Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]
Reactant: N#Cc1cccc(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1COc1cccc(C#N)c1
Temperature: 25 °C

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (6.27 g, 46.1 mmol) and diisopropyl azodicarboxylate (DIAD, 9.24 g, 45.7 mmol) in dry THF (30 ml) was added drop wise to a solution of 3-Hydroxybenzonitrile (5 g, 37 mmol) and triphenylphosphine (TPP, 11.99 g, 45.7 mmol) in THF (100 ml) at 0° C. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10]C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.C[N:19](C)[CH:20]=[O:21]>CCOCC>[CH2:1]([O:8][CH2:9][CH2:10][N:19]=[C:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: O=C(O)CCOCc1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C=NCCOCc1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4 ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yielding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:24]([OH:25])=[C:22]([OH:23])[CH:21]=1>>[OH:23][C:22]1[CH:24]=[CH:26][C:27]([C:6]([N:8]2[CH2:15][CH2:14][CH2:13][C@H:9]2[C:10]([NH:17][CH2:18][CH2:19][C:20]2[CH:27]=[CH:26][C:24]([OH:25])=[C:22]([OH:23])[CH:21]=2)=[O:12])=[O:7])=[CH:20][CH:21]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Product: O=C(NCCc1ccc(O)c(O)c1)[C@@H]1CCCN1C(=O)c1ccc(O)cc1
Yield: 69.1 %

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-L-proline (108 mg, 0.50 mmol) in a coupling reaction with dopamine hydrochloride (189 mg, 1.0 mmol) according to example 6. Purification by flash column chromatography (5% MeOH/CHCl3) provided the desired compound as a syrup (128 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[N:14]([C:7]1[N:6]=[C:5]([NH2:8])[N:4]=[C:3]([NH2:9])[C:2]=1[NH2:1])=[O:15]
Reactant: O=N[O-]
Reactant: Nc1ncc(N)c(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N)c(N=O)n1
Temperature: 8 °C

Procedure:
In a 500-gallon glasslined reactor, crude damp triaminopyrimidine was dissolved in 150 gallons of deionized water with the aid of 117 pounds of acetic acid. HPLC assay showed 137 pounds of triaminopyrimidine in solution. The solution was cooled to 8° C. and treated with 80 pounds of sodium nitrite in 45 gallons of deionized water over a period of 13 minutes, with full refrigeration on the reactor jacket. A dense granular slurry of nitrosotriaminopyrimidine formed during the next 15 minutes as the temperature rose to 13° C. Analysis showed less than 0.1% of the triaminopyrimidine remaining unreacted in the filtrate, and a sample of the slurry was taken for small scale experiments. It remained a stable slurry under refrigeration for several days. The remainder of the slurry was reduced in situ to tetraaminopyrimidine sulfite by reaction with 382 pounds of sodium dithionite, filtered hot and chilled to 0°-5° C. to precipitate 609 pounds of damp cake, containing 186 pounds of tetraaminopyrimidine sulfite.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C@@:7]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1)[CH:2]=C.[O:37]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([N:10]2[CH2:9][CH2:8][C@@:7]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)([CH2:6][CH2:5][O:4][CH2:1][CH2:2][OH:37])[O:12][C:11]2=[O:13])[CH3:15])=[CH:17][CH:18]=1
Reactant: O=[O+][O-]
Reactant: C=CCOCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of (S)-6-(2-(allyloxy)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (100 mg, 0.20 mmol) in CH2Cl2 (10 mL) was treated with O3 at −78° C. till the mixture was turned blue. Then NaBH4 (50 mg, 1.0 mmol) was added, and the mixture was stirred at rt overnight. The solution was concentrated and the residue was purified by preparative HPLC to give (S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(2-hydroxyethoxy)ethyl)-1,3-oxazinan-2-one (40 mg, 30%). LC-MS Method 3 tR=1.41, min, m/z=500, 522; 1H NMR (CDCl3): 1.48-1.61 (d, 3H), 1.92-2.05 (m, 2H), 2.09-2.41 (m, 5H), 2.88-3.02 (m, 1H), 3.27-3.56 (m, 2H), 3.58-3.69 (m, 2H), 5.63-5.72 (m, 1H), 6.82-7.08 (m, 6H), 7.17-7.34 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH:10][CH:11]1[CH2:13][CH2:12]1)=[O:4].N#N.[Cl:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:13][CH2:12]1)[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:23]=1[Cl:22])=[O:4]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC1CC1
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C1CC1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of 3-Cyclopropylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (52 mg, 0.19 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichlorobenzoyl chloride (45 mg, 0.21 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvant was removed and the residue was purified by flash chromatography (8:2 Hexane/EtOAc) to obtain 85 mg (99%) of 3-[Cyclopropyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.64 ppm (d, 2H, Haro); 7.47 ppm (m, 2H, Haro); 7.44-7.33 ppm (m, 3H, Haro); 7.21-7.12 ppm (m, 2H, Haro); 3.89 ppm (s, 3H); 3.33 ppm (m, minor rotamer); 3.13 ppm (m, 1H, major rotamer) 1.01-0.49 ppm (m, 4H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>P(Cl)(Cl)(Cl)=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: C1=COCCC1
Reactant: OCCCCCBr
Solvent: O=P(Cl)(Cl)Cl
Product: BrCCCCCOC1CCCCO1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
Three drops of phosphoryl chloride were added to a stirred mixture of 5-bromopentanol (34.3 g, 205 mmol) and dihydropyran (19.0 g, 226 mmol). After standing for one hour, the mixture was fractionated. Yield 34.7 g, b.p. 102° C. (0.2 bar). Chromatography on alumina eluted with petroleum ether gave the pure title compound (25.1 g, 52% of theory) as an oil.
Reaction SMILES: [C:1]([CH:4]1[CH:8]2[CH2:9][C:10](=[O:13])[CH:11]=[CH:12][C:7]2([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)OC1=O)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].O>C(Cl)Cl>[C:23]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:8]([CH2:4][C:1](=[O:3])[CH3:2])[CH:9]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C1C(=O)OC2(C#Cc3ccccc3)C=CC(=O)CC12
Solvent: O
Solvent: ClCCl
Product: CC(=O)Cc1cc(OC(C)=O)ccc1C#Cc1ccccc1
Reaction time: 1 h

