Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.[CH3:29]O.[BH4-].[Li+].Cl>O1CCCC1.O>[CH:21]1([CH:20]([NH:19][N:16]2[C:17](=[O:18])[C:12]([C:4]3[NH:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[S:2](=[O:1])(=[O:28])[N:3]=3)=[C:13]([OH:27])[C:14]3[S:26][CH:25]=[CH:24][C:15]2=3)[CH3:29])[CH2:22][CH2:23]1
Reactant: CO
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 269A (0.058 g, 0.14 mmol) in tetrahydrofuran (4 mL) and methanol (0.012 mL, 0.3 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.12 mL, 0.24 mmol). The reaction was stirred at 25° C. for 2 hour, acidified with 1 M hydrochloric acid a pH of approximately 2-4, diluted with water (20 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethane to dichloromethane/methanol (99:1) to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (m, 8 H) 2.44 (m, 1 H) 5.81 (d, J=2.57 Hz, 1 H) 7.23 (m, 3 H) 7.53 (m, 1 H) 7.64 (d, 1=7.72 Hz, 1 H) 7.74 (s, br, 1 H) 15.95 (s, 1 H). MS (ESI−) m/z 429 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.Cl.[NH:19]1[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]1[CH2:26][OH:27].C(=O)([O-])O.[Na+]>CC(C)=O.CC(C)=O.O.O>[Cl:8][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=[C:2]([N:19]2[C@@H:23]([CH2:24][OH:25])[CH2:22][CH2:21][C@H:20]2[CH2:26][OH:27])[N:7]=1
Reactant: OC[C@@H]1CC[C@H](CO)N1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(Cl)n2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,4-dichloro-6-(4-nitrophenyl)-1,3,5-triazine (2.2 g, 8.0 mmol) in acetone (40 mL) was added to magnetically stirred ice water (60 mL). The mixture was treated with a solution of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (1.0 g, 6.0 mmol) in acetone/water (20 mL, 3:1), followed by a suspension of sodium hydrogen carbonate (1.0 g, 12 mmol) in water (12 mL). After 30 minutes of stirring at 0° C., the mixture was treated with an additional quantity of (2S,5R)-pyrrolidine-2,5-diyldimethanol hydrochloride (0.26 g, 1.6 mmol) in water (3 mL), followed by sodium hydrogen carbonate (0.35 g) in water (5 mL). The suspension was allowed to stir overnight while regaining room temperature. The title compound was isolated by Buchner filtration, washed with water, and dried under house vacuum. Compound identification by mass spectrometry was achieved via the analysis of the product reaction product of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol with excess morpholine in ethanol. MS (ES+)=417.2 (M+morpholine−Cl)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[CH2:14][NH2:15].[CH:16](OCC)=[O:17]>C1(C)C=CC=CC=1>[CH:16]([NH:15][CH2:14][CH:9]1[C:10]2[C:5](=[C:4]([O:3][CH3:2])[CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)=[O:17]
Reactant: COc1cccc2c1CCCC2CN
Reactant: CCOC=O
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCCC2CNC=O

Procedure:
The product from Example 14 was converted to its free base (3.4 g) and dissolved into toluene (30 ml). Ethyl formate (5 ml) was added and the reaction stirred at reflux for 5 hr. The solvent was removed to afford a solid. Recrystallization from Et2O/CH2Cl2 afforded 3.07 g of desired product. Anal. calcd. for C13H17NO2 ; C, 71 21; H, 7.81; N, 6.39. Found: C, 71.26; H, 7.82; N, 6.41.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10]
Reactant: OCCOCCOCCCl
Reactant: CNC
Product: CN(C)CCOCCOCCO
Temperature: 25 °C
Reaction time: 30 h

