Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:12][CH:13]=C)[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I([O-])(=O)(=O)=[O:22].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8](=[O:11])[CH2:9][CH3:10])[CH2:12][CH:13]=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCC(C(=O)CC)(c1ccccc1)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(=O)C(CC=O)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 17.2 %

Procedure:
4,4-diphenyl-6-hepten-3-one (144 mg) was dissolved in a mixture of dioxane and water (3:1, 11 ml). A 10% aqueous osmium tetroxide solution (0.5 ml) was added. The resultant solution was stirred at room temperature for 5 min. A solution of sodium periodate (550 mg) in water was then added dropwise. The reaction mixture was allowed to stir for 16 hours. Water was added, and the aqueous mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water (once) and dried (MgSO4). Rotary evaporation of the solution gave a crude product which was purified by preparative thin layer chromatography (PTLC) on silica gel. Development with hexane/ethyl acetate (2:1) produced three bands. The lowest band (Rf 0.66) was scraped off the plate and eluted with methanol to yield 25 mg of 3,3-diphenyl-4-oxo-hexanal.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][C@@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[C:50]2[CH3:54])=[C:35]3[C:39]([O:41]C(C)(C)C)=[O:40])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)=O>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:55][O:56][CH3:57])[C:27]([NH:29][C@@H:30]2[C:37](=[O:38])[N:36]3[C@@H:31]2[CH2:32][S:33][C:34](/[CH:46]=[CH:47]/[CH2:48][N:49]2[CH:53]=[CH:52][N:51]=[C:50]2[CH3:54])=[C:35]3[C:39]([OH:41])=[O:40])=[O:28])[N:25]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(C)(C)C)=C(/C=C/Cn3ccnc3C)SC[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C/Cn3ccnc3C)SC[C@H]12)c1csc(N)n1

Procedure:
80.5 mg of the product of Step A and 1 ml of 66% formic acid were heated for 3 hours at 60°-65° C. and then was evaporated to dryness under reduced pressure. The residue was taken up twice consecutively with 5 ml of water, then evaporated to dryness. The residue was taken up in 7 ml of ether, stirred for half-an-hour, then separated to obtain 41.5 mg of syn isomer of (6S,7S) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[3-(2-methyl-1H-imidazol-1-yl)1-(E)-propenyl]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([C:18]3[CH:40]=[CH:39][C:21]([N:22]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[CH:20][CH:19]=3)=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:11]=2)=[C:4]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:3]=1.C1(C)C=CC=CC=1.[CH2:54]([PH:58](=[O:62])[O:59]CC)[CH2:55][CH2:56][CH3:57].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:22]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:21]2[CH:39]=[CH:40][C:18]([C:9]3[S:8][C:7]([C:5]4[S:6][C:2]([P:58]([CH2:54][CH2:55][CH2:56][CH3:57])(=[O:59])[OH:62])=[CH:3][C:4]=4[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[CH:11][C:10]=3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: CCCC[PH](=O)OCC
Reactant: CCCCCCc1cc(-c2sc(Br)cc2CCCCCC)sc1-c1ccc(N(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCc1cc(-c2sc(P(=O)(O)CCCC)cc2CCCCCC)sc1-c1ccc(N(c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Temperature: 110 °C

