Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NCCCCCC(O)=[O:8].[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O>[CH:19]1([NH:18][C:17](=[O:8])[NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: NCCCCCC(=O)O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 18 atom homobifunctional linker was then synthesized from 5.0 g disuccinimidyl ester intermediate dissolved in 150 ml dry dimethylformamide, 4.20 g 6-aminocaproic acid and 6.93 g dicyclohexylcarbodiimide. The 6-aminocaproic acid was added to the dimethylformamide solution, and the resulting reaction mixture was stirred under a nitrogen blanket for three hours at room temperature of about 22°. The dicyclohexylcarbodiimide was then added, and the reaction mixture was stirred under a nitrogen blanket for about 16 hours at room temperature. Dicyclohexyl urea precipitate which had formed was then separated from the reaction mixture by filtration, and dimethylformamide was evaporated from the filtrate under reduced pressure. Trituration with ether followed by drying under high vacuum yielded 7.94 g 18 atom homobifunctional linker.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[N:20]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]2[CH:40]=[CH:41][C:42]([C:44]3[CH:45]=[C:46]([CH:49]=O)[O:47][CH:48]=3)=[CH:43][C:18]=2[O:17]1.[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH2:58])[CH2:54][CH2:53]1.C(O)(=O)C>ClCCCl.ClCCl>[CH3:51][N:52]1[CH2:57][CH2:56][CH:55]([NH:58][CH2:49][C:46]2[O:47][CH:48]=[C:44]([C:42]3[CH:41]=[CH:40][C:19]4[N:20]([C:21]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:16](=[O:15])[O:17][C:18]=4[CH:43]=3)[CH:45]=2)[CH2:54][CH2:53]1
Reactant: O=Cc1cc(-c2ccc3c(c2)oc(=O)n3C(c2ccccc2)(c2ccccc2)c2ccccc2)co1
Reactant: CN1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCC(NCc2cc(-c3ccc4c(c3)oc(=O)n4C(c3ccccc3)(c3ccccc3)c3ccccc3)co2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 41.5 %

Procedure:
Sodium triacetoxyborohydride (339 mg, 1.6 mmol) was added to a solution of 4-(2-oxo-3-trityl-2,3-dihydro-benzooxazol-6-yl)-furan-2-carbaldehyde (377 mg, 0.8 mmol) and 1-methyl-piperidin-4-ylamine (219 mg, 1.92 mmol) and acetic acid (192 mg, 3.2 mmol) in 10 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 21 h, and then it was diluted with dichloromethane and washed with saturated sodium carbonate solution. The aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to leave the crude product. Chromatography (elution with dichloromethane/methanol/acetic acid/water) gave 189 mg of product. LC/MS: Retention time, 2.38 min; (M+H)=570.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[CH2:13][CH:5]2[CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:3]1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Br:19][C:10]1[CH:9]=[CH:8][C:7]2[N:6]3[C:2](=[O:1])[O:3][CH:4]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[CH:5]3[CH2:13][C:12]=2[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NCC1OC(=O)N2c3ccccc3CC12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CC(=O)NCC1OC(=O)N2c3ccc(Br)cc3CC12

Procedure:
(±) (1S,9aS/1R,9aR) N-[(9,9a-Dihydro-3-oxo-1H,3H-oxazolo[3,4-a]indol-1-yl)methyl]acetamide (X, diastereomer B, [SS,RR-trans], EXAMPLE 11, 299 mg) is dissolved in acetonitrile (10 ml). To this mixture N-bromosuccinimide (235 mg) and a catalytic amount of benzoylperoxide are added as solids to the mixture at 20°-25°. The mixture is stirred at 20°-25° in a sealed flask over night. Then a small portion is removed and examined by NMR. The mixture was then concentrated under reduced pressure to give the title compound, NMR (CDCl3, 300 MHz) 7.30, 6.49, 4.63, 4.52, 3.72, 3.29, 3.12, 2.76 and 2.06 δ.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:29])[C:5]([CH3:28])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:18])=[C:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)c(-c3ccccc3)c2)=C(C)C1=O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCOCC3)c(-c3ccccc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.1 %

