Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C2C(=C(N)C=1)[N:9]=CC=C2.C(OC(=O)C)(=O)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([NH:33][C:34]([CH3:36])=[O:35])[CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2>N1C=CC=CC=1>[NH2:9][C:24]1[C:23]([O:22][CH3:21])=[CH:32][C:31]([NH:33][C:34]([CH3:36])=[O:35])=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[N:29]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: COc1cc(NC(C)=O)c2ncccc2c1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: COc1cc(NC(C)=O)c2ncccc2c1N

Procedure:
Commercially available 6-methoxy-8-aminoquinoline (Chemical Procurement Laboratories) was acetylated with acetic anhydride and pyridine. The resultant 6-methoxy-8-acetaminoquinoline was nitrated and reduced using the procedure described in Example 33 to give 5-amino-6-methoxy-8-acetaminoquinoline. This product was coupled with 2-(hexylthio)decanoic acid according to Example 25 and hydrolyzed with aqueous hydrochloric acid and isopropanol to give the title compound. Mass spectrum m/e: 459.3 (M+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:18]4[CH2:22][CH2:21][N:20](CC5C=CC=CC=5)[CH2:19]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd].C(O)(=O)C>[C:1]1([S:7]([C:10]2[CH:31]=[CH:30][C:13]3[N:14]([CH:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OCCN2C1CCNC1
Reaction time: 24 h
Yield: 44.7 %

Procedure:
7-Benzenesulfonyl-4-(1-benzyl-pyrrolidin-3-yl)-3,4-dihydro-2H-benzo[1,4]oxazine (0.127 g, 0.292 mmol) was dissolved in 15 mL ethanol and this solution was added to a flask containing 35 mg of 5% palladium on charcoal, followed by 3 drops of glacial acetic acid. The system was purged with hydrogen gas and stirring was continued for 24 hours under 1 atm. of hydrogen gas. The reaction mixture was filtered through celite, the filtrate concentrated in vacuo, and the resulting solid purified by flash (6:0.4:0.04 of CH2Cl2:MeOH:NH4OH) to give 45 mg of 7-benzenesulfonyl-4-pyrrolidin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine as free base. This solid was dissolved in 1 mL methanol and combined with 0.5 mL of 2N ethanolic hydrogen chloride and the resulting solution is concentrated in vacuo and subjected to a vacuum of 0.3 Torr for 2 hours to give a foam which was triturated twice with 50 mL ethyl ether to give, after drying under reduced pressure, 25 mg (0.07 mmol, 25%) of 7-benzenesulfonyl-4-pyrrolidin-3-yl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride as a tan solid. MS: 345 (M+H)+, mp: 122.8-127.6° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]3[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][CH:14]3O)=[O:11])=[CH:8][C:7]=2[F:26])[CH2:3][CH2:2]1.C(N(CC)CC)C.O>CS(C)=O>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]3[O:11][C:22]4[CH2:21][C:16]5([O:20][CH2:19][CH2:18][O:17]5)[CH2:15][CH2:14][C:13]=4[N:12]=3)=[CH:8][C:7]=2[F:26])[CH2:2][CH2:3]1
Reactant: O=C(NC1CCC2(CC1O)OCCO2)c1ccc(OCC2CC2)c(F)c1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1cc(-c2nc3c(o2)CC2(CC3)OCCO2)ccc1OCC1CC1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 4-(cyclopropylmethoxy)-3-fluoro-N-(7-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)benzamide (4.53 g) in dimethyl sulfoxide (40 mL) were added triethylamine (5.18 mL) and sulfur trioxide-pyridine complex (5.92 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in THF (30 mL) was added (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (4.66 g), and the mixture was stirred at 60° C. for 30 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.18 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]4[N:26]([CH:27]=3)[C:25]3[CH:28]=[CH:29][C:30]([O:32][CH2:33][CH2:34]Cl)=[CH:31][C:24]=3[S:23]4)=[CH:16][CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])C.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[CH3:37][O:39][C:40](=[O:43])[CH2:41][NH:42][CH2:34][CH2:33][O:32][C:30]1[CH:29]=[CH:28][C:25]2[N:26]3[CH:27]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([NH:13][C:11]([NH:10][C:7]5[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][N:8]=5)=[O:12])=[CH:15][CH:16]=4)[N:21]=[C:22]3[S:23][C:24]=2[CH:31]=1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCCl)ccc34)cc2)no1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)CNCCOc1ccc2c(c1)sc1nc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)cn12