Procedure:
The 5′-(4-(bis(4-methoxyphenyl)amino)phenyl)-3,4′-dihexyl-2,2′-bithiophen-5-yl(butyl)phosphinic acid was prepared applying a modified procedure of Y. Xu et al., Synthesis, 1984, 778. 4-(5′-Bromo-3′,4-dihexyl-2,2′-bithiophen-5-yl)-N,N-bis(4-methoxyphenyl)aniline (216 mg, 0.8 mmol) was placed in a Schlenck tube, and toluene (0.2 ml), ethyl butylphosphinate (152 mg, 0.88 mmol), triethylamine (0.36 ml, 2.6 mmol), and tetrakis[triphenylphosphine]palladium (46.2 mg, 0.04 mmol) was added under a stream of argon, stoppered, and heated in an oil bath at 110° C. for 10 h. After the mixture has been cooled, ethyl acetate (5 ml) is added and the solid is removed by filtration. The filtrate is concentrated on a rotatory evaporator and the residue is purified by column chromatography on silica gel eluting with petroleum ether (bp. 60-90° C.)/ethyl acetate. The ester thus obtained was hydrolised with 12% aqueous HCl (2×2 mL) evaporating to dryness on a waterbath yielding 5′-(4-(bis(4-methoxyphenyl)amino)phenyl)-3,4′-dihexyl-2,2′-bithiophen-5-yl(butyl)phosphinic acid (190 mg, 82%).
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)C.[OH-].[K+:14]>C(O)C>[K+:14].[N:6]1([CH2:5][C:4]([O-:12])=[O:3])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)CN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CN1CCOCC1
Reaction time: 3 h
Yield: 99.4 %

Procedure:
To a solution of morpholin-4-yl-acetic acid ethyl ester (117 mg, 0.67 mmol) in ethanol (4 mL) was added 6N KOH (110 μL, 0.67 mmol) via syringe and stirring was continued for 3 h. Concentration in vacuo afforded 122 mg (100%) of morpholin-4-yl-acetic acid potassium salt. To a mixture of morpholin-4-yl-acetic acid potassium salt (29 mg, 0.15 mmol), 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide trifluoroacetic acid salt (65.1 mg, 0.13 mmol, as prepared in Example 14, step (b)) and PyBroP (93 mg, 0.19 mmol) in CH2Cl2 (4 mL) was added DIEA (51 μL, 0.29 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. Purification of the crude product by silica gel preparative TLC afforded 8.1 mg (12%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 1.68-2.04 (m, 5H), 2.20-2.29 (m, 4H), 2.53-2.78 (m, 5H), 3.09-3.23 (m, 6H), 3.35-3.40 (m, 1H), 3.72 (br s, 4H), 4.16-4.22 (m, 1H), 4.73-4.77 (m, 1H), 5.82 (s, 1H), 7.00 (s, 1H), 7.12 (dd, 1H, J=0.6, 8.0 Hz), 7.73 (s, 1H), 8.27 (d, 1H, J=8.1Hz), 9.48 (s, 1H); Mass spectrum (ESI, m/z): Calcd. for C28H34N6O3, 503.27 (M+H), found 503.1.
Reaction SMILES: [OH-].[K+].[C:3]([NH:6][NH:7][C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].[CH2:11]([O:14][CH2:15][CH2:16]Cl)[CH2:12]Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.CS(C)=O>[C:3]([N:6]1[N:7]([C:8](=[O:10])[CH3:9])[CH:16]=[CH:15][O:14][CH:11]=[CH:12]1)(=[O:5])[CH3:4]
Reactant: ClCCOCCCl
Reactant: CC(=O)NNC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: CC(=O)n1ccoccn1C(C)=O
Temperature: 70 °C

Procedure:
105.6 g of finely pulverised potassium hydroxide are introduced into a solution of 92.9 g of N,N′-diacetylhydrazine and 1410 g of dimethyl sulfoxide. When the heat of reaction has died away, 229.9 g of 2,2′-dichlorodiethyl ether are added and then 221.1 g of finely ground potassium carbonate are introduced. The reaction mixture is heated to 70° C. and maintained at 70 to 75° C. for 2 hours, then cooled to 20 to 25° C. and filtered, and the filtration residue is washed with dimethyl sulfoxide. Concentration of the combined filtrates by evaporation yields an oil, to which 157 g of isopropanol are added. After cooling to −10° C., filtration is carried out and the crystalline residue is washed with isopropanol. After drying of the residue, 99.4 g (65.1%) of 4,5-diacetyl-[1,4,5]-oxadiazepine are obtained in a purity of 97.6%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>C(Cl)Cl>[CH3:19][C:20]([CH3:25])([CH3:24])[C:21]([NH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[O:22]
Reactant: N#Cc1ccc(CCN)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NCCc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.7 %