Procedure:
4-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-phenylbenzoic acid (18 mg, 0.0459 mmol) and morpholine (6 mg, 0.0689 mmol) were dissolved in methylene chloride (3 ml), then WSC-HCl (22 mg, 0.1147 mmol) was added thereto and the mixture was stirred at room temperature for 6 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (hexane:ethyl acetate=1:1) to give the title compound (10 mg, 0.0216 mmol, 47%).
Reaction SMILES: Cl.Cl.[CH:3]1([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4]1.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[N:20]1([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH:3]1([N:6]2[CH2:11][CH2:10][N:9]([C:31]([C:30]3[CH:29]=[CH:28][C:27]([CH2:26][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:35][CH:34]=3)=[O:32])[CH2:8][CH2:7]2)[CH2:5][CH2:4]1
Reactant: C1CN(C2CC2)CCN1
Reactant: O=C(Cl)c1ccc(CN2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(CN2CCOCC2)cc1)N1CCN(C2CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 250 mL, two-neck flask fitted with an addition funnel and thermocouple probe was charged with 1-cyclopropyl-piperazine dihydrochloride (7.1 g, 0.036 mol, 1.0 eq) and toluene (70 mL) and then cooled to 0° C. Aqueous NaOH solution (1.0 M, 70 mL, 2.0 eq) was added at such a rate that the reaction temperature did not exceed 10° C. Na2CO3 powder (7.5 g, 0.071 mol, 2.0 eq) was then added to the reaction mixture. The 4-morpholin-4-ylmethyl-benzoyl chloride, prepared as in Step A above (9.8 g, 0.036 mol, 1.0 eq) was added in portions over 3 minutes, while the temperature of the reaction mixture was maintained below 5° C. The reaction mixture was then stirred for 2 hrs. The reaction mixture was filtered, the layers were separated, the aqueous layer was extracted with toluene (30 mL×2), and the combined organic layers washed with brine (30 mL) and dried over Na2SO4. The solvent was removed in vacuo to yield the title compound as a as pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>O1CCOCC1>[S:17]1[CH2:18][CH2:19][N:14]([C:2]2[C:11]3[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([Cl:13])[N:3]=2)[CH2:15][CH2:16]1
Reactant: Cc1cccc2c(Cl)nc(Cl)cc12
Reactant: C1CSCCN1
Solvent: C1COCCO1
Product: Cc1cccc2c(N3CCSCC3)nc(Cl)cc12

Procedure:
A mixture of 23.3 gm (0.11 mol) of 1,3-dichloro-5-methyl-isoquinoline [prepared according to G. Simchen et al, Chem. Ber. 102, 3666 (1969); m.p. 120°C], 28.3 gm (0.275 mol) of thiomorpholine and 110 ml of dry dioxane was refluxed for 4 hours. The mixture was then evaporated, the residue was taken up with a mixture of tolune and water, and the toluene phase was isolated, dried and evaporated. The residue was recrystallized from 100 ml of ethyl acetate, yielding 22.7 gm (72% of theory) of the desired compound, m.p. 134°-136°C.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[CH3:23][C:24]1[NH:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:25]4[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:28]=[C:24]4[CH3:23])[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: Cc1nc(C(F)(F)F)c[nH]1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)cn1C1CCN(c2cnn(-c3ccc(Cl)cc3)c2C(C)C)C1=O
Temperature: 65 °C
Reaction time: 2 h
Yield: 26.7 %

