Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[C@@H:15]2[C@H:26](OCC3C=CC=CC=3)[C@H:12]1[C@@H:13]([O:35]C)[O:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>FC(F)(F)C(O)=O.O.O>[CH2:1]([O:8][C:9]([N:11]1[C@H:16]([CH2:17][OH:18])[C@H:15]([OH:14])[C@H:26]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:12]1[CH2:13][OH:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H]2[C@H](OCc3ccccc3)[C@@H]1N(C(=O)OCc1ccccc1)[C@@H]2CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)[C@H]1[C@@H](O)[C@@H](CO)N(C(=O)OCc2ccccc2)[C@H]1CO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 176.5 %

Procedure:
The compound (997 mg, 1.89 mmol) synthesized in Example 7 (7c) was dissolved in trifluoroacetic acid:water (4:1, 12 mL) and the mixture was stirred at room temperature for 15 minutes. After water (20 mL) was added to the reaction mixture at 0° C. and the mixture was extracted with dichloromethane (30 mL), the organic layer was washed with saturated aqueous sodium hydrogencarbonate (20 mL) and saturated brine (20 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was dissolved in ethanol (15 mL) and the compound obtained by dissolving sodium borohydride (35.7 mg, 0.10 mmol) in water (5 mL) was added thereto, followed by stirring of the mixture at 0° C. for 20 minutes. After saturated aqueous ammonium chloride (2 mL) was added to the reaction mixture at 0° C., ethanol was distilled off under reduced pressure. After water (15 mL) was added thereto and the mixture was extracted with ethyl acetate (15 mL), the organic layer was washed with saturated brine (15 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 2:1, V/V) to obtain the desired title compound (643 mg, yield 85%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C@@H:20]([CH2:23][CH3:24])[CH2:21]Br.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>CN(C=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:19][C@@H:20]([CH3:21])[CH2:23][CH3:24])=[CH:13][CH:12]=1)[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(O)cc1
Reactant: CC[C@H](C)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC[C@H](C)COc1ccc([C@H](CO)NC(=O)OC(C)(C)C)cc1
Temperature: 70 °C
Yield: 64.6 %

Procedure:
[(R)-2-Hydroxy-1-(4-hydroxy-phenyl)-ethyl]-carbamic acid t-butyl ester (10 mmol), (S)-2-methylbutyl bromide (2.60 g, 17 mmol) and Cs2CO3 (7.47 g, 23 mmol) were combined in DMF (50 ml). The reaction mixture was heated at 70° C. overnight. Saturated NH4Cl was added to quench the reaction. The aqueous layer was extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with brine, then dried over MgSO4, filtered and concentrated to give a white crude solid. The crude product was purified via column chromatography on silica gel (0%-50% ethyl acetate in hexanes) to afford the title compound (2.09 g, 65% yield of 3 steps) as a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (d, J=8.6 Hz, 2H), 6.90 (m, 2H), 5.13 (d, J=6.6 Hz, 1H), 4.73 (br. s., 1H), 3.83 (m, 3H), 3.74 (m, 1 H), 2.39 (br. s., 1H), 1.87 (m, 1H), 1.58 (m, 1H), 1.42 (m, 9H), 1.29 (m, 1H), 1.01 (m, 3H), 0.96 (m, 3H); LCMS (ESI) m/e 324.2 [(M+H), calcd for C18H30NO4 324.4].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[O:22]1[CH:26]=[CH:25][CH2:24][CH2:23]1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[N:12]=[CH:11][N:10]([CH:23]3[CH2:24][CH2:25][CH2:26][O:22]3)[C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: C1=COCC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(-c2ncn(C3CCCO3)c2-c2ccc(OC)cc2)cc1
Yield: 76.9 %

