Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][C@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:33][C:34]([NH2:36])=[O:35].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][C@H:18]([N:21]([CH2:33][C:34]([NH2:36])=[O:35])[CH3:22])[C@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@H]1CC[C@H](N[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](N[C@H]1CC[C@H](N(C)CC(N)=O)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 66.5 %

Procedure:
A solution of 40 mg of product from Step F, 25 mg of iodoacetamide and 0.10 mL of DIPEA in 0.5 ml of acetonitrile was stirred at room temperature for 16 h and then evaporated. The residue was purified on a 1 mm preparative silica gel plate eluted with 5% methanol in methylene chloride to give 30 mg of title compound as an oil. Mass specs (NH3 /CI): 506 (M+1).
Reaction SMILES: O1CCOC1C([O-])=O.[C:9]([OH:17])(=[O:16])[C@H:10]([CH2:12][C:13]([OH:15])=O)[OH:11].O1C[CH2:21][CH2:20][CH2:19]1>COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:15][CH2:13][CH2:12][C@@H:10]1[O:11][C:20]([CH3:21])([CH3:19])[O:17][C:9]1=[O:16]
Reactant: C1CCOC1
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])C1OCCO1
Solvent: COC(C)(C)OC
Product: CC1(C)OC(=O)[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
In a 500 mL flame-dried round bottom flask fitted with a septum and under argon was placed 11.0 g (63.2 mmol) of the dioxolanate of (S)-malic acid (prepared by reaction of commercially available (S)-malic acid with excess dimethoxypropane and p-toluenesulfonic acid as a catalyst) dissolved in 200 mL anhydrous tetrahydrofuran. The reaction was cooled (-20° C. to -30° C.) and 70 mL of 1 M borane-tetrahydrofuran complex was added dropwise over 2 h. Following addition the reaction vessel was placed in a refrigerator at 4° C. for 11 h, warmed to room temperature, stirred at room temperature for 9 h and chromatographed (silica gel) using acetone as eluant. Following evaporation under reduced pressure, the residue was chromatographed as before to generate 9.1 g (90%) of the alcohol as a colorless unstable liquid which was dried under reduced pressure and utilized as such in the next reaction: IR (neat, cm-1) 3480 (br), 2994, 2940, 2888, 1791, 1220; 1H NMR (CDCl3) δ 4.58 (dd, J=5.1, 7.0 Hz, 1H), 3.91-3.79 (m, 2H), 2.28-2.13 (m, 1H), 2.13-1.97 (m, 1H), 1.64 (s, 3H), 1.57 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.[C:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])[CH3:8]>>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([OH:9])[CH3:8]
Reactant: Cc1cscn1
Reactant: CC(=O)c1cccs1
Product: Cc1ncsc1C(C)(O)c1cccs1