Procedure:
A mixture of 3-bromo-1-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]pyrrolidin-2-one (0.110 g, 0.29 mmol), 2-methyl-4-(trifluoromethyl)-1H-imidazole (0.080 g, 0.53 mmol) and K2CO3 (0.080 g, 0.58 mmol) in DMF (1.8 mL) was stirred at 65° C. for 2 hrs. The mixture was then cooled to room temperature, quenched with water (30 mL), extracted with EtOAc (50 mL), and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.035 g, TFA salt, 21%). 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.27 (s, 1H), 5.03 (dd, J=10.4, 8.8 Hz, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 3.04 (heptet, J=6.8 Hz, 1H), 2.88 (m, 1H), 2.58 (s, 3H), 2.40 (m, 1H), 1.23 (m, 6H); MS: (ES) m/z calculated for C21H21ClF3N5O [M+H]+452.1. found 452.1.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4](/[CH:7]=[CH:8]/[CH2:9][O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])=[CH:3][CH:2]=1.CCCCCCCCC[C:31]1[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=1.C=O.OCC(CO)(CO)CO.CCCCCCCCCC1C=CC(O)=CC=1.C1C=CC(/C=C/CO[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)=CC=1>>[C:34]1([OH:37])[CH:35]=[CH:36][CH:31]=[CH:32][CH:33]=1.[CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9][O:10][C@@H:11]2[O:16][C@H:15]([CH2:17][OH:18])[C@@H:14]([OH:19])[C@H:13]([OH:20])[C@H:12]2[OH:21])=[CH:5][CH:6]=1
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: C=O
Agent: OCC(CO)(CO)CO
Agent: OC[C@H]1O[C@@H](OC/C=C/c2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Product: Oc1ccccc1
Temperature: 170 °C

Procedure:
A polyol (pentaerythritol) ester of a phenol-rosin (nonylphenol-tall oil rosin) condensate was prepared in the following manner. To a nitrogen purged reactor and under a continuous nitrogen flow of 0.003 pounds of nitrogen per pound of rosin per hour were added 11,100 pounds of tall oil rosin, 1,120 pounds of nonylphenol, and 14 pounds of lime. At a temperature of 170° C. and with stirring, 1,270 pounds of formalin (37% aqueous formaldehyde) were added over the course of 4 hours. Pentaerythritol (1,400 pounds) was then added, and the reaction temperature was raised to 280° C. where it was held until the acid number was less than 20. The pentaerythritol ester of the nonylphenol-rosin condensate had a softening point of 113° C., an acid number of 17, and a Gardner viscosity of Z3-- as measured at 25° C. and at 60% resin solids in a commercially available high-boiling hydrocarbon solvent known as Magiesol 47.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]([N:17]2[C@@:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[C@@:20]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)([CH3:30])[N:19]=[C:18]2[C:38]2[CH:39]=[N:40][C:41]([C:47]([CH3:48])([CH3:50])[CH3:49])=[CH:42][C:43]=2[O:44][CH2:45][CH3:46])=[O:16])[CH2:12][CH2:13]1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCNCC1
Reaction time: 2 h
Yield: 96.8 %

Procedure:
A solution of 4-{[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (640 mg, 0.885 mmole, example 205) in dichloromethane (6 mL) was treated with trifluoroacetic acid (6 mL) at 0° C. and allowed to stir for 2 h before concentrated to dryness under reduced pressure. The residue was then taken up in dichloromethane (100 mL), washed with aqueous sodium carbonate (2×15 mL), water (15 mL) and concentrated to give (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carboxylic acid piperidin-4-yl amide (533.3 mg) which was used without purification.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][C:11]1[CH2:12][C:13]([C:22](OC)=[O:23])=[C:14]([C:18](OC)=[O:19])[CH2:15][C:16]=1[CH3:17].CO>ClCCl>[OH:19][CH2:18][C:14]1[CH2:15][C:16]([CH3:17])=[C:11]([CH3:10])[CH2:12][C:13]=1[CH2:22][OH:23]
Reactant: COC(=O)C1=C(C(=O)OC)CC(C)=C(C)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: ClCCl
Product: CC1=C(C)CC(CO)=C(CO)C1
Yield: 35 %