Procedure:
Dissolve 4-(2-amino-ethyl)-benzonitrile hydrochloride (300 mg, 1.65 mmol) into saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over Na2SO4 and concentrate in vacuo to obtain 4-(2-amino-ethyl)-benzonitrile (205 mg, 85%). Dissolve 4-(2-amino-ethyl)-benzonitrile (200 mg, 1.37 mmol) in DCM (2 mL), add triethylamine (54 μL, 0.38 mmol) and cool the mixture at 0° C. Add 2,2-dimethyl-propionyl chloride (169 μL, 1.37 mmol) dropwise and allow to stir the mixture at 0° C. for 15 min and at room temperature for 2 h. Add water, separate the organic phase and extract the aqueous phase twice with DCM. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate (182 mg, 58%).
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH2:38])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(=O)C)C>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH:38][S:7]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]3)(=[O:9])=[O:8])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1c(Nc2ccc(I)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2N(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.4 %

Procedure:
1-Allyl-cyclopropanesulfonyl chloride (259 mg, 0.001 mol) was added to a stirred solution of 8-amino-7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (350 mg, 0.001 mol) in pyridine (3 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer concentrated to afford the crude product. Purification by column chromatography on silica gel (75% ethylacetate in hexane) afforded 125 mg of the product (27.7% yield).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:41][OH:42]>[Cl-].[Na+].O.CN(C=O)C>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6](=[CH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:41][OH:42])=[O:27])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)C=C1C=Cc2ccccc2-c2ccccc21
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=C1C=Cc2ccccc2-c2ccccc21)NCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
6-(2-(5H-dibenzocyclohepten-5-ylidene)acetamido)hexanoic acid (361 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (143 mg, 38%) as a yellow solid.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[C:19]#[N:20])[CH2:10][CH2:9]1.Cl[CH2:22][C:23]([NH:25][C:26]1[C:31](C)=[CH:30][CH:29]=[CH:28][C:27]=1C)=[O:24]>>[C:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[C:11]1[CH2:10][CH2:9][N:8]([CH2:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([CH3:2])[CH:31]=2)=[O:24])[CH2:13][CH:12]=1)#[N:20]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: N#Cc1ccsc1C1=CCNCC1
Product: Cc1cccc(NC(=O)CN2CC=C(c3sccc3C#N)CC2)c1

Procedure:
The desired material was prepared according to the procedure of Example 145 by substituting the product from Example 143B with the product from Example 155A, and 2-chloro-N-(2,6-dimethylphenyl)acetamide with the product from Example 33A. Yield 13 mg (36%). 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H), 2.90 (m, 2H), 3.50-4.20 (m, 4H), 4.30 (s, 2H), 6.43 (br s, 1H), 6.98 (m, 1H), 7.24 (m, 1H), 7.42 (m, 2H), 7.50 (m, 1H), 7.78 (m, 1H), 10.42 (m, 1H), 10.44 (br s, 1H); MS (ESI/APCI+) m/e 338 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2([NH2:41])[CH2:40][CH2:39]2)[N:33]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:41][C:38]5([C:34]6[N:33]=[N:32][CH:37]=[CH:36][CH:35]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: NC1(c2cccnn2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cccnn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(pyridazin-3-yl)cyclopropanamine HCl salt (0.018, 0.099 mmol, 1 eq) and Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.031 mg (60%). 1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 7.92-7.96 (m, 3H), 7.77-7.69 (m, 4H), 7.65 (s, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (dd, J=1.6, 8.4 Hz, 1H), 7.23-7.19 (m, 2H), 5.94 (bs, 1H), 3.0 (s, 3H), 2.33 (s, 3H), 1.89-1.86 (m, 2H), 1.60-1.57 (m, 2H). 19F NMR (376.47 MHz, CDCl3): δ −75.82 (TFA), −109.29 LCMS: (ES+) m/z=521.0 (M+H)+
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Br:18][C:19]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22](B(O)O)=[C:21]([CH2:30][CH3:31])[CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Br:18][C:19]1[CH:24]=[C:23]([CH2:25][CH3:26])[C:22]([Pb+3:17])=[C:21]([CH2:30][CH3:31])[CH:20]=1
Reactant: CCc1cc(Br)cc(CC)c1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Product: CCc1cc(Br)cc(CC)c1[Pb+3]
Temperature: 60 °C
Yield: 44.1 %