Procedure:
Starting with 4-methylthiazole and 2-acetylthiophene and following the general method of Example 15 the title compound was prepared. M.p. 146.5°-147.5° C.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]3[N:11]=[C:12]([NH2:14])[CH:13]=[C:7]3[CH2:6]2)[CH2:2]1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[N:19]=[C:20]([Cl:22])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:22][C:20]1[CH:21]=[C:16]([NH:14][C:12]2[CH:13]=[C:7]3[CH2:6][N:5]([CH:3]4[CH2:4][O:1][CH2:2]4)[CH2:10][CH2:9][N:8]3[N:11]=2)[C:17](=[O:24])[N:18]([CH3:23])[N:19]=1
Reactant: Nc1cc2n(n1)CCN(C1COC1)C2
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2cc3n(n2)CCN(C2COC2)C3)c1=O
Temperature: 100 °C
Yield: 67.8 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (25 mL), 155b (640 mg, 3.3 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (1.1 g, 4.95 mmol), Pd2(dba)3 (302 mg, 0.33 mmol), XantPhos (381 mg, 0.66 mmol), and cesium carbonate (2.15 g, 6.6 mmol). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was washed with ethyl acetate to afford 155c (754 mg, 68%) as a yellow solid. MS-ESI: [M+H]+ 337.3
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[O]N(S(=O)([O-])=O)S(=O)([O-])=[O:22].[K+].[K+].C(OCC)C>CN(C)C=O.O>[CH3:8][C:7]1[C:2](=[O:1])[C:3]([CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH3:10])[C:5](=[O:22])[C:6]=1[CH3:9]
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: Cc1cc(C)c(C(O)CCCCCO)c(O)c1C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CC1=C(C)C(=O)C(C(O)CCCCCO)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(2'-hydroxy-3',4',6'-trimethylphenyl)-1,6-hexanediol (formula III-3 wherein R=H3C, X=H, Y=OH, n=4 in the free form) (0.32 part) in dimethyl formamide (20 volume parts) was added all at once a mixture of Fremy's salt (0.5 part) and potassium biphosphate(0.5 part) in water (50 volume parts). The mixture was stirred for 3 hours at room temperature. The reaction product was taken up with diethyl ether. The diethyl ether layer was washed with water and dried over anhydrous sodium sulfate. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with ethyl acetate-diethyl ether (4:1) to give 2,3,5-trimethyl-6-(1',6'-dihydroxyhexyl)-1,4-benzoquinone (formula IV-3 wherein R=H3C, n=4, in the free form) (0.26 part) as a yellow oil.
Reaction SMILES: C([Li])CCC.CCCCCC.[N:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19].C(NCC)C.[CH3:25][N:26]([CH:28]=O)[CH3:27].[Cl-].[NH4+]>O1CCCC1>[CH3:25][N:26]([CH3:28])[CH:27]=[CH:18][C:15]1[CH:16]=[CH:17][N:12]=[C:13]([CH3:19])[CH:14]=1
Reactant: CN(C)C=O
Reactant: Cc1ccnc(C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCNCC
Product: Cc1cc(C=CN(C)C)ccn1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
n-Butyl lithium in hexane (1.6 M, 35 ml, 56 mmol) was added dropwise to a solution of 2,4-lutidine (5.0 g, 46 mmol) in tetrahydrofuran (50 ml) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Successively, diethylamine (5.1 g, 69 mmol) was added to the mixture, and the mixture was stirred at −78° C., and the mixture was stirred at the same temperature for 30 minutes. Furthermore, DMF (6.8 g, 93 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was combined with aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (7.5 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH3:12].[Br:14]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:5]([CH3:12])=[CH:6][C:7]([Br:11])=[CH:8][C:9]=1[CH2:10][Br:14]
Reactant: COC(=O)c1c(C)cc(Br)cc1C
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(C)cc(Br)cc1CBr

Procedure:
A mixture of 4-bromo-2,6-dimethyl-benzoic acid methyl ester (3.4 g, 14.2 mmol), N-bromosuccinamide (2.5 g, 14.2 mmol), and benzoyl peroxide (0.060 g, 0.25 mmol) in carbon tetrachloride (50 mL) was heated at reflux until majority of ester was consumed (as analyzed by GC/MS). The resulting mixture was filtered and the filtrate concentrated to afford 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester. The product obtained was used without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:16]=[C:15]([C:17]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)=[O:18])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([C:12]2[CH:16]=[C:15]([C:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]3[N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:18])[O:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: O=C(C1=CCCCC1)c1cc(-c2ccccc2)no1
Product: O=C(c1cc(-c2ccccc2)no1)C1CCCCC1N1CCCC1