Procedure:
3-Acetyl-3a,7a-dihydro-7a-(phenylethynyl)benzofuran-2,5(3H,4H)dione, the product of Example 1A, (10.0 g, 34 mmole) and acetic anhydride (25 mL) were placed in a 100 mL flask and heated at reflux overnight under argon. Heating was stopped and the reaction was treated with water (25 mL) and stirred for 1 hr. The reaction was poured into water and extracted with Et2O. The combined ether extracts were washed with water and saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to yield 9.4 g of crude product. Chromatography of the crude product over silica gel, using methylene chloride as eluent, gave 4.2 g of pure 1-[5-Acetoxy-2-(phenylethynyl)phenyl]-2-propanone product as a viscous oil.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([OH:17])[CH:14]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>O1CCCC1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH:15]([O:17][CH3:3])[CH:14]([N:18]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N(Cc2ccccc2)Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC1CN(C(=O)OC(C)(C)C)CC1N(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
0.19 g (0.0047 mole) of sodium hydride (as a 60% w/w dispersion in mineral oil) and 0.89 g (0.0063 mole) of methyl iodide were added, in that order, to a solution of 1.2 g (0.0031 mole) of 1-t-butoxycarbonyl-3-dibenzylamino-4-hydroxypyrrolidine [prepared as described in Step (1) above] dissolved in 10 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 5 hours. At the end of this time, water was added to the reaction mixture, which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, eluted with a 5:95 by volume mixture of ethyl acetate and toluene, to give 0.99 g of 1-t-butoxycarbonyl-3-dibenzylamino-4-methoxypyrrolidine as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N-:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.NN>C(O)C.[Ni]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH3:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: C[N-]S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)c1ccc(N)cc1
Reaction time: 1 h

Procedure:
To a solution of the crude 4-nitrobenzenesulfonyl methylamide prepared above in 45 mL of ethanol, was added a 1 mL slurry of Raney Nickel. Hydrazine monohydrate (18 mmol) was added slowly in several portions. A change in the solution colour from yellow to colourless indicated the reaction was complete. The mixture was stirred for an additional 1 hr. The solids were removed by filtration and the solvent was evaporated. The resulting crude material was purified by flash column chromatography eluting with CH2Cl2:MeOH=10:1 to yield 2.09 g (90% for two steps) of the title compound as a pale orange powder.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3](C)[CH:2]=1.[CH2:9]=O.[NH3:11]>>[NH3:11].[C:5]1([CH3:9])[C:6]([OH:7])=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: C=O
Agent: N
Product: Cc1ccccc1O

Procedure:
A mixture of 1.0 mole of p-cresol, 1.2 moles of formaldehyde and 0.2 mole of ammonia is heated on a water bath to form an ammonia-cresol base resin. A quantity (40 parts) of this resin and 60 parts of a bisphenol-A type epoxy resin (Epikote® 1007 manufactured by Shell Chemical) are dissolved in a mixed organic solvent made up of equal amounts of methyisobutyl ketone and methylethyl ketone to form a base resin solution. Next, a modified olefin resin of the type indicated in Table 1 is dissolved in hot xylene to form a 10% solution. This solution is added to the base resin solution with sufficient agitation so that the amount of the modified olefin resin added to the base resin is as indicated in Table 1. In this way, a primer coating composition having a total solids content of about 30% is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH:31]C(OC(C)(C)C)=O)([CH3:7])[CH3:6])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:30][NH2:31])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CN
Reaction time: 2.5 h
Yield: 133.7 %