Procedure:
Commercial Cl(CH2CH2O)3H (abb. ClE3H) (2.0 mole) and dimethylamine (20.0 mole) were mixed in a flask (3.0 l) fitted with a condenser and stirred (RT) for 30 hours. TLC (Si-gel) examination showed the complete consumption of the ClE3H. Excess dimethylamine was removed by two consecutive evaporations under reduced pressure. The residual material was reconstituted in CHCl3, dried (MgSO4), filtered and evaporated to dryness to produce the product, 8-dimethylamino-3,6-dioxaoctanol.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH:23]([OH:25])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])=[CH:15][CH:14]=3)=[O:9])=[CH:26][CH:27]=1
Reactant: CC(O)C#Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Agent: C#C
Solvent: ClCCl
Solvent: CO
Product: CC(O)CCc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 2.17 h
Yield: 28 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-butynyl)-3-quinolinecarboxamide from Example No. 152 (106.3 mg) and Pd/C (10%, 21.3 mg) is dissolved in 40 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 34 psi H2 and monitored by mass spectroscopy for complete reduction of the acetylene. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction is taken off the Parr. In this case, the reaction is taken off the Parr twice. The reaction is complete in 130 min . The reaction mixture is filtered over celite to remove the palladium. The filtrate is condensed to obtain a solid. The crude product is adsorbed onto silica and chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 30.0 mg (28%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]2[N:9]=[N:8][NH:7][C:6]=2[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl.ClCCl>[Br:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)[C:6]=2[CH:10]=1
Reactant: Fc1ccc(Oc2cc3nn[nH]c3cc2Br)c(F)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(Oc2cc3nnn(C4CCCCO4)c3cc2Br)c(F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-5-(2,4-difluorophenoxy)-1H-1,2,3-benzotriazole (0.047 g, 0.14 mmol) and p-toluenesulfonic acid monohydrate (0.0027 g, 0.014 mmol) in chloroform (0.65 mL) was treated with dihydropyran (0.0197 mL, 0.216 mmol) and stirred at 60° C. for 1 h. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The aqueous layer was separated and re-extracted with dichloromethane. The combined organic layers were separated, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated to a crude oil. Purification by flash column chromatography (100% hexanes to 60% EtOAc/hexanes) gave the desired product as a mixture of isomers that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[C:10]=1[SH:11])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C)C=O>C(#N)C>[CH2:24]([S:11][C:10]1[N:9]([C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)[CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1ncn(-c2nc(C)cs2)c1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(-c2nc(C)cs2)c1SCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture consisting of 4.2 g of 4-ethoxycarbonyl-1-(4-methylthiazol-2-yl)imidazole-5-thiol, 3.2 g of anhydrous potassium carbonate, 2.2 g of benzyl chloride, 20 ml of dimethylformamide and 100 ml of acetonitrile was stirred at room temperature for 2 hours. After the reaction, solid materials were separated by filtration, and the filtrate was condensed under reduced pressure to obtain crude 5-benzylthio-4-ethoxycarbonyl-1-(4-methylthiazol-2-yl)imidazole as oily product. The resulting oily product was dissolved in 100 ml of chloroform and after addition of 13 g of conc. hydrochloric acid and 30 ml of water, 28 g of a 10% sodium hypochlorite solution was added dropwise to the mixture at -10° C. to -5° C. over 15 minutes. After the reaction mixture was stirred at 0° C. or lower for 20 minutes, an organic layer was separated and an aqueous layer was extracted with chloroform. After the organic layers were combined and washed with water, 60 ml of tetrahydrofuran was added to the organic layer and then 20 ml of a 28% aqueous ammonia was added dropwise under icc-cooling, and the mixture was stirred at room temperature for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, ethyl acetate and water were added thereto, an organic layer was separated and an aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried, and then concentrated under reduced pressure to obtain oily product. The resulting oily product was identified as 5-benzylsulfinyl-4-ethoxycarbonyl-1-(5-chloro-4-methylthiazol-2-yl)imidazole by NMR and MS analyses.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:21]C)=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=[O:20])[CH2:10]2)[CH:8]=1.O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([OH:21])=[C:7]([CH:9]2[CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=3[C:11](=[O:20])[CH2:10]2)[CH:8]=1
Reactant: COc1ccc(F)cc1C1CC(=O)c2c(C)ccnc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccnc2c1C(=O)CC(c1cc(F)ccc1O)C2
Yield: 43 %

Procedure:
To 7-(5-fluoro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one hydrochloride (2.13 g) were added water (20 ml), anhydrous potassium carbonate (1.5 g) and ethyl acetate (50 ml). The mixture was shaken, and the separated upper layer was concentrated under reduced pressure. The residue was dissolved in dichloromethane (15 ml), and to the solution was added dropwise a solution of 1M-boron tribromide-dichloromethane (21 ml), while stirring in ice-cooling bath. The bath was removed, and the mixture was stirred for 2 hours, and poured onto ice-water. To the mixture was added excess amount of sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified with silica gel column chromatography to give 7-(5-fluoro-2-hydroxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.773 g).
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]/[CH2:8][CH:9]([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])CCC.[I:30]I>CCOCC>[I:30]/[CH:6]=[CH:7]/[CH2:8][CH:9]([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: II
Reactant: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Solvent: CCOCC
Product: CCCCC(C/C=C/I)O[Si](CC)(CC)CC