Procedure:
Pyrrolidine (5 ml) was added to 0.98 g (3.9 mmol) of 3-phenyl-5-(1-cyclohexenoyl)isoxazole prepared above in the procedure (1). The resultant mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. To the concentrate was added diethyl ether and then 10% hydrochloric acid, whereby the reaction product was extracted in a water layer. The water layer was collected, alkalinized with a 10% aqueous solution of sodium hydroxide, and then extracted with dichloromethane. The solvent was distilled off, so that 3-phenyl- 5-{2-(1-pyrrolidinyl)cyclohexanoyl}isoxazole was obtained as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:9](Cl)(=[O:12])[CH:10]=[CH2:11].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9](=[O:12])[CH:10]=[CH2:11])[CH2:4][CH2:3]1
Reactant: C=CC(=O)Cl
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N1CCCN(C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution is prepared of 20 g (175 mM) of N-methylhomopiperazine in 100 ml of dichloromethane, to which is added, dropwise, at 0° C., a solution of 15.85 g (175 mM) of acryloyl chloride in 20 ml of dichloromethane. The reaction mixture is agitated for 1 hour at 0° C., and then for 2 hours at ambient temperature, and then hydrolysed with a solution of 12 g of sodium carbonate in 20 ml of water. The mixture is decanted, the organic phase is washed once with water and then dried over magnesium sulphate and concentrated under reduced pressure. 23 g of the compound sought after are thus obtained, as an orangy oil, which is used, without other purification, in the next step.
Reaction SMILES: [CH:1]([CH:3]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:15])=[CH2:2].C(=C1/C(=O)CCCCCCCCCC/1)/C>>[CH:1](=[C:3]1/[C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/1)\[CH3:2]
Reactant: C=CC1CCCCCCCCCCC1=O
Agent: C/C=C1/CCCCCCCCCCC1=O
Product: C/C=C1\CCCCCCCCCCC1=O

Procedure:
On the other hand, 2-vinylcyclododecanone (2) which is the object product is one having the lowest boiling point among the components of the equilibrated mixture. Specifically, the average relative volatility of each of these components is as follows though it varies depending on temperature: when the boiling point is 110° C., the average relative volatility of each of 2-(Z)-ethylidenecyclododecanone (1-b) and 2-vinylcyclododecanone (2) is 1.15 and 1.44, respectively provided that the average relative volatility of 2-(E)-ethylidenecyclododecanone (1-a) is defined as 1.00.
Reaction SMILES: N1CCNCC1.[N:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Cl)=[CH:27][CH:26]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][N:10]2[CH2:11][CH2:12][N:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:8][CH2:9]2)=[CH:29][CH:30]=1
Reactant: ClCc1ccc(Oc2ccccn2)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: C1CNCCN1
Product: CCOC(=O)N1CCN(Cc2ccc(Oc3ccccn3)cc2)CC1

Procedure:
As depicted in Scheme 5, the known piperazine intermediate, for example, ethyl 1-piperazinecarboxylate (2000-2001 Aldrich Chemical catalog, pg 795), was reacted with the known methyl halide, for example 4-(2-pyridyloxy)phenylmethyl chloride (WO 97/26252) under basic conditions in an appropriate solvent, affording the corresponding ethyl ester, ethyl 4-[(4-(2-pyridyloxy)phenyl)methyl]piperazinecarboxylate (AA). Intermediate (AA) was then oxidized with, for example 30% hydrogen peroxide, providing the corresponding 4-oxide, ethyl 4-[(4-(2-pyridyloxy)phenyl)methyl]-4-oxypiperazinecarboxylate (BB), which in turn was decarboxylated with a strong aqueous base, providing the corresponding free piperazine 4-oxide, for example 2-[4-(4-oxypiperazin-1-ylmethyl)phenoxy]pyridine (CC).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](O)=[O:32])=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[OH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:10][CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(O)cc1)OCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To triphenylpropanol (3.98 mmol), 4-hydroxyphenylacetic acid (3.98 mmol), and triphenylphosphine (4.39 mmol) in dry THF (20 mL) at 0° C. under a nitrogen atmosphere, was added DEAD (4.39 mmol) in dry THF (20 mL) over 15 minutes. The reaction was stirred at room temperature for 16 h and then the THF was evaporated. The residue was chromatographed on silica gel using 15-30% EtOAc/hexanes. White solid, mp=136°-138° C. (ether), 34% yield. 1H NMR δ 7.15-7.27 (m, 15H), 7.10 (d, J=8.5 Hz, 2H), 6.77 (d, J=8.5 Hz, 2H), 4.90 (s, 1H), 3.90 (t, J=7.9 Hz, 2H), 3.47 (s, 2H), 2.93 (t, J=7.9 Hz, 2H). Anal. calcd. for C29H26O3 : C, 82.44; H, 6.20. Found: C, 82.29; H, 6.24.
Reaction SMILES: [CH3:1][C:2]#[C:3][CH3:4].[N+:5](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:6]>CCCCC>[CH3:1][C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]=1[CH3:4].[N+:5](=[CH:7][C:8]([O:10][CH2:3][CH3:4])=[O:9])=[N-:6]
Reactant: CC#CC
Agent: CCOC(=O)C=[N+]=[N-]
Solvent: CCCCC
Product: CCOC(=O)C1C(C)=C1C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 2-butyn (9.50 g, 176 mmol) was cooled to 0° C. and Rh2(OAc)4 (195 mg) was added. To the resulting suspension was added slowly over a period of 4.5 hours ethyl diazoacetate (8.02 g, 70 mmol). The mixture was stirred for 30 minutes and pentane (30 mL) was added. The solids were removed by filtration over Celite and the filtrate was concentrated in vacuo to afford ethyl 2,3-dimethylcycloprop-2-enecarboxylate (below) as a mixture with ethyl diazoacetate.
Reaction SMILES: [OH:1][C:2]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H].[ClH:19].OC(C1C=CN=CC=1)(C)CC1C=CC=CC=1.Cl>[Pd].O.C(O)(=O)C>[ClH:19].[OH:1][C:2]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)([CH3:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(O)(Cc1ccccc1)c1ccncc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(O)(Cc1ccccc1)C1CCNCC1