Procedure:
5.61 g of 4,5-bis(4-methoxyphenyl)imidazole is suspended in 150 ml of absolute 1,2-dichloroethane and combined with 2.8 g of 2,3-dihydrofuran as well as 0.2 ml of tin tetrachloride. The mixture is heated under agitation for 12 hours to 70°, allowed to cool, and poured into 200 ml of cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate, and concentrated under vacuum. The residue is dissolved in dichloromethane and subjected to a hexane precipitation. The precipitate is subjected to column chromatography on 250 g of aluminum oxide, neutral, activity stage II. Elution with ethyl acetate/hexane 2:3 yields 5.39 g of 4,5-bis(4-methoxyphenyl)-1-(tetrahydrofuran-2-yl)imidazole, which is obtained in the form of a foam after removal of the solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1C
Yield: 63.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.045 g (63%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCc1ccncc1
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) was heated at 80°-90° C. overnight. The reaction mixture was poured into water (200 ml)/NH4OH (1 ml) and the mixture was extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined, dried over MgSO4 and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191°-192° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[C:9]1([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[N:3]=2)=[O:23])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Brc1cccc(Sc2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=S(c1ccccc1)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-6-phenylsulfanyl-pyridine (0.5323 g, 2 mmol) was dissolved in CH2Cl2 (20 mL) and m-chloroperbenzoic acid (0.345 g, 2 mmol) was added. The reaction was stirred at room temperature overnight then submitted to aqueous workup and purification on silica gel to give the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][NH2:4].C(O/[CH:8]=[CH:9]/[C:10](=O)[C:11]([F:14])([F:13])[F:12])C.C(OCC)(=O)C.CCCCCC>C(O)C>[F:12][C:11]([F:14])([F:13])[C:10]1[CH:9]=[CH:8][NH:4][N:3]=1
Reactant: NN
Reactant: CCO/C=C/C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: FC(F)(F)c1cc[nH]n1

Procedure:
Hydrazine dihydrochloride (225 g, 2.14 mol) in ethanol (1400 mL) was stirred well. TEA (185.4 mL, 1.34 mol) was added drop wise for 45 min at ambient temperature. Then (E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (225 g, crude) was added drop wise at room temperature and the overall reaction mixture was refluxed overnight. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.4). On completion of the reaction, ethanol was distilled off completely, residue was taken in ice water (500 mL) and the product extracted with ethyl acetate (2×400 mL). Combined extract was washed with ice water (300 mL), dried over sodium sulfate and concentrated under reduced pressure to yield 3-(trifluoromethyl)-1H-pyrazole as a off white solid (175 g, crude).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=1)(=[O:11])=[O:10]>CO.C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=1)(=[O:11])=[O:10]
Reactant: Nc1ccc(OS(=O)(=O)c2c(Cl)cccc2Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(OS(=O)(=O)c2c(Cl)cccc2Cl)cc1N
Yield: 49 %

