Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[O:15]C)[CH3:2]>C(Cl)Cl>[OH:15][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCOC(=O)Cc1ccc(CC)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(CC)c(O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.1 %

Procedure:
A solution of ethyl 4-ethyl-3-methoxyphenylacetate (4f; 3.0 g; 13.50 mmol) and CH2Cl2 (80 mL) cooled to −78° C. and a solution of (5.10 mL; 53.94 mmol; 1.0 M in CH2Cl2) over 30 min. After 1 at −78° C. the reaction was allowed to warm to rt and stirred for 12 h. The reaction was cooled in an ice-water bath and the reaction quenched with 20 mL of water. The aqueous phase was extracted with CH2Cl2:EtOAc (4:1 v/v), dried (Na2SO4), filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with a CH2Cl2:EtOAc gradient (100:1→100:4) to yield 5b (2.0 g; 71%): m.s. 209.2 (M+H)+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 130.8 %

Procedure:
To a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.23 mmol) in dioxane (35 ml) and water (2.0 ml) was added 2-bromopyridine (2.9 g, 18.35 mmol), K3PO4 (3.8 g, 17.90 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol), and the resulting mixture was allowed to react with stirring for 3 hours at 90° C. The reaction mixture was diluted with water (180 ml) and extracted with ethyl acetate (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as pink oil (1.1 g, 70%).
Reaction SMILES: [Br:1][C@@H:2]1[C@@H:8]2[CH2:9][C@@H:5]([C:6](=[O:10])[O:7]2)[CH2:4][CH2:3]1.[CH3:11][NH:12][CH3:13].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[OH:7][C@@H:8]1[C@@H:2]([Br:1])[CH2:3][CH2:4][C@H:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:10])[CH2:9]1
Reactant: CNC
Reactant: O=C1O[C@H]2C[C@@H]1CC[C@@H]2Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@H]1CC[C@H](Br)[C@@H](O)C1
Reaction time: 14 h
Yield: 90 %

Procedure:
Ethyl acetate (1250 ml) was cooled to 5° C., and (1S,4S,5S)-4-bromo-6-oxabicyclo[3.2.1]octan-7-one (250 g) was then added thereto. Thereafter, a 50% dimethylamine aqueous solution (382 ml) was added to the above obtained solution, and the obtained mixture was then stirred for 14 hours. Thereafter, citric acid (234.2 g), 20% saline (500 ml), and ethyl acetate (625 ml) were added to the reaction mixture, and the obtained mixture was then stirred for 30 minutes, so that the organic layer was separated. Further, the aqueous layer was extracted with ethyl acetate (1875 ml). The organic layers were gathered, and the gathered organic layer was then concentrated to 1250 ml. Thereafter, water (500 ml) was added to the concentrated solution, and the mixed solution was then concentrated again to obtain the title compound (274.5 g, yield: 90%) in the form of an aqueous solution (625 ml).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[C:7]([NH:17][CH2:18][C:19](O)=[O:20])([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C=O>[C:11]1([CH2:10][O:9][C:7](=[O:8])[NH:17][CH2:18][C:19](=[O:20])[NH:1][N:2]2[CH:6]=[CH:5][CH:4]=[CH:3]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: Nn1cccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CNC(=O)OCc1ccccc1)Nn1cccc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 18.8 %