Procedure:
The mixture of 4.0 g of 4-(α-hydroxy-α-methylphenethyl)-pyridine, 100 ml of glacial acetic acid, 20 ml of water and 2.0 g of 10% palladium on charcoal is treated with hydrogen at 4.1 atm and room temperature. Following the theoretical uptake of hydrogen the reaction mixture is filtered to remove the catalyst. The filtrate is evaporated to dryness under reduced pressureand the residue treated with 50% aqueous sodium hydroxide. The resulting mixture is extracted with methylene chloride; the extract is dried and evaporated under reduced pressure to give an oil which is converted into the hydrochloride with ethanolic hydrogen chloride to give 4-(α-hydroxy-α-methylphenethyl)-piperidine hydrochloride of melting point 162°-164°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1.[CH2:17]([O:24][CH2:25][CH2:26][O:27][CH2:28]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[Cl:3][C:4]1[N:5]([CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]2[C:12]([Cl:13])=[C:11]([Cl:14])[C:10]([Cl:15])=[C:9]([Cl:16])[C:7]=2[N:8]=1
Reactant: ClCOCCOCc1ccccc1
Reactant: Clc1nc2c(Cl)c(Cl)c(Cl)c(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1c(Cl)c(Cl)c2c(nc(Cl)n2COCCOCc2ccccc2)c1Cl
Yield: 38.4 %

Procedure:
NaH (0.033 g, 1.52 mmole, 90% oil dispersion) was added to a stirred suspension of 2,4,5,6,7-pentachlorobenzimidazole (14) (0.3 g, 1.03 mmole) in dry CH3CN (35 mL) under a N2 atmosphere. The solution was stirred until H2 evolution had ceased and a clear solution was obtained (20 min.). (2-Benzyloxyethoxy)methylchloride (0.31 g, 1.54 mmole) in CH3CN (10 mL) was then added dropwise. The reaction mixture was stirred for an additional 15 hr. The resulting mixture was concentrated under reduced pressure, diluted with H2O (50 mL), extracted with EtOAc (100 mL), washed with H2O (100 mL), dried (anhyd. Na2SO4) and the solvent was removed under reduced pressure to yield an oil. The resulting oil was purified by flash column chromatography (2×24 cm) (230-400 mesh). Elution of the column with hexane:EtOAc (6:4, v/v) and evaporation of the appropriate fractions followed by crystallization from hexane:EtOAc afforded 0.18 g (38.4%) of blocked product: m.p. 95° C.; 1H NMR (CDCl3): d 7.22-7.34 (m, 5H, C6H5), 5.93 (s, 2H, C-1'), 4.47 (s, 2H, CH2C6H5), 3.70-3.73 (m, 2H, C-3'), 3.45-3.57 (m, 2H, C-4'), 1.83 (s, 3H, Ac). Anal. Calcd. for C17H13NCl5O2 : C, 44.88; H, 2.86; N, 6.16. Found: C, 44.95; H, 2.59; N, 6.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17])=O.[NH2:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:18][CH2:19][CH2:20][CH:21]([OH:23])[CH3:22])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[OH:17]
Reactant: O=C(c1cc(Cl)ccc1O)c1ccccc1Cl
Reactant: CC(O)CCN
Product: CC(O)CCN=C(c1cc(Cl)ccc1O)c1ccccc1Cl