Procedure:
To a solution of 2 g of 4-amino-3-nitrophenyl 2,6-dichlorobenzenesulfonate in 85 cm3 of methanol and 33 cm3 of pure acetic acid are added 2.25 g of iron powder. The reaction medium is refluxed for three hours. The insoluble material is filtered off and washed with three times 10 cm3 of preheated methanol. The filtrate is evaporated to dryness under reduced pressure (2 kPa) at a bath temperature of 50° C. The residue is taken up in 50 cm3 of water and then brought to pH 8-9 with sodium hydrogen carbonate and extracted with five times 80 cm3 of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure (2 kPa). After flash chromatography on a column of silica [eluent: dichloromethane/methanol (98/2 by volume)], 900 mg of 3,4-diaminophenyl 2,6-dichlorobenzenesulfonate are obtained in the form of orange crystals, the characteristics of which are as follows:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=2[CH2:19][CH3:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])[N:10]=2
Reactant: N#C[S-]
Reactant: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc(N)cn1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CCc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
Potassium thiocyanate (972 mg, 10 mmol) was suspended in acetic acid (20 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-ethylphenyl}-3-(1-cyano-1-methylethyl)benzamide (1.0 g, 2.50 mmol) in acetic acid (20 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 15 min. A solution of bromine (439 mg, 2.75 mmol) in acetic acid (14 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and washing solution were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (250 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100), and the obtained solution was concentrated under reduced pressure to give the title compound (1.0 g, 87%) as a pale-yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O.[CH2:28]([C:30](=[CH2:33])[CH:31]=O)[CH3:29]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:6]([CH:31]=[C:30]([CH2:28][CH3:29])[CH:33]=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: C=C(C=O)CC
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: CCc1cnc2cc(Br)ccc2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a well-stirred mixture consisting of 3-bromo-aniline (5.40 g, 31.4 mmol), sodium 3-nitro-benzene sulfonate (4.25 g, 18.9 mmol), 8.5 g (177 mmol) of concentrated sulfuric acid, and 3.2 ml of water heated to 100° C., 2-ethyl acrolein (5.0 ml, 51 mmol) was added. After maintaining the reaction temperature at 100° C. for 1 hour, the temperature was elevated to 110° C. An additional portion of 2-ethyl acrolein (1.0 ml, 10.2 mmol) was added, and the reaction was stirred at 110° C. for 1 hour. The reaction temperature was then elevated to 120° C. prior to addition of another 1.0 ml (10.2 mmol) portion of 2-ethyl acrolein. After heating the reaction at 120° C. for 1 hour, the temperature was increased to 130° C. prior to addition of 1.0 ml (10.2 mmol) of 2-ethyl acrolein. Finally, the reaction temperature was raised to 140° C. and maintained at that temperature for 2 hours after addition of a final portion (1.3 ml, 13.2 mol) of 2-ethyl acrolein. The cooled reaction was quenched with ice (50 g), and the pH of the resulting mixture was adjusted to by addition of 6 N aqueous sodium hydroxide. The mixture was then extracted with two 30 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo, affording an amber oil. Flash chromatography of the entire sample utilizing the Biotage Flash 401i™ silica gel flash chromatography module and manufacturer's prepacked silica gel cartridges described in Example 1, Step 4, and eluting with methylene chloride, afforded the title compound (1.46 g, 19.7% yield) as a viscous light amber syrup which solid on standing.
Reaction SMILES: CC1N=C(C(O)C=C)C=CC=1.S(Cl)(Cl)=O.ClC(C1C=CC=C(C)N=1)C=C.[C-]#N.[Na+].[CH3:30][C:31]1[N:36]=[C:35]([CH:37]([CH:40]=[CH2:41])[C:38]#[N:39])[CH:34]=[CH:33][CH:32]=1.[SH2:42]>>[CH3:30][C:31]1[N:36]=[C:35]([CH:37]([CH:40]=[CH2:41])[C:38]([NH2:39])=[S:42])[CH:34]=[CH:33][CH:32]=1
Reactant: S
Reactant: C=CC(C#N)c1cccc(C)n1
Agent: C=CC(Cl)c1cccc(C)n1
Agent: C=CC(O)c1cccc(C)n1
Agent: [C-]#N
Solvent: O=S(Cl)Cl
Product: C=CC(C(N)=S)c1cccc(C)n1

Procedure:
By the procedures described in Example 9, α-(6-methyl-2-pyridyl)-2-propenol is treated with thionyl chloride, the resulting 2-(1-chloro-2-propenyl)-6-methylpyridine is reacted with sodium cyanide and the 2-(6-methyl-2-pyridyl)-3-butenenitrile is treated with hydrogen sulfide to give 2-(6-methyl-2-pyridyl)-3-thiobutenamide.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[H-].[Na+].[CH3:13][O:14][C:15](=[O:18])[CH2:16]Br>CN(C=O)C.O>[CH3:13][O:14][C:15](=[O:18])[CH2:16][N:7]1[C:6](=[O:8])[C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=[C:2]1[Cl:1]
Reactant: O=c1[nH]c(Cl)nc(Cl)c1Cl
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(Cl)nc(Cl)c(Cl)c1=O
Reaction time: 0.5 h
Yield: 22.1 %