Procedure:
To a solution of DIBAL in dichloromethane (1.0M, 45 ml, 0.045 mol) cooled to ice bath temperature under nitrogen was added dimethyl 4,5-dimethylcyclohexa-1,4-diene-1,2-dicarboxylate (2.24 g, 0.01 mol) in dry dichloromethane (30 ml) over 30 min. The resultant solution was stirred for a further 60 mins at this temperature after which methanol (10 ml) was added. The mixture was allowed to come to room temperature, filtered through a "Celite" pad, and the filtrate concentrated in vacuo to give an oil. Crystallisation from ethyl acetate/petroleum ether (40°-60° C.) gave the title compound in 35% yield. N.m.r: δH (90 MHz, CD3OD) 4.15 (s,4H), 3.55 (bs,2H), 2.82 (s,4H), 1.69 ppm (s,6H)
Reaction SMILES: N1C=CC=CC=1.[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[C:31]([O:38][CH:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1)[CH3:40])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[C:31]([O:38][CH:39]([C:41]1[CH:49]=[CH:48][C:44]([C:45]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:16][N:15]=3)=[CH:12][CH:13]=2)=[O:46])=[CH:43][CH:42]=1)[CH3:40])(=[O:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC(=O)OC(C)c1ccc(C(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCOc1cnc(-c2ccc(OC(=O)c3ccc(C(C)OC(=O)CCCCC)cc3)cc2)nc1
Yield: 96 %

Procedure:
Into 20 ml of pyridine were dissolved 1.97 g (6 millimoles) of 2-(4-hydroxyphenyl)-5-decyloxypyrimidine, and then 1.41 g (5 millimoles) of an acid chloride derived from (+)-4-(1-hexanoyloxyethyl)benzoic acid were added thereto, to subject to reaction at 30° to 40° C. for 2 hours. After completion of the reaction, the reaction mixture was poured into 200 ml of water, adjusted to pH 3 to 4 with hydrochlolic acid, followed by extraction with 200 ml of toluene, and the organic phase was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in this order and then the organic phase was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 2.76 g (yield: 96%) of 4-(5-decyloxy-2-pyrimidyl)phenyl (+)-4-(1-hexanoyloxyethyl)benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14]Cl.BrC1C=C2C(=CC=1O)[O:23][C:22](=[O:28])[CH:21]=C2CCl>>[C:22]([O:28][CH2:14][C:5]1[C:4]2[C:9](=[CH:10][C:11]([OH:12])=[C:2]([Cl:1])[CH:3]=2)[O:8][C:7](=[O:13])[CH:6]=1)(=[O:23])[CH3:21]
Reactant: O=c1cc(CCl)c2cc(Br)c(O)cc2o1
Reactant: O=c1cc(CCl)c2cc(Cl)c(O)cc2o1
Product: CC(=O)OCc1cc(=O)oc2cc(O)c(Cl)cc12
Yield: 28 %

Procedure:
This compound was prepared by the same method as compound 5, starting with compound 12 rather than compound 11, to yield 75.4 mg (0.281 mmol, 28% yield) of compound 4 as an oil. 1H NMR (CDCl3+5% CD3OD) δ 7.43 (1H, s), 6.85 (1H, s), 6.25 (1H, s), 5.16 (2H, s), 3.30 (1H, s), 2.14 (3H, s); MS (ES, negative) 267.2 and 269.1; UV (KMOPS, pH 7.2) λmax (ε) 370 nm (16,000 M−1cm−1). ps 3,6,8-Tribromo-4-chloromethyl-7-hydroxycoumarin (13).
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[NH2:7][C@@H:8]([CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][OH:10].[CH3:20][C:21]([CH3:35])([CH3:34])[CH2:22][O:23][CH:24]([O:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25](=O)[CH3:26].C([BH3-])#N.[Na+].C(O)(=O)C>O1CCCC1>[CH2:13]([O:12][CH2:11][C@H:8]([NH:7][C@@H:25]([CH3:26])[CH:24]([O:23][CH2:22][C:21]([CH3:35])([CH3:34])[CH3:20])[O:28][CH2:29][C:30]([CH3:33])([CH3:31])[CH3:32])[CH2:9][OH:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)C(OCC(C)(C)C)OCC(C)(C)C
Reactant: N[C@H](CO)COCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](N[C@H](CO)COCc1ccccc1)C(OCC(C)(C)C)OCC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add magnesium sulfate (30.23 g, 251.10 mmol) to (R)-2-amino-3-benzyloxypropan-1-ol (12.30 g, 67.87 mmol) and 1,1-bis-(2,2-dimethylpropoxy)-propan-2-one (23.45 g, 101.80 mmol) in tetrahydrofuran (100 mL) at room temperature and stir for 2 hours. Filter and concentrate. Dissolve in methanol (200 mL) and cool in an ice water bath. Add sodium cyanoborohydride (8.53 g, 135.73 mmol) and then acetic acid (4.08 g, 67.87 mmol) dropwise. Warm to room temperature, stir 2 hours and concentrate to −50 mL. Dilute with ethyl acetate (˜200 mL) and add water (˜50 ml) followed by 1 N sodium hydroxide (˜200 mL). Stir 20 minutes and dilute with saturated aqueous sodium chloride. Dry (sodium sulfate), filter and concentrate to give the title compounds.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35][CH:36]=[CH2:37])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:38](=[O:42])/C=C/C>ClCCl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([C@@H:25]([CH2:35]/[CH:36]=[CH:37]/[CH:38]=[O:42])[CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C/C=C/C=O
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(CCCCC)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClCCl
Product: CCCCCN([C@@H](C/C=C/C=O)CO[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1
Yield: 74.2 %