Procedure:
To a solution of E-1-tri-n-butystannyl-4-triethylsilyloxy-1-octene (11 g) in 200 ml ether is added 0.9 equivalents of iodine in one portion. After 25 minutes the color of the iodine has disappeared. An additional 0.1 equivalents of iodine is added in portions until the iodine color persists. The ether is removed in vacuo to provide (E)-1-iodo-4-triethylsilyloxy-1-octene. This residue is placed on a silica-gel column (240 g SilicAR CC-7) packed in hexane. A liter fraction of hexane contains 7.5 g of mostly tri-n-butylidostannane. A 500 ml elution of benzene gives only a small amount of material. An elution with 600 ml of ether provides 7.0 g of 1-iodo-4-hydroxy-1-octene as an oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16](=[O:33])[C@@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:18][CH2:19]SC)[C@H:11]([CH2:34][CH2:35][CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+]>IC>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]2=[O:33])[C@H:11]([CH2:34][CH2:35][CH3:36])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCC[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 30 °C
Reaction time: 72 h
Yield: 24.7 %

Procedure:
A sample of benzyl (S)-1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-propylcyclohexylamino)-4-(methylthio)-1-oxobutan-2-ylcarbamate (4.0 g, 7.45 mmol) was dissolved in iodomethane (8 mL) and stirred at 30° C. for 3 days. The solution was concentrated in vacuo. The residue was dissolved in methylene chloride and the resultant solution was concentrated in vacuo again; this procedure was repeated twice before the residue was placed under high vacuum for 4 h. The resultant pale yellow foam solid was dissolved in THF (40 mL) and the resultant solution was cooled to 0° C. before being treated with sodium hydride (0.9 g, 37 mmol) in one portion. The mixture was slowly warmed to 30° C. and stirred for 12 h before being quenched with saturated ammonium chloride. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl (S)-1-((1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-propylcyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (0.9 g). MS found: (M+H)+=489.2.
Reaction SMILES: [Si]([N:8]1[C:11](=[O:12])[CH2:10][CH:9]1[CH2:13][CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(C(C)(C)C)(C)C.C([O:30]O)(C)(C)C>C(O)(=O)C.[Na+].[Na+].Cl[Pd+2](Cl)(Cl)Cl>[O:30]=[C:14]([CH2:13][CH:9]1[CH2:10][C:11](=[O:12])[NH:8]1)[CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)(C)OO
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC=CC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CC(=O)OCc1ccccc1)CC1CC(=O)N1
Temperature: 55 °C
Reaction time: 11 h

Procedure:
To a solution of benzyl 4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate (50 mg) in 60% aqueous acetic acid (1.5 ml) were added tert-butyl-hydroperoxide (40 μl) and sodium tetrachloropalladate (18 mg). The solution was heated at 55° C. for 5.5 hours. Additional tert-butyl-hydroperoxide (100 μl) and sodium tetrachloropalladate (18 mg) were added and stirring at 50° C. was continued for further 11 hours. After evaporation of the solvent in vacuo, the residue was taken up into ethyl acetate and washed in turn with water (twice) and brine. Drying over magnesium sulfate and removal of the solvent left an oil (30 mg) which was chromatographed on a silica gel plate (developing solvent: 25% acetone in benzene) afforded benzyl 3-oxo-4-[(2RS)-4-oxoazetidin-2-yl]butanoate (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH2:4][Mg]Cl.[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][O:22][CH:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([OH:26])[CH2:4][C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Fc1cccc(Cl)c1C[Mg]Cl
Solvent: C1CCOC1
Product: OC(Cc1c(F)cccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirred solution of 2-chloro-6-fluorobenzyl magnesium chloride (12.8 mL, 3.20 mmol, 3 equiv., available from Rieke Metals) in anhydrous tetrahydrofuran (15 ml) at 0° C. under nitrogen was added a solution of (4-Benzyl-morpholin-2-yl)-phenyl-methanone (300 mg, 1.07 mmol, 1 equiv.) in tetrahydrofuran (5 ml) dropwise over 15 minutes. The reaction was then stirred at 0° C. for one hour. The reaction mixture was allowed to warn to room temperature over two hours and stirred for a further 18 h. The solvent was then evaporated “in vacuo” and the residue redissolved in dichloromethane (30 mL). The organic solution was washed with aqueous saturated solution of NaHCO3 (50 mL). The aqueous solution was extracted with dichloromethane using a hydrophobic phase separator. The dichloromethane was evaporated “in vacuo” and redissolved in methanol (2 mL). The sample was bound to SCX-2 (5 g) and washed with methanol (30 mL). The sample was eluted using 2M ammonia in methanol (30 mL). The solvent was then evaporated using a reacti-therm blow down station to give 450 mg of a yellow amorphous solid. This material was used in step b) without further purification. LCMS (6 minutes method) [M+H]+=426 @ Rt 3.27 min. major peak.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].O1CCOCC1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(F)cc1Cl
Yield: 85 %