Procedure:
The enantiomers of this compound were prepared in the same manner by a reaction between (2-chlorophenyl)-(5-chloro-2-hydroxyphenyl)-methanone and the enantiomers of 4-aminobutan-2-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 80 °C
Yield: 58.5 %

Procedure:
4-tert-Butoxycarbonylamino-phenylboronic acid (500 mg, 2.11 mmol), 1,4-dibromo-benzene (2.00 g, 8.44 mmol) Pd(PPh3)4 (122 mg, 0.106 mmol) and a 2 M aqueous solution of potassium carbonate (4.2 mL, 8.44 mmol) were degassed in 1,2-dimethoxyethane (20 mL) for 10 min. The stirred suspension was heated to 80° C. for 3 hours then diluted with ethyl acetate (60 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The residue was purified by silica column chromatography (0% to 20% EtOAc/hexanes) to provide (4′-Bromo-biphenyl-4-yl)-carbamic acid tert-butyl ester (430 mg, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11]C(N)=[CH:9][C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].CI.O.[CH3:23][N:24]([CH:26]=O)[CH3:25]>>[CH2:7]([NH:6][C:4](=[O:5])[C:3]1[CH:9]=[C:26]([N:24]([CH3:23])[CH3:25])[CH:11]=[CH:12][C:2]=1[Cl:1])[CH3:8]
Reactant: CCNC(=O)c1cc(N)ccc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CCNC(=O)c1cc(N(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of the above amine (3 g, 0.015 mol), potassium carbonate (3.8 g, 0.028 mol) and MeI (1.4 mL, 0.022 mol) in DMF stirred at RT overnight. The reaction mixture was poured into water and extracted with ether. The ether layer was washed with water and brine, dried (MgSO4) and concentrated to give an oil. Purification by flash chromatography (0-50% ethyl acetate/ hexanes) gave N-ethyl 2-chloro-5-(dimethylamino)benzamide as a yellow solid in 29% yield.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C.C1COCC1.[H][H]>[Pt].C(OCC)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Oc2ccc(O)cc2)cc1
Yield: 96.2 %

Procedure:
1-(4-Hydroxyphenoxy)-4-nitrobenzene X (8.93 g, 38.62 mmol), 0.5% platinum catalyst on activated charcoal (1.5 g), THF (100 mL), and ethyl acetate (20 mL) were charged into a 250 mL hydrogenation vessel. Hydrogenation was carried out under 60 psi of hydrogen at room temperature for 16 hr. The reaction mixture was filtered and the organic solvents were removed under reduced pressure at 40° C. to give 4-(4-aminophenoxy)phenol XI (8.10 g, 96.2% yield), mp 130°-4° C. The IR and 1H-NMR spectra agreed with the assigned structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:43])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1.Cl>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][O:43][S:52]([C:49]4[CH:50]=[CH:51][C:46]([CH3:45])=[CH:47][CH:48]=4)(=[O:54])=[O:53])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Agent: Cl
Solvent: c1ccncc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CCOS(=O)(=O)c3ccc(C)cc3)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-4-hydroxybutanoate (0.54 g), 4-methylbenzenesulfonyl chloride (0.70 g) and pyridine (6 mL) was stirred at room temperature for 75 min. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.45 g, 65%).