Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1>C(O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropylamine (3 mL) is added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (700 mg, 3.18 mmol) in ethanol. The reaction may be stirred for an appropriate time at an appropriate temperature, such as room temperature for overnight and concentrated. The residue may be purified by any appropriate method such as Biotage column chromatography to give 4-bromo-N-isopropyl-2-nitroaniline (770 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reaction time: 0.5 h

Procedure:
N-methylpiperazine 3.6 mL, N,N-diisopropylethylamine 5.7 mL and tetrahydrofuran 31 mL were mixed and dropped into a solution of 4-chloro-3-nitrobenzenesulfonyl chloride 8.19 g in tetrahydrofuran 51 mL, under cooling with ice, followed by stirring for 30 minutes under cooling with ice. The stirring was then continued for 17 hours at room temperature. The solvent was distilled off and the residue was poured in water, of which pH was raised to 9 with saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate-tetrahydrofuran mixed solvent. The organic layer was washed with saturated brine, dried over magnesium sulfate, and from which the solvent was distilled off. Recrystallizing the crude product from ethyl acetate-hexane mixed solvent, 4.29 g of the title compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[N:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(Br)cn1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2nnn[nH]2)nc1
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in N,N-dimethylformamide (20 mL) was heated for 1 h at 120° C. The reaction mixture was diluted with ethyl acetate (˜100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O.CN(C)C1C=CC=CC=1.S(Cl)([Cl:26])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:26]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(OC)c1OC
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COc1cc(CCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxybenzyl alcohol (1.0 g, 5.04 mmol) and N,N-dimethylaniline (0.904 g, 7.46 mmol) in dichloromethane (10 mL). Cool in an ice bath. Add dropwise thionyl chloride (0.904 g, 7.6 mmol). Warm to ambient temperature. After 1 hour, partition the reaction mixture between a 1 M aqueous hydrochloric acid solution and dichloromethane. Separate the layers and extract the organic layer with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1.O>CN(C)C=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:19][CH:18]=1
Reactant: COC(=O)CC(=O)OC
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
A mixture of dimethyl malonate (42.6 g, 322.73 mmol, 4.00 equiv) and potassium carbonate (22.3 g, 161.59 mmol, 2.00 equiv) in N,N-dimethylformamide (200 mL) was stirred for 30 min at 50° C. A solution of 1-bromo-4-(bromomethyl)benzene (20 g, 80.65 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was then added dropwise with stirring to the reaction mixture. The resulting solution was stirred at 50° C. for 2 h. Water (100 mL) was added and the mixture was extracted with 1×400 mL of ethyl acetate. The organic layer was washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 22 g (91%) of dimethyl 2-(4-bromobenzyl)malonate as a white solid. LC-MS: (ES, m/z): 301 [M+H]+, 126, 120.
Reaction SMILES: [OH:1]O.[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N:9][CH:10]=1>C(O)(=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[N+:9]([O-:1])[CH:10]=1
Reactant: OO
Reactant: COc1ccc(C)nc1
Solvent: CC(=O)O
Product: COc1ccc(C)[n+]([O-])c1
Reaction time: 3 h
Yield: 77 %

Procedure:
120 g pf 30% strength hydrogen peroxide solution are added dropwise to a solution of 60.9 g of 5-methoxy-2-methylpyridine in 300 ml of glacial acetic acid at 60° C. in the course of 1 hour and the mixture is subsequently stirred for 3 hours. After destruction of excess percompounds by addition of active manganese dioxide, the mixture is filtered, the filtrate is concentrated, the residue is clarified hot in 500 ml of ethyl acetate, the mixture is concentrated again and the residue is distilled under 0.3 mbar. 54 g (77% of theory) of 5-methoxy-2-methylpyridine 1-oxide are obtained as a rapidly solidifying oil (b.p. 130° C.); m.p. 80°-84° C.
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH:7]=O.[Br-].[Li+].C[Si](Cl)(C)C.C[SiH](C)O[SiH](C)C.[C-:29]#[N:30].[Na+]>O.C(#N)C>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:29]#[N:30])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(C=O)cc1OC(F)F
Reactant: [C-]#N
Agent: C[SiH](C)O[SiH](C)C
Agent: C[Si](C)(C)Cl
Agent: [Br-]
Solvent: CC#N
Solvent: O
Product: COc1ccc(CC#N)cc1OC(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
To 3-difluoromethoxy-4-methoxybenzaldehyde (2 g, 9.8 mmol) was added lithium bromide (1.7 g, 19.6 mmol) and acetonitrile (11 mL). Upon dissolution, the reaction mixture was cooled to 0° C. Trimethylsilylchloride (1.86 mL, 14.7 mmol) was slowly added and the reaction mixture was allowed to warm to room temperature and was stirred for 15 min. The reaction mixture was again cooled to 0° C., 1,1,3,3-tetramethyldisiloxane (2.6 mL, 14.7 mmol) was added and the resulting mixture was allowed to warm to room temperature. After stirring for 3 h, the mixture was separated into two layers. The lower layer was removed, diluted with methylene chloride and filtered. The filtrate was concentrated under reduced pressure, dissolved in methylene chloride and refiltered. The solvent was removed in vacuo to provide an oil, which was dissolved in dimethylflormamide (10 mL) under an argon atmosphere and treated with sodium cyanide (1.08 g, 22 mmol). The resulting mixture was stirred at room temperature overnight, then poured into cold water (250 mL) and extracted three times with ethyl acetate. The organic extract was washed three times with water, once with brine and was dried (potassium carbonate). The solvent was removed in vacuo to provide a yellow oil (1.54 g, 74%), which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[C:20]([N:11]3[C:10]2=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[Br:24]Br>[Zn].C(O)(=O)C>[Br:24][C:18]1[CH:19]=[C:20]2[C:15]([NH:14][CH:13]=[C:12]3[C:21](=[O:22])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:10](=[O:23])[N:11]32)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Reactant: BrBr
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1ccc(-n2c(=O)c3c[nH]c4ccc(Br)cc4n-3c2=O)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg) inanhydrous dioxane (4 mL) was added bromine (200 mg). The reaction was stirred at 20° C. for 15 min, and was then poured directly into boiling acetic acid (50 mL) containing zinc powder (500 mg). The reaction was refluxed for 5 min and allowed to cool to room temperature. After dilution with 10% methanol/methylene chloride (100 mL), the mixture was filtered through silica gel, the solvent was removed in vacuo, and the resulting solid was treated with boiling ethanol (25 mL) followed by dilution with water (100 mL). The mixture was cooled to 0° C. and the solid was filtered and dried to yield 8-Bromo-2-(4-methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 33) as a yellow solid, m.p.154°(dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[C:20]([N:11]3[C:10]2=[O:23])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[Br:24]Br.C(O)(=O)C>O1CCOCC1.[Zn]>[Br:24][C:18]1[CH:19]=[C:20]2[C:15]([NH:14][CH:13]=[C:12]3[C:21](=[O:22])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:10](=[O:23])[N:11]32)=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2c(=O)c3c[nH]c4ccccc4n-3c2=O)cc1
Reactant: BrBr
Agent: [Zn]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1ccc(-n2c(=O)c3c[nH]c4ccc(Br)cc4n-3c2=O)cc1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 2-(4-Methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (100 mg) in anhydrous dioxane(4