Procedure:
Combine 4-fluoro-3-nitroaniline (1.0 g, 6.4 mmol) with dioxane (20 mL). Treat mixture with 2-chloro-4-fluorobenzoyl chloride (1.6 g, 8.3 mmol). Stir the reaction overnight at room temperature. Transfer the reaction mixture into ethyl acetate (220 mL), then wash successively with aqueous HCl (1N, 50 mL), aqueous NaOH (1N, 50 mL), saturated aqueous NaCl (50 mL). Dry the organic layer over anhydrous sodium sulfate, then evaporate the solvent under reduced pressure. Further purify the residue by chromatography on silica gel, using a gradient of 10-30% ethyl acetate in hexanes to obtain the title intermediate (1.7 g, 85% yield): mass spectrum (ion spray): m/z=313.0 (M+1).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[F:2].[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]([CH2:4][CH:3]([OH:5])[CH2:1][F:2])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCNCc1ccccc1
Reactant: FCC1CO1
Solvent: CCO
Product: OCCN(Cc1ccccc1)CC(O)CF
Yield: 95.2 %

Procedure:
A solution of 22.20 g (0.3 mole) of epifluorohydrin and 67.95 g (0.45 mole) of N-benzylethanolamine dissolved in 200 ml of ethanol was heated under reflux for 5 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel using ethyl acetate as the eluent, to give 64.93 g of N-benzyl-N-(3-fluoro-2-hydroxypropyl)ethanolamine as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:38][CH2:37][CH2:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:4]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)CCNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 38.6 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 30 mg, 0.070 mmol),2-(methylsulfonyl)ethanamine (12.85 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide 2-hydroxy-N-(2-(methylsulfonyl)ethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (15 mg, 0.027 mmol, 38.2% yield) as a single enantiomer. LCMS=537.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (2 H, d, J=8.58 Hz), 7.54-7.74 (7 H, m), 5.14 (1 H, s), 3.73 (2 H, t, J=6.60 Hz), 3.35 (2 H, t, J=6.60 Hz), 2.97 (3 H, s); HPLC peak RT=9.3 min (Method A).
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]>O1CCCC1.[Pd]>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)c1ccc(N)cc1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
8.7 g of ethyl 2-methyl-2-(4-nitrophenyl)propanoate are dissolved in 90 ml of tetrahydrofuran, 2 g of 5% Pd/C (52.3% of water) are added, and the mixture is stirred at 23° C. under a hydrogen atmosphere for 1 h. After aeration, the solid material is filtered off, and the filtrate is evaporated to dryness in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Br[CH2:11][C:12]1[C:13]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[N:14][O:15][C:16]=1[CH:17]1[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]2[C:13]([C:20]3[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=3[Cl:26])=[N:14][O:15][C:16]=2[CH:17]2[CH2:19][CH2:18]2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Temperature: 80 °C
Yield: 90.2 %

Procedure:
A solution of 4-bromo-3-methyl-phenol (143 mg, 0.764 mmol) and 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (221 mg, 0.636 mmol) in dimethylformamide (1 mL) is treated with potassium carbonate (89 mg, 0.637-mmol). The reaction mixture is heated to 80° C. for 60 minutes and cooled to room temperature. The mixture is loaded directly onto a silica gel column and purified by flash chromatography eluting with 15% EtOAc/Hexanes. The fractions are combined to provide the title compound (0.26 g, 92%). LC-MS: (M+1);
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C1C=CC=CC=1>CO.[Pd]>[N:11]1([CH2:10][C:9]([OH:17])=[O:8])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(CN1CCCCC1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CN1CCCCC1

Procedure:
10.4 g (44 mMol) (piperidine-1-yl)-acetic acid-benzylester 9 was stirred with 0.25 g Pd/C (5%) in 100 ml Methanol at RT. Under normal pressure, the reaction mixture was reduced (hydrated) with H2. After having removed the catalyst, the solution was evaporated and the residue was resuspended in EtOAc and filtered off.