Procedure:
A solution of the material from Step 3 (9.5 g, 16.67 mmol) and crotonaldehyde (6.90 mL, 83 mmol) in dichloromethane (183 mL) was heated at reflux. Grubbs' 2nd Generation catalyst (0.71 g, 0.833 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated to dryness in vacuo and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 7.4 g of the title compound. LCMS (M+Na)=620.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:20])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:20])[C:8]([C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2Cl)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2ccc3c(Cl)c(O)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by reacting 1,5-dichloro-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.15 g, 0.45 mmol) with boron tribromide (1.4 mL of 1N solution) according to method D to yield 0.10 g (73%) of a white solid: mp 204–206° C.; 1H NMR (DMSO-d6): δ 6.89 (2H, d, J=8.47 Hz), 7.33 (2H, d, J=8.45 Hz), 7.46 (1H, d, J=9.26 Hz), 7.56 (1H, d, J=8.80 Hz), 8.06 (1H, d, J=8.81 Hz), 8.17 (1H, d, J=9.28 Hz), 9.68 (1H, bs), 10.84 (1H, bs); MS (ESI) m/z 303/305/307(M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](O)=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([C:27]([O:31][N:32]1N=NC2C=CC=N[C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:27][O:31][N:32]([CH3:33])[C:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH:10]1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reaction time: 0.25 h

Procedure:
In a 100 mL round bottom flask with a magnetic stirrer 900 mg (2.72 mmol) (3RS,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid and 1.14 g (3 mmol) HATU was dissolved in 20 mL dry DMF. The greenish solution was stirred for 15 min, 320 mg (3.28 mmol) N,O-dimethylhydroxylamine hydrochlorideowed and 2.32 mL DIPEA was added. The mixture was stirred for 3 h at room temperature and concentrated under high vacuum. The green viscous oil was taken up in 60 mL ethyl acetate and 75 mL 5% aqueous NaHCO3-solution. The aqueous layer was separated and extracted once with 60 mL ethyl acetate. The combined organic layers were washed with 75 mL 1% AcOH/water-solution and once with 100 ml brine, dried over Na2SO4, filtered off and concentrated under vacuum. The residue was purified over silica eluting with a gradient formed from ethyl acetate/heptane to yield after evaporation of the product containing fractions 990 mg (97%) of the title compound as colorless viscous oil. MS (m/e): 373.3 [(M+H)+].
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])[CH:12]=[CH:13][C:14]=2[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[C:5]1=[O:37])(=O)C.CO.[OH-].[Na+].Cl>O>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:14]3[CH:13]=[CH:12][C:11]([N:31]4[CH2:35][CH2:34][O:33][C:32]4=[O:36])=[CH:10][C:9]=3[N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:37])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CC(=O)N1CCN(c2cc(N3CCOC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCNC3=O)CC2)c(C)c1
Temperature: 50 °C
Yield: 9.1 %

Procedure:
To 3-{3-(3-acetyl-2-oxoimidazolidin-1-yl)-4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (156 mg) described in Example 209 were added methanol (2 mL) and 1N aqueous sodium hydroxide solution (0.31 mL), and the mixture was stirred at 50° C. 1N hydrochloric acid (0.31 mL) and water were added, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (13 mg).