67][C:63]([CH3:66])([CH3:65])[CH2:64][O:52][N:47]1[C:46]([CH3:54])([CH3:53])[CH2:45][CH:44]([CH2:43][CH2:42][CH2:41][CH2:40][NH:39][C:19]2[N:18]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:7]3[CH2:6][C:5]([CH3:56])([CH3:55])[N:4]([O:3][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:9]([CH3:11])([CH3:10])[CH2:8]3)[N:22]=[C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:33][C:32]([CH3:34])([CH3:35])[N:31]([O:36][CH2:64][C:63]([CH3:66])([OH:67])[CH3:65])[C:30]([CH3:38])([CH3:37])[CH2:29]3)[N:20]=2)[CH2:49][C:48]1([CH3:51])[CH3:50]
Reactant: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(O)C(C)(C)C3)n2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)nc(NCCCCC3CC(C)(C)N(OCC(C)(C)O)C(C)(C)C3)n2)CC1(C)C
Temperature: 60 °C
Yield: 37.2 %

Procedure:
A solution of 40 g (0.35 mol) of 30% aqueous hydrogen peroxide is added over 1.25 hours to a mixture of 11.7 g (0.011 mol) of 2,4,6-tris[N-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl]butylamino}-s-triazine and 3.0 g (0.015 mol) of ferrous chloride tetrahydrate in 100 g of tert-butyl alcohol and 9 g of water. The reaction temperature is maintained at 60-65° C. during the peroxide addition. Two equal portions (2 g, 0.29 mol) of 50% aqueous hydrogen peroxide are added to the reaction mixture while the temperature is maintained at 60° C. for 9.5 hours. After the reaction mixture is diluted with ethyl acetate and cooled to room temperature, a solution of 100 g of 20% aqueous sodium sulfite is added. The reaction mixture is heated at 60° C. for one hour to decompose the excess peroxide. The aqueous layer is extracted with ethyl acetate, and the combined organic layers are concentrated. The crude product is purified by flash chromatography on silica gel with 2:1 (v/v) cyclohexane/ethyl acetate to afford a material which is triturated with 1:1 (v/v) cyclohexane/acetone to give 4.0 g of the title compound as a white solid, melting at 172-176° C.
Reaction SMILES: N([O-])=[O:2].[Na+].[CH:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20](N)[C:21]([OH:23])=[O:22])=[O:14])=[CH:7][CH:6]=1>O.OS(O)(=O)=O.C(#N)C>[CH2:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([OH:2])[C:21]([OH:23])=[O:22])=[O:14])[C:8]1[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: NC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(NCCCCC(O)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of NaNO2 in water (200 ml) was added dropwise during 3 hr to an ice-cooled and stirred solution of N-ε-CBZ-L-lysine in 1 N H2SO4 and acetonitrile. The mixture was stirred for an additional 2 hr after the addition of 0-5° C. and left to stand overnight. The resulting clear solution was concentrated under reduced pressure. The residual semi-solid was extracted with ether, and the ether extract was then crystallized in ether/petroleum ether. The products recovered was α-(N-CBZ-4-aminobutyl) glycolic acid.
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH2:28][OH:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH2:38][CH:39]=[CH2:40])[C:31](=O)OC(C)(C)C)[S:24]2)[C@H:20]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@@H:19]1[C@@H:27]([CH:28]=[O:29])[O:26][C@H:25]2[C@H:21]([N:22]=[C:23]([N:30]([CH3:31])[CH2:38][CH:39]=[CH2:40])[S:24]2)[C@H:20]1[O:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](CO)O[C@@H]2S1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(C)C1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Temperature: -30 °C
Reaction time: 3 h

Procedure:
A solution of DMSO (4.1 g, 52 mmol) in dry dichloromethane (70 mL) was treated with (COCl)2 (4.9 g, 40 mmol) at −78° C. for 30 minutes, followed by addition of 139 (3 g, 6.6 mmol) in dichloromethane (10 mL) slowly. The resulting solution was stirred for 3 hours at −30° C., then cooled down to −78° C. again and triethylamine (10 g, 90 mmol) was added. After additional 30 minutes at −50° C., the resulting mixture was quenched by water (50 mL), and the aqueous layer was extracted with dichloromethane (3×30 mL). The combined organic layer was dried over sodium sulfate, and concentrated to afford crude the title compound as light yellow syrup, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[C:6]([N:8]1[C@@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11][CH2:12][C@@H:13]1[CH3:14])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
To a stirred solution of 1-(tert-Butoxycarbonyl)-6-methyl-2-n-pentyl-1,2,3,4-tetrahydropyridine (1.0 g, 3.74 mmol) in 250 mL of CH2Cl2 was added sodium cyanoborohydride (1.41 g, 22.43 mmol). After being stirred 15 minutes at room temperature, the heterogeneous solution was cooled to −42° C. and TFA (2.9 mL, 37.4 mmol) was added slowly dropwise. After being stirred for 4 h at −42° C., the cold bath was removed, and the reaction mixture was immediately quenched with 200 mL of a saturated aqueous NaHCO3/THF mixture (50:50). The aqueous phase was extracted with CH2Cl2 (2×70 mL) and the combined organic extracts were washed with water and brine. The organic phase was dried with K2CO3, filtered through Celite, and evaporated to give crude product. Column chromatography using 5% EtOAc in hexanes gave 0.8 g (70%) of the product which was homogeneous by TLC analysis. 1H NMR (300 MHz) d 3.92-3.81 (m, 1H), 3.69-3.80 (m, 1H), 1.91-1.21 (m, 26H), 0.90-0.86 (t, 3H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][OH:5].O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([NH2:16])=[O:15]
Reactant: OC[C@H]1CO1
Reactant: NC(=O)Nc1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: NC(=O)Nc1ccccc1OC[C@H]1CO1
Temperature: 25 °C
Yield: 40.3 %