Procedure:
To a mixture of lead tetraacetate (9.5 g, 0.02 mol) and mercuric diacetate (0.25 g, 0.78 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (25 ml) and toluene (25 ml). This mixture is warmed to 60° C. and 4-bromo-2,6-diethylphenylboronic acid (5 g, 0.019 mol) is added in one portion and the mixture is stirred and heated at this temperature for 4 hours. After cooling in an ice bath, the mixture is filtered through a plug of diatomaceous earth and the filtrate is concentrated to approximately a quarter of its volume. Hexane is added to induce crystallization and the solvents evaporated under reduced pressure. Trituration with hexane gives 4-bromo-2,6-diethylphenyllead triacetate (5 g).
Reaction SMILES: C(NCC)C.[CH2:6]([O:8][C:9](=[O:28])[CH:10]([CH2:14][C@H:15]1[CH2:19][C@@H:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16]1)[C:11](O)=O)[CH3:7].C=O.C(Cl)Cl>O>[CH2:6]([O:8][C:9](=[O:28])[C:10]([CH2:14][C@H:15]1[CH2:19][C@@H:18]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]=[CH:16]1)=[CH2:11])[CH3:7]
Reactant: CCOC(=O)C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)O
Agent: C=O
Solvent: ClCCl
Solvent: O
Solvent: CCNCC
Product: C=C(C[C@@H]1C=C[C@H](NC(=O)OC(C)(C)C)C1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Diethyl amine (0.31 mL; 3.0 mmol) was added to a mixture of 2-(cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-malonic acid monoethyl ester (0.66 g, 2.0 mmol) in 36% aqueous solution of formaldehyde (0.25 mL, 3.2 mmol), CH2Cl2 (1.6 mL) and water (1.6 mL) at 0° C. The reaction mixture was stirred at room temperature overnight, poured onto ice-water (400 mL) and extracted with CH2Cl2. During the extraction, phase separation was improved by the addition of brine. The combined organic phases were washed with 5% NaHCO3, dried and concentrated under reduced pressure to yield 2-(cis-4-tert-butoxycarbonylamino-cyclopent-2-enylmethyl)-acrylic acid ethyl ester (0.56 g, 94%) as an oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:28][O:29][CH2:30]OCOCCl.OC1C=CC=CC=1C=O>ClCCCl>[CH3:28][O:29][CH2:30][O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: ClCOCOCOCCl
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=Cc1ccccc1O
Product: COCOc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (10 g, 40 mmol) in 1,2-dichloroethane (200 mL) was added N,N-diisopropylethylamine (6.97 mL, 40 mmol) and the solution was stirred for 1 h at room temperature. Chloromethoxymethyl ether (3.77 mL, 50 mmol) was added and the reaction mixture was stirred for 1 h at room temperature and then refluxed for 16 h until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.70 for starting, material using 1:1 hexanes/EtOAc). The reaction mixture was cooled to room temperature and washed with water. The organic layer was concentrated and the residue applied to a silica gel column and eluted with mixture of pentane/EtOAc. The title compound was isolated in 100% yield as a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:16][CH2:17][C:18]1[CH:29]=[CH:28][C:21]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[C:20]([OH:30])[CH:19]=1>>[OH:30][C:20]1[CH:19]=[C:18]([CH2:17][O:16][C:8](=[O:9])[C:7]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH:6]=2)[CH:29]=[CH:28][C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23]
Reactant: COc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(CO)cc1O
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(OC)c(C(C)(C)C)c2)cc1O