Procedure:
To a solution of 1-aminopyrrole (2.46 g) and carbobenzyloxyglycine (6.28 g) in 120 ml of dry DCM and 10 ml of dry dimethylformamide was added DCC (8.00 g). The reaction mixture was stirred at room temperature over a period of 64 hours. The precipitate was removed by filtration and stirred in boiling ethyl acetate. The mixture was filtered and the filtrate was combined with the filtrate of the reaction mixture and evaporated to dryness. The residue was purified by flash column chromatography (silica gel, DCM/methanol 20:1) yielding a first fraction (2.97 g) which was contaminated by DCU. A second fraction recrystallized from ethyl acetate afforded 1.54 g of the product as crystals, m.p. 146°-147° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.[CH:11](I)([CH3:13])[CH3:12]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([O:8][CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: COc1ccc(Br)cc1O
Reactant: CC(C)I
Product: COc1ccc(Br)cc1OC(C)C
Yield: 86 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference Example 7-(a) except for using 10.1 g (49.8 mmol) of 5-bromo-2-methoxyphenol, and using 15 ml of isopropyl iodide in place of 1-bromo-2-chloroethane, whereby 10.4 g of the title compound was obtained as a pale yellowish solid. (Yield: 86%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-])=O)=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].CCO.[Cl-].[NH4+]>[Zn].O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:3]=1[NH2:9]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Nc1cccc(Cl)c1N
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-chloro-2-nitroaniline (684 mg) and EtOH (5 mL) were added ammonium chloride (353 mg) and water (1.5 mL), followed by adding zinc powder (1.38 g) at 80° C., and heating and stirring at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature, filtered over Celite, and washed with EtOAc. This filtrate was washed with a saturated aqueous NaHCO3 solution and brine in this order, dried over MgSO4, and then concentrated under reduced pressure to obtain 3-chlorobenzene-1,2-diamine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
A solution of 0.65 g (5.4 mmol) 4-hydroxybenzaldehyde, 0.94 g (5.3 mmol) of 2-quinolinylmethylchloride, and 0.75 g (5.4 mmol) of potassium carbonate in 15 ml of DMF is heated at 60° C. overnight. The reaction mixture is poured into water. The precipitated product is collected on a filter and purified by dry column chromatography to give 4-(2-quinolinylmethyloxy)benzaldehyde.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].C([O-])([O-])=O.[K+].[K+].Cl[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][C:21]([N+:28]([O-:30])=[O:29])=[CH:20][N:19]=1>C1COCC1>[C:1]([CH:3]([C:18]1[C:23]([C:24]([F:26])([F:27])[F:25])=[CH:22][C:21]([N+:28]([O-:30])=[O:29])=[CH:20][N:19]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C#N)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Reaction time: 10 h
Yield: 97.7 %

Procedure:
To a solution of tert-butyl 2-cyanoacetate (523 mg, 3.71 mmol) in THF (15 mL) was added K2CO3 (854 mg, 6.18 mmol). Then 2-chloro-5-nitro-3-(trifluoromethyl)pyridine (700 mg, 3.09 mmol) was added into the mixture and the mixture was at 50° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative TLC (DCM/MeOH=20:1, Rf=0.4) to yield a light yellow solid of tert-butyl 2-cyano-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)acetate (1 g, 3.02 mmol, 98.0% yield): 1H NMR (400 MHz, CD3OD) δ 8.99 (d, J=2.43 Hz, 1H), 8.36 (d, J=2.43 Hz, 1H), 3.35 (s, 1H), 1.49 (d, J=1.54 Hz, 9H); ES-LCMS m/z 276 (M−55).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH2:16][OH:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:17][CH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:10]1[N:9]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C[C@H](N[C@H]1CCCC[C@@H]1CO)c1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO

Procedure:
A solution of (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) (339.1 g) dissolved in acetonitrile (2.2 L) was charged to a reactor followed by ethyl bromoacetate (12) (234.2 mL) and anhydrous sodium carbonate (224.2 g) under nitrogen. The contents were heated to reflux temperature for NLT 18 hours with vigorous agitation. Acetonitrile was distilled under vacuum to about 1 L volume, cooled to <30° C. and diluted with 0.75 L of heptanes and 1.0 L of water. The aqueous layer was separated and extracted with heptanes (2×0.75 L), and the combined organic layers were washed with water (0.75 L) followed by 0.75 L 3.5 M aqueous sodium chloride solution. The heptane layer was dried with anhydrous magnesium sulfate and concentrated under vacuum to afford 557.8 g of ethyl 2-((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino) acetate (13) as the major isomer.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=2[OH:21])[C:15]([OH:17])=[O:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[H][H]>O1CCCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH:8]=[C:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:6]=1[OH:26])[NH:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[OH:21])[C:15]([OH:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)C1=CC(=Nc2cc(C(=O)O)ccc2O)C=C(C(C)(C)C)C1=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(Nc2cc(C(=O)O)ccc2O)cc(C(C)(C)C)c1O
Yield: 63.6 %