Procedure:
A mixture of 1-(5-tert-butyl-isoxazol-3-yl)-3-{4-[7-(2-chloro-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (1 equivalent), glycine ethyl ester hydrochloride (1-3 equivalents), potassium carbonate (2-6 equivalents), and sodium iodide (2-5 equivalents) in anhydrous DMF is stirred at selected temperatures between rt and 80° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is partitioned between water and either dichloromethane or a mixture of isopropanol and dichloromethane. The organic layer is separated and the aqueous layer is further extracted with dichloromethane or a mixture of isopropanol and dichloromethane. The combined extracts are washed with water or brine, then dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford [2-(2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yloxy)-ethylamino]-acetic acid methyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@@H:20]([C:45](=[O:58])N4[C@@H](C5C=CC=CC=5)COC4=O)[C@@H:21]([C:30]4[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:32][CH:31]=4)[NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][C@H:20]4[C:45](=[O:58])[N:22]([C:23]5[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=5)[C@@H:21]4[C:30]4[CH:44]=[CH:43][C:33]([O:34][CH2:35][C:36]([O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:37])=[CH:32][CH:31]=4)[O:11][CH2:12][C:13]([CH3:16])([CH3:17])[CH2:14][O:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(N[C@H](c2ccc(OCC(=O)OC(C)(C)C)cc2)[C@@H](SCC2(c3ccc4c(c3)OCO4)OCC(C)(C)CO2)C(=O)N2C(=O)OC[C@@H]2c2ccccc2)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: Cc1ccccc1
Product: Cc1ccc(N2C(=O)[C@H](SCC3(c4ccc5c(c4)OCO5)OCC(C)(C)CO3)[C@H]2c2ccc(OCC(=O)OC(C)(C)C)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
tert-Butyl (4-{(1R,2R)-2-({[2-(1,3-benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-1-[(4-methylphenyl)amino]-3-oxo-3-[(4S)-2-oxo-4-phenyl-1,3-oxazolidin-3-yl]propyl}phenoxy)acetate (Method 20) (1.70 g, 2.03 mmol) was dissolved in dry toluene (200 mL) and heated to 90° C. under inert atmosphere. N,O-Bis(trimethylsilyl)acetamide (BSA, 1.50 mL, 6.10 mmol) was added and the mixture was stirred at 90° C. for one hour. The mixture was then given 45° C. and tetrabutylammonium fluoride (TBAF, cat., 0.1 g) was added and the mixture was stirred at 45° C. for 19 hours. The mixture was then concentrated under reduced pressure and purified by flash-chromatography (heptane:EtOAc 4:1). This afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.BrC1C=CC=CC=1C#N>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(Br)ccc1N
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: N#Cc1ccccc1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cc(C#Cc2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
A solution of 3.00 grams (0.015 mole) of 2-amino-5-bromobenzonitrile and 2.3 mL (0.021 mole) of phenylacetylene in 50 mL of acetonitrile was stirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride were added in order. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 20 hours. After this time, thin layer chromatographic (TLC) analysis of the reaction mixture indicated that no reaction had taken place. The reaction mixture was warmed to 70° C., where it was stirred for about 7.5 hours. An additional 0.38 gram of phenylacetylene was added, and the reaction mixture was warmed to reflux temperature where it was stirred during about an additional 16.5 hour period. After this time, TLC analysis of the reaction mixture indicated that it contained about a 1 to 1 mixture of starting bromobenzonitrile and product. An additional 5.0 mL of triethylamine and 0.09 gram of bis(triphenylphosphine)palladium(II) chloride catalyst was added to the reaction mixture, and the heating at reflux was continued during an additional 24 hour period. After this time, the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in ethyl acetate, and the solution was washed with 50 mL of aqueous, dilute hydrochloric acid. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 15/10/75 tetrahydrofuran/methylene chloride/petroleum ether. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.85 gram of 2-amino-5-(2-phenylethynyl)benzonitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(C(OC(C)(C)C)=O)[CH2:11][C:10]([F:13])([F:12])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:8]2[CH2:9][C:10]([F:13])([F:12])[CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1(c2ncccc2Cl)CC(F)(F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CC(c2ncccc2Cl)C1
Temperature: 90 °C
Reaction time: 18 h
Yield: 80.7 %