Procedure:
To a solution of 2,5,6-trichloro-3H-pyrimidin-4-one (20.0 g, 0.1 mol) in DMF (150 mL) was added NaH (60% in mineral oil, 6.0 g, 0.12 mol) in portions at 0° C. and the mixture was stirred for 30 min. Bromoacetic acid methyl ester (18.3 g, 0.12 mol) was then added, and the reaction mixture was stirred at RT overnight. The solution was diluted with water (800 mL) and extracted with EA (200 mL, 3×). The combined organics were washed with water (800 mL, 3×), washed with brine (500 mL), dried (Na2SO4) and concentrated. The residue was purified by silica chromatography (1:50, EA:PE) to give 6.0 g of the title product (22%). 1H NMR (400 MHz, CDCl3): δ 3.80 (s, 3H), 5.04 (s, 2H). [M+H] Calc'd for C7H5Cl3N2O3, 271. Found, 271.
Reaction SMILES: [CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:2]1[O:4][CH2:3]1.O.C(OCC1C=CC=CC=1)[C@@H]1OC1>CC(O)=O.C1COCC1>[CH2:1]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:7])[CH3:8])[C@H:2]1[O:4][CH2:3]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CO1
Agent: c1ccc(COC[C@H]2CO2)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Yield: 48.3 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-(tert-butyldimethylsilyl) glycidyl ether (5.64 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 mL, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-(tert-butyldimethylsilyl) glycidyl ether 5c (2.72 g, 14.5 mmol, 48%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 Torr). The product was determined to be present in >99% ee by derivatization through ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C. and direct analysis of the 2-napthylsulfide thus obtained (Chiralcel OD, 99.25:0.75 hexanes:EtOH, 1 mL/min, 230 nm).
Reaction SMILES: [NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[C:11]=2[S:10][C:9]=1[C:27]([O:29]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:32]>C(OC(O)C)C>[NH:1]([C:8]1[C:16]2[CH:15]=[CH:14][C:13](=[O:17])[N:12]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[NH:23][CH:22]=[CH:21]4)[C:11]=2[S:10][C:9]=1[C:27]([NH2:32])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc3[nH]ccc3c2)c1Nc1ccccc1
Agent: CCOC(C)O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccc3[nH]ccc3c2)c1Nc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of Example 37 (200 mg) and liquid ammonia (5 mL) in ethoxyethanol (10 mL) was heated in a sealed vessel at 80° C. at 400 p.s.i. for 48 h. The solvent was removed in vacuo and purification by column chromatography (silica, 10% to 40% EtOAc in DCM) gave the title compound (42 mg). δH (CDCl3) 9.00 (1H, br s), 8.65 (1H, br s), 7.57 (1H, s), 7.37 (1H, d, J 8.5 Hz), 7.30-7.24 (2H, m), 7.20-7.18 (2H, m), 7.16 (1H, d, J 9.7 Hz), 7.18-6.98 (3H, m), 6.52 (1H, br s), 6.33 (1H, d, J 9.7 Hz), 5.20 (2H, br s). LCMS (ES+) RT 3.77 minutes, 430 (M+H)+. LCMS (ES+) RT 2.93 minutes, 401 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:6]2.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:2]=[C:3]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=1)[CH2:6][N:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:4]2
Reactant: COc1cc(OC)c2c(c1Br)CN(Cc1ccc(Cl)cc1)C2
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)CN(Cc1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 46.1 %

Procedure:
To a solution of 4-bromo-5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-lone (0.100 g, 0.25 mmol) in benzene under N2 atmosphere was added 2,2′-azobis(2-methyl proponitrile) AIBN (5.0 mg), followed by tributyl tin hydride (0.132 mL, 0.5 mmol). The resulting mixture was refluxed in an oil bath for 2 h. The reaction was monitored by GC-MS for the disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 min. The solids were filtered and the filtrate was concentrated. The resulting material was purified using column chromatography (typically 40% ethyl acetate in hexanes) to give 5,7-Dimethoxy-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-lone (0.035 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.15 (s, 2H), 4.69 (s, 2H), 6.43 (d, 2H), 7.25 (m, 4H). GC-MS: m/z 317 (M)+, 299 (M-18)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C@:12]2([CH3:15])[CH2:14][O:13]2)=[O:11])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].[Na].[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]([OH:13])([C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)=[O:11])[CH2:14][S:28]([C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)(=[O:30])=[O:29]
Reactant: O=S([O-])c1ccc(F)cc1
Reactant: C[C@@]1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
180 mg of the chiral epoxide of example 17 was dissolved in a mixture of 12 ml chloroform and 12 ml of water. 133 mg of sodium-p-fluorobenzenesulfinate and 107 mg of tetrabutylammonium bromide were added. The reaction mixture was heated till reflux and kept at reflux, while stirring vigorously. The reaction was monitored with HPLC. After 4 days at reflux, the starting epoxide was completely converted. The mixture was cooled to room temperature. 10 ml of chloroform was added. The organic layer was washed with 3×20 ml of water, dried (Na2SO4), filtrated and evaporated to dryness. Residue: 226 mg (brown oil). Purification of the residue by column chromatography (Merck silica gel 60; eluens: heptane/ethyl acetate=1/1) afforded R-enantiomer of bicalutamide as a white/yellow solid material. Purified yield: 122 mg (43%). HPLC: 96.3% purity. HPLC (chiral column): 94.7% e.e. 1H and 13C NMR in agreement with R-bicalutamide