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)-4-hydroxybenzoic acid, 0.05 g of 5% palaldium on charcoal catalyst, 250 ml of ethanol and 50 ml of tetrahydrofuran was placed on a Paar apparatus. Hydrogen uptake was complete in about 10 minutes. The reaction mixture was filtered to remove catalyst. The filtrate was evaporated to give a tan solid which was recrystallized from a mixture of 40 ml of ethanol and 15 ml of water to give 3.2 g of reddish tan granular 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)-4-hydroxybenzoic acid, m.p. 254.5°-255° C. (dec). Analysis: Calculated for C21H27NO4 : % C, 70.6; % H, 7.6; % N, 3.9; Found: % C, 71.0; % H, 7.6; % N, 4.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34](OS(C(F)(F)F)(=O)=O)[CH:35]=[CH:36][CH:37]=1)[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH3:13])=[N:7]2.[CH3:47][N:48](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:46])[N:5]([C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=1)[C:47]#[N:48])[C:6]([CH:12]([NH:14][C:15]1[N:23]=[CH:22][N:21]=[C:20]3[C:16]=1[N:17]=[CH:18][N:19]3[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH3:13])=[N:7]2
Reactant: CN(C)C=O
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(OS(=O)(=O)C(F)(F)F)c3)c(=O)c12
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(C#N)c3)c(=O)c12
Temperature: 120 °C
Yield: 66 %

Procedure:
A 5-mL reaction vial equipped with a magnetic stirrer was charged with compound 138 (200 mg, 0.300 mmol), tetrakis(triphenylphosphine)pallasium (34.0 mg, 0.029 mmol), zinc cyanide (70 mg, 0.60 mmol) and anhydrous DMF (1 mL). The vial was purged with nitrogen, heated to 120° C. for 3.5 h then cooled to ambient temperature and poured into a saturated aqueous sodium bicarbonate solution (25 mL). The resulting suspension was extracted with methylene chloride (3×20 mL), and the organic extracts were combined, dried over sodium sulfate and filtered. Concentration of the filtrate followed by purification by column chromatography gave a 66% yield of compound 141 as a white solid. 1H NMR (CDCl3) δ (ppm) 8.30 (d, 1H, J=6.9 Hz), 7.58-8.02 (m, 7H), 7.30 (d, 1H, J=7.0 Hz), 5.60 (s, 2H), 5.07 (bs, 1H), 3.65 (m, 2H), 2.84 (s, 3H), 1.58 (d, 3H, J=6.7 Hz), 0.96 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=2)=[CH:5][C:6]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccsc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)Cc1cc(C(=O)c2ccc(I)c([N+](=O)[O-])c2)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of 230 mg (1 mmol) methyl (2-bromothiophene-3-yl)acetate and 310 mg (1 mmol) 4-iodo-3-nitrobenzoyl chloride in 15 mL of dry CH2Cl2 was added 432 mg of AlCl3 (4 mmol) in four portions at room temperature. The resulting mixture was stirred overnight. The reaction mixture was slowly poured onto 5 g of ice and allowed to warm to room temperature. The organic layer was dried over MgSO4, filtered, and then concentrated in vacuo. The residue was purified by flash chromatography. (Hex/EtOAc=1:5) to give 310 mg of product as a light yellow solid (yield 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13][CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
Cool a solution of 3-(3,4-dichlorophenyl)-2-propeneoic acid (100 g, 461 mmol) in dry DMF (500 mL) to 0° C. and treat with Cs2CO3 (100 g, 307 mmol). Stir the resulting off-white slurry for 15 min., then add CH3I (33 mL, 530 mmol) via syringe. After 1 h, add additional DMF (250 mL) and stir the slurry for 14 h, then partition between ethyl acetate (EtOAc) (1.5 L) and half saturated aqueous NaHCO3 (500 mL). Separate the organic layer and extract the aqueous layer with EtOAc (1 L, 500 mL). Wash the combined organic layers with half saturated aqueous NaHCO3 (500 mL) and water (5×500 mL), then dry over Na2 SO4 and concentrate to obtain methyl 3-(3,4-dichlorophenyl)-2-propenoate, 105.4 g (456 mmol, 99%, as light brown needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O-:12][CH2:13][CH3:14].[Na+]>C(O)C.C(Cl)Cl>[CH2:13]([O:12][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To 4-bromo-2-fluoro-1-nitrobenzene (8.2 g, 37.27 mmol) in 50 mL of ethanol was added 21% by weight sodium ethoxide (16.4 mL, 52.2 mmol). The mixture was stirred at 60° C. for 1 h. The EtOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (MgSO4), filtered, and rotovaped down to give the title compound of step A (9.14 g, 37.14 mmol, 99.7%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.71 (d, J=8.61 Hz, 1H), 7.20 (d, J=1.83 Hz, 1H), 7.14 (dd, J=8.61, 1.83 Hz, 1H), 4.16 (q, J=7.02 Hz, 2H), 1.47 (t, J=6.96 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.O.[CH3:19]O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:19])=[O:6]
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CO
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred suspension of 3-methyl-4-nitrobenzoic acid (100 g, 0.55 mole) in methanol (400 mL) was added thionyl chloride (36 g, 0.30 mole), over a period of 1 hour (the temperature of the reaction mixture rising to about 35°-40° C.). The mixture was heated to reflux for 1.5 hours, then cooled to 50°-55° C. and maintained at this temperature for 30 minutes prior to cooling to ambient temperature. Water (100 mL) was added over 30 minutes, with cooling applied to maintain the temperature at 20°-25° C. Filtration was followed by washing of the solid with water (100 mL twice), and drying at 40° C. under vacuum, to afford 103 g (95%) of methyl 3-methyl-4-nitrobenzoate as a yellow solid; mp 83°-85° C.; NMR (250 MHz, CDCl3): 2.62 (s, 3H, ArCH3), 3.98 (s, 3H, CO2CH3), 8.01 (m, 3H).
Reaction SMILES: [CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C:9](=[O:12])[CH2:10][Cl:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>C(O)C>[CH2:1]([C@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@H:9]([OH:12])[CH2:10][Cl:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)C(=O)CCl
Agent: Cl
Solvent: CCO
Solvent: O
Product: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Yield: 90.3 %