Procedure:
In a manner similar to Example 1(d), by reaction of 2.4 g (10.5 mmol) of 3-tert-butyl-4-methoxybenzoyl chloride with 2.2 g (10.5 mmol) of allyl 4-hydroxymethyl-2-hydroxybenzoate, 2.5 g (61%) of the expected allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][CH:34]([N:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][C:38]2=[O:47])[CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([N:31]3[CH2:36][CH2:35][CH:34]([N:37]4[C:46]5[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH2:40][CH2:39][C:38]4=[O:47])[CH2:33][CH2:32]3)=[O:23])=[C:17]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C1CCc2ccccc2N1C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)O)c(OCC(F)(F)F)c2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(CC(=O)N3CCC(N4C(=O)CCc5ccccc54)CC3)c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 4-(N-tert-butyloxy-carbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetic acid from Step 8 of Example 1 and 1-(piperidin-4-yl)-3,4-dihydroquinolin-2(1H)-one prepared by the method of Ogawa, et al., J. Med. Chem. (1993), vol. 36, pp. 2011-2017) in DMF was added HOBT, EDC, and DIEA. The solution was stirred at ambient temperature for 14 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and 0.25 M aqueous citric acid (75 mL). The organic phase was separated and washed with H2O (25 mL), saturated aqueous NaHCO3 (75 mL), and brine (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using EtOAc as eluant. The product-containing fractions were evaporated under reduced pressure to give 1-(1-(4-(N-tert-butyloxycarbonyl-4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenylacetyl)piperidin-4-yl)-3,4-dihydro-quinolin-2(1H)-one as an amorphous solid (HPLC retention time=10.8 min (method A); TLC Rf=0.7 (EtOAc)).
Reaction SMILES: [N+](C1C=C[C:7]([O:8][C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15](/[C:18](/[C:28]3[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:38]C(C)(C)C)=[O:37])=[CH:30][CH:29]=3)=[C:19](\[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)/[CH2:20][CH3:21])=[CH:14][CH:13]=2)=[O:10])=[CH:6]C=1)([O-])=O.CCO.CCN(CC)CC>C(Cl)Cl>[CH2:7]([O:8][C:9]([O:11][C:12]1[CH:13]=[CH:14][C:15](/[C:18](/[C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37])=[CH:30][CH:29]=2)=[C:19](\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)/[CH2:20][CH3:21])=[CH:16][CH:17]=1)=[O:10])[CH3:6]
Reactant: CC/C(=C(\c1ccc(/C=C/C(=O)OC(C)(C)C)cc1)c1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(/C(=C(/CC)c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.9 %

Procedure:
To a solution of 38 (0.050 g, 0.084 mmol) in CH2Cl2 (2 mL) was added EtOH (0.050 g, 1.08 mmol) and Et3N (0.016 g, 0.16 mmol). The mixture was stirred at ambient temperature for 18 h, diluted with CH2Cl2, washed with water and 0.1 N hydrochloric acid, dried (Na2SO4), and concentrated. The residue was separated by preparative RP-HPLC (C-18 Luna column, 85% MeCN/H2O/0.1% TFA) and the corresponding fractions were concentrated. The residue was dissolved in CH2Cl2 (0.3 mL) and cooled to 0° C. TFA (0.3 mL) was added and the mixture stirred at 0° C. for 1 h. The solvent was evaporated and co-evaporated with CH2Cl2 (2×10 mL) and the residue crystallized from a small amount of EtOAC to provide 37 (0.010 g) as an off-white solid; mp 135-136° C.; 1HNMR (DMSO-d6): δ 0.85 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H), 2.39 (q, J=7.2 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H), 6.5 (d, J=16 Hz, 1H), 6.85 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 7.08-7.22 (m, 5H), 7.24 (d, J=7.9 Hz, 2H), 7.58 (d, J=16 Hz, 1H), 7.69 (d, J=7.9 Hz, 2H), 12.45 (br s, 1H); MS, m/z 465 (M+Na)+; Anal. calculated for C28H26O5.0.13H2O: C, 75.60; H, 5.95; Found: C, 75.61; H, 5.93.