Procedure:
To a solution of tert-butyl 1-(3-chloropyridin-2-yl)-3,3-difluorocyclobutanecarboxylate (Preparation 229, 500 mg, 1.65 mmol) in DCM (6.5 mL) was added TFA (0.50 mL, 6.6 mmol) at room temperature under N2. The resulting solution was stirred for 18 hours. The solvent was removed in vacuo and toluene (5 mL) was added. The resulting mixture was warmed up to 90° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc and water. The organic phase was washed with saturated aqueous NaHCO3 solution, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a dark brown oil. The crude product was purified by silica gel column chromatography eluting with 0-30% EtOAc in heptane to give the title compound (271 mg, 81%) as a colourless oil.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[C:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1.[CH:23]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[ClH:32].CCO>CC(O)C>[ClH:32].[OH:1][CH:2]([CH2:22][NH:31][CH:23]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:21])[C:10]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][O:12]2)=[CH:7][CH:6]=1
Reactant: NC1CCCCCCC1
Reactant: O=c1c(-c2ccccc2)coc2cc(OCC3CO3)ccc12
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: O=c1c(-c2ccccc2)coc2cc(OCC(O)CNC3CCCCCCC3)ccc12

Procedure:
Using Method B, the reaction of 7-(2,3-epoxypropoxy)isoflavone with cyclooctylamine followed by acidification of the resulted free base with HCl/EtOH gave the hydrochloride as light yellow prisms, m.p. 185°-186° (iPrOH).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([O-:9])=[O:8].Br[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].O>CN(C=O)C>[N+:7]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])([O-:9])=[O:8]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9.67 g (70 mmol) of potassium carbonate is added to a solution of 6.96 g (50 mmol) of 3-nitrophenol in 500 ml DMF, and then it is stirred for 10 minutes at room temperature. It is mixed with 14.1 g (50 mmol) of 2-(4-bromo-butyl)-isoindole-1,3-dione and stirred for 4 hours at 60° C. After cooling, it is mixed with water and extracted with ethyl acetate. The combined organic phases are dried (MgSO4), filtered and concentrated by evaporation. 17.2 g (50 mmol, corresponding to 100% of theory) of the product is obtained.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N+:19]([C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:19]([C:22]1[N:23]=[CH:24][N:25]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH:26]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc([N+](=O)[O-])c2)CC1
Temperature: 120 °C
Yield: 32.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 243a (7.0 g, 25.1 mmol), DMF (120 mL), 4-nitro-1H-imidazole (2.80 g, 25.1 mmol), and K2CO3 (6.9 g, 50.2 mmol). The mixture was heated at 120° C. for overnight. After this time the reaction was cooled to room temperature and filtered. The filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 2:2:1 ethyl acetate/petroleum ether/dichloromethane to afford 243b (2.4 g, 32.4%) as a yellow solid. MS-ESI: [M+H]+ 297.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:22])[CH2:58][CH2:59]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)NC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 2-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (72 mg, 0.21 mmol) and TBTU (74 mg, 0.23 mmol) in DMF (3 mL) was added DIPEA (178 μL, 1.05 mmol). Then 4-aminotetrahydropyran (23 mg, 0.23 mmol) was added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purification by chromatography (silica, 30 to 80% ethylacetate in heptane) afforded the title compound (68 mg, 76%) as a light yellow solid. MS: m/e=428.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][C@@H:15]([OH:34])[CH2:16][N:17]2[CH2:22][CH2:21][N:20]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)Cl.[K+].[Br-].N1CCNCC1>C(Cl)Cl.[Pd]>[OH:34][C@@H:15]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:19][CH2:18]1)[CH2:14][O:13][C:12]1[CH:35]=[CH:36][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Agent: C1CNCCN1
Agent: [Br-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCN(C[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
Pd/C at 10% (290 mg) is suspended in a solution of (S)-1-(4-benzyloxyphenoxy)-2-hydroxy-3-[4-(4-methoxyphenylsulfonyl)piperazin-1-yl)propane (Example 26) (583 mg, 1.14 mM) in CH2Cl2 (10 ml) and maintained in agitation in H2 atmosphere (1 atm) for 18 hours. The catalyst is then removed by filtering the reaction mixture on Celite, and the solvent is distilled under vacuum. The oily residue is crystallized (ethyl acetate/petroleum ether). A white solid is obtained (90% of yield). Pf 148.3-149.2° C.s. [α]D=−7.6 (c 1.07, CHCl3). FT-IR (KBr): 3466, 3050, 2969, 2941, 2921, 2896, 2864, 1593, 1576, 1511, 1468, 1458, 1445, 1348, 1328, 1306, 1254, 1234, 1200, 1177, 1165, 1136, 1101, 1051, 1017, 946, 833, 804, 737 cm−1. 1NMRs (500 MHz CD3OD, δ): 7.90-7.80 (bs, 1H, OH); 7.71-7.68 (m, 2H, aromatic protons); 7.13-7.10 (m, 2H, aromatic protons); 6.75-6.73 (m, 2H, aromatic protons); 6.68-6.66 (m, 2H, aromatic protons); 4.00-3.98 (m, 1H, CHOH), 3.88 (s, 3H, OCH3), 3.86-3.83 (dd, 1H, J=9.7 and 4.4 Hz, CH2OAr); 3.80-3.77 (dd, 1H, J=9.7 and 5.9 Hz, CH2OAr); 3.70-3.50 (bs, 1H, OH); 2.98 (m, 4H, 2 CH2N of piperazine); 2.60 (m, 4H, 2 CH2 of piperazine); 2.55-2.52 (dd, 1H, J=13.0 and 4.8 Hz, CHOHCH2N); 2.50-2.46 (dd, 1H, J=13.0 and 7.5 Hz, CHOHCH2N). 13C NMRs (75 MHz CD3OD, δ): 163.72, 152.47, 150.31, 129.97, 126.98, 115.60, 115.55, 114.25, 71.35, 67.31, 60.45, 55.08, 52.81, 46.07. MS-ESI m/z (%): 445 [M+Na]+ (100). MS-MS (445): 445(100), 335 (69), 292 (54), 279 (13), 250 (8), 222 (32). Anal. Calc. for C20H26N2O5S: C, 56.86; H, 6.20; N, 6.63. Found: C, 57.03; H, 6.16; N, 6.66.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4](=[S:6])=[S:5].O=O>C(O)(C)C>[CH3:1][N:2]([C:4]([S:6][S:6][C:4]([N:2]([CH3:3])[CH3:1])=[S:5])=[S:5])[CH3:3]
Reactant: S=C=S
Reactant: CNC
Agent: O=O
Solvent: CC(C)O
Product: CN(C)C(=S)SSC(=S)N(C)C
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
13.5 g (0.3 mol) of dimethylamine and 24.4 mg (0.1×10-3 mol) of Mn(CH3COO)2.4H2O were dissolved in 100 g of isopropanol in the reaction equipment described in Example 1. 22.8 g (0.3 mol) of carbon disulfide were added to this solution. The resulting clear, dark brown solution was heated to 50° C., stirred vigorously, and subjected to 1.7 bar of oxygen. Under these conditions, the reaction came to an end after 90 minutes. TMTD was obtained with a yield of 98.6%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCOc1ccc(CCCO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCc1ccc(OCCCC(=O)O)cc1
Reaction time: 4 h