Procedure:
33.06 g of lithium aluminum tri-tert.-butoxyhydride were added portionwise at -15° C. to a suspension of 25.57 g of methyl (S)-(1-benzyl-3-chloro-2-oxo-propyl)-carbamate in 280 ml of ethanol and the mixture was subsequently hydrolyzed at 0° C. with 140 ml of 3N hydrochloric acid and 170 ml of water. The suspension was concentrated to 370 ml, filtered and the residue was washed with water/ethanol (4:1) and dried, there being obtained 23.27 g (90%) of isomerically-pure methyl (1S,2S)-(1-benzyl-3-chloro-2-hydroxy-propyl)-carbamate, m.p. 163°-164.5° C. IR (KBr): 3323s, br. (NH, OH), 1689 (C=O), 1546s (amide II).
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: CN1CCOCC1
Solvent: CN(C)C=O
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: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.[CH2:11](O)[CH2:12][OH:13].C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:13][CH2:12][CH2:11][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: CCOC(OCC)OCC
Product: Fc1cc(Br)ccc1C1OCCO1

Procedure:
4-bromo-2-fluorobenzaldehyde (9.4 g, 46.3 mmol), ethylene glycol (13.2 mL), triethyl orthoformate (6.6 mL) and p-toluenesulfonic acid (0.09 g, 0.473 mmol) were stirred in DCE (50 mL) at 80° C. for 2.5 hours. Room temperature was attained and the solution was washed successively with saturated NaHCO3, H2O and brine, dried over MgSO4 and concentrated in vacuo to give the product (pale yellow oil). 1H NMR (CDCl3) δ 7.41 (t, J=8.1 Hz, 1H), 7.30 (dd, J=8.1, 1.8 Hz, 1H), 7.25 (dd, J=9.6, 1.8 Hz, 1H), 6.02 (s, 1H), 4.13 (m, 2H), 4.04 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](ON)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Yield: 98.2 %

Procedure:
Following a procedure analogous to Example 27, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (R)-tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (606 mg) described in Reference Example 13, 904.6 mg of the title compound was afforded (yield 98.3%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([NH:1][C:2]2[S:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:18]([N+:24]([O-:26])=[O:25])[CH:19]=1
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Product: CCOC(=O)c1c(Nc2ccc(C)cc2[N+](=O)[O-])sc2ccccc12
Yield: 100.9 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (4.0 g), 4-fluoro-3-nitrotoluene (3.3 g) and dimethyl sufoxide (55 ml), ethyl 2-(4-methyl-2-nitroanilino)benzo[b]thiophene-3-carboxylate (6.5 g) was obtained.