Procedure:
To a mixture of (2S)-oxiran-2-ylmethanol (296 mg, 4.0 mmol), N-(2-hydroxyphenyl)urea (609 mg, 4.0 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in THF (10 mL) was dropwise added DEAD (697 mg, 4.0 mmol) in THF (3 mL) at room temperature. After addition was completed the reaction mixture was stirred at room temperature over night. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum spirit) to give sub-title compound (336 mg).
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([C:12]([O:14]CC)=O)[CH2:6]1)=[O:4].Cl.[C:20]([NH2:26])(=[NH:25])[CH2:21][CH2:22][CH2:23][CH3:24].C[O-].[Na+]>C(O)C.CO.CC(C)=O>[CH2:21]([C:20]1[NH:26][C:12](=[O:14])[C:7]2[CH2:6][N:5]([C:3](=[O:4])[C:2]([OH:1])([CH3:17])[CH3:18])[CH2:10][CH2:9][C:8]=2[N:25]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C1CN(C(=O)C(C)(C)O)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: CC(C)=O
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(=O)C(C)(C)O)CC2
Yield: 81.4 %

Procedure:
A mixture of 0.7 g of ethyl 1-(2-hydroxy-2-methyl-1-oxopropyl)-4-oxo-3-piperidinecarboxylate and 0.4 g of valeramidine hydrochloride in 8 ml of anhydrous ethyl alcohol is treated with 2.8 ml of a 1M solution of sodium methoxide in methanol. The resulting mixture is stirred and heated at reflux for one hour. The reaction mixture is allowed to cool over 30 minutes then filtered. The filtrate is evaporated to a syrup which is stirred with 50 ml of ether overnight. The ether is decanted to afford a oily solid which is dissolved in acetone and applied to thick layer silica gel plates. The plates are eluted with ethyl acetate and the major zone washed stirred with water and the water decanted. The residue is dried and chromatographed on thick layer silica gel chromatography plates using ethyl acetate as the elution solvent. The major band at Rf=0.2 is isolated by washing with acetone to afford 0.65 g of the desired product as a colorless solid, m.p. 159°-161° C.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[C:16](I)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(NC1C=C(C2C3N(C4C=CC=CC=4)C=NC=3C=C(C#N)C=2)C=CC=1)(=O)C>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.C(O)C.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:17]=[C:16]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)Nc1cccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(C#N)cc3ncn(-c4ccccc4)c23)cc1
Yield: 28.9 %

Procedure:
This was prepared from 5-cyano-7-iodo-1-phenylbenzimidazole (173 mg, 0.5 mmol), toluene (3.0 ml), tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol), 4-methoxyphenylboronic acid (76 mg, 0.5 mmol), ethanol (3.0 ml) and potassium carbonate (138 mg, 1.0 mmol) In a similar manner to 7-(3-acetamidophenyl)-5-cyano-1-phenylbenzimidazole. Purification by a similar procedure afforded the title compound (47 mg, 29%) m/z, 326.5 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[HeH]O.C[O:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#N)=[CH:12][CH:11]=1.O>C1C=CC=CC=1.CCOCC>[O:9]1[CH:12]2[CH2:11][CH:10]1[CH2:17][C:16]1[C:13]2=[CH:14][CH:3]=[CH:2][CH:1]=1
Reactant: COc1ccc(C#N)cc1
Reactant: [Li]CCCC
Agent: [HeH]O
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: c1ccc2c(c1)CC1CC2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Butyl lithium (1.6M hexane solution: 36 ml) was added dropwise to a solution of helioalcohol (4.0 g) in benzene (100 ml) at room temperature. The mixture was stirred at room temperature for one hour, followed by addition of 4-methoxybenzonitrile (3.85 g) in benzene (20 ml). The mixture was stirred at room temperature overnight, followed by addition of water and extraction with ether. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in toluene (75 ml), followed by addition of dimethyl fumarate (7.58 g) and trichloroacetic acid (0.3 g). The mixture was refluxed for 3 hours and concentrated under reduced pressure. The reside was dissolved in ethyl acetate and washed with water, an aqueous saturated sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (silica gel: 50 g. eluent:ethyl acetate−hexane=1:2) to yield tetrahydro-2,4-epoxynaphthalene derivative (2.84 g) as a mixture of diastereoisomers. This was dissolved in a mixture of THF (5 ml) and methanol (5 ml), followed by addition of an aqueous NaOH (1.1 g) solution (5 ml). The mixture was stirred overnight and concentrated under reduced pressure. After being diluted with water, the mixture was washed with ethyl acetate. Conc. HCl was added to the aqueous layer until its pH becomes about 2.The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ether (50 ml), followed by addition of conc. HCl. The mixture was refluxed for 10 minutes and concentrated under reduced pressure, followed by addition of water. The resulting precipitate was collected by filtration and washed with methanol and ether to yield the title compound (2.64 g).