Procedure:
A 1.19 g (5.00 mmol) sample of 4-[4-(3-hydroxypropyl)phenoxy]butanoic acid is dissolved with stirring in 250 mL of methylene dichloride. Next, 3.77 g (17.49 mmol) of pyridinium chlorochromate is added, the mixture is stirred for 4 hours, and then filtered through a celite pad. The reaction mixture is then diluted with an equal volume of ether, precipitating out salts. This mixture is then filtered through a silica gel pad, and the filtrate evaporated, giving a brown solid. The solid is recrystallized from an ether-hexane mixture producing 0.21 (18%) of 4-[4-(3-oxopropyl)phenoxy]butanoic acid as off-white crystals: m.p. 100°-03° C.; IR (KBr) 1715 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (CI) m/e 237 (M+ +H). Analysis calculated. for C13H16O4 : C, 66.09; H, 6.83; O, 27.09. Found: C, 65.91; H, 6.72; O, 27.35.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CC[C@@H](CO)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
The product from step 2 was dissolved in dry CH2Cl2 and the solution was cooled to 0° C. Triethylamine (1.5 molar equiv) was added. After 10 min, trityl chloride (1.1 molar equiv) followed by DMAP (0.2 molar equiv) were added and stirred over night at room temperature. The reaction was then quenched with saturated NH4Cl solution, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography afforded (5S)-5-(trityloxymethyl)-2-oxo-tetrahydrofuran in 76% yield.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[C:11]([CH3:18])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:20]1[C:21]([CH3:36])=[C:22]([CH:33]=[CH:34][CH:35]=1)[CH2:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:20]2[CH:35]=[CH:34][CH:33]=[C:22]([CH2:23][O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][N:26]=3)[C:21]=2[CH3:36])=[C:11]([CH3:18])[CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1c(Br)cccc1COc1ccc(C=O)cn1
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1-c1cccc(COc2ccc(C=O)cn2)c1C
Temperature: 60 °C

Procedure:
In an atmosphere of nitrogen, a mixture of (4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylphenyl)boronic acid, 6-[(3-bromo-2-methylbenzyl)oxy]nicotinaldehyde, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred with heating at 60° C. for 2 days to obtain 6-[(4′-{[tert-butyl(dimethyl)silyl]oxy}-2,2′-dimethylbiphenyl-3-yl)methoxy]nicotinaldehyde.