Procedure:
A solution of 2-{2-(tert-butoxycarbonylamino-methyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester (350 mg, 0.650 mmol) in CH2Cl2 (10 mL) was treated at ambient temperature with TFA (4 mL) and stirred for 2.5 h. The solution was concentrated and co-evaporated with CCl4 (3×) to yield the title compound as a foam (381 mg, quantitative).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[CH:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)CCCC#CCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 23 mg, 0.58 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (171 mg, 0.64 mmol) in THF (2.0 mL) at 0° C. After 10 min at 0° C., the solution was allowed to warm to rt. After 50 min at rt, the solution was recooled to 0° C. and 7-(2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (crude, prepared in accordance with example 1, step 4, ˜0.64 mmol) in THF (2.0 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with acetic acid (50% aqueous, 20 mL) and extracted with EtOAc (3×20 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel twice (1st CH2Cl2→2% MeOH/CH2Cl2, gradient and 2nd CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 51 mg (21%) of the title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]2([CH3:46])[CH3:45].Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:39]([CH3:44])([CH3:43])[CH2:38][CH2:37][C:36]([CH3:46])([CH3:45])[C:35]=4[CH:34]=3)[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(Cn3c(=O)c(C(=O)NCC(=O)O)c(O)n(C4CCCCC4)c3=O)ccc21
Reaction time: 8 h
Yield: 34.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (250 mg, 0.89 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (156 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (br. s., 1 H), 7.24 (dd, J=4.80, 3.28 Hz, 2 H), 6.98 (dd, J=8.21, 1.39 Hz, 1 H), 4.93 (s, 2 H), 4.66 (t, J=11.87 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.19-2.36 (m, 2 H), 1.79 (d, J=12.63 Hz, 2 H), 1.62 (s, 7 H), 1.01-1.37 (m, 15H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S@:20]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=O)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[I-].[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:30])([CH3:29])[CH2:12][C@:13]([CH2:19][S:20][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)([OH:18])[C:14]([F:17])([F:15])[F:16])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: Cc1ccc([S@](=O)C[C@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1ccc(SC[C@](O)(CC(C)(C)c2cc(Cl)cc3c2OCC3)C(F)(F)F)cc1
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a suspension of (S)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-((R)-toluene-4-sulfinylmethyl)pentan-2-ol (1.49 g, 3.23 mmol) and sodium iodide (1.45 g, 9.70 mmol) in 25 mL of anhydrous acetone at −40° C. was added a solution of trifluoroacetic acid anhydride (2.28 mL, 16.2 mmol) in 5 mL of anhydrous acetone via a syringe dropwise over 5 minutes. A greenish brown mixture was formed instantaneously. After 15 minutes, the reaction mixture was quenched with saturated aqueous sodium sulfite solution and neutralized with saturated aqueous sodium carbonate solution. The brown color disappeared and the crude was concentrated in vacuo to remove most of the acetone solvent. The resulting material was diluted with 50 mL of water and extracted with three 100 mL portions of ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford (S)-4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-1,1,1-trifluoro-4-methyl-2-p-tolylsulfanylmethylpentan-2-ol as a yellow oil (1.43 g, 99%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.N1C=CC=CC=1.[C:39](Cl)(=[O:42])[CH2:40][CH3:41]>C(OCC)(=O)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([C:39](=[O:42])[CH2:40][CH3:41])[CH2:18][CH2:19][CH3:20])[C:14]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:25][CH:26]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: CCCNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(OCCC)cc1
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCOc1ccc(C2=NN(C(=O)Nc3ccc(C(F)(F)F)cc3)CC2N(CCC)C(=O)CC)cc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To 2 g (4.5 mmole) of N-(4-trifluoromethylphenyl)-3-(4-propoxyphenyl)-4-(N-propylamino)-4,5,-dihydro-1H-pyrazole-1-carboxamide Example (586) dissolved in 25 ml of ethyl acetate and cooled to -5° C., was added 0.8 g (9 mmole) of pyridine and, finally, 0.8 g (9 mmole) of propionyl chloride was added. After 30 minutes, the reaction mixture was washed with water and brine, concentrated in vacuo, and chromatographed over silica gel using hexanes and ethyl acetate to yield 0.5 g of the desired compound, mp 152°-154° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:22]>CC#N>[C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:22])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)c1
Reactant: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)c2)COS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide (10.4 g, 28 mmol) in CH3CN (50 mL) at 0° C. was added RuO4 (0.5% in stabilized aq., 50 mg, 0.1% by weight) in H2O (10 mL) amd NaIO4 (8.9 g, 41.5 mmol, 1.5 eq) in H2O (35 mL). The mixture was stirred at RT for 2 h. The mixture was partitioned between Et2O (200 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layer was dried (Na2SO4), and concentrated to give 10.8 g (100%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) as a white solid (˜10.8 g, yield: 100%). 1H NMR (CDCl3) 7.56 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.41 (dd, J1=9.3 Hz, J2=20.4 Hz, 2H), 2.01 (s, 3H), 1.39 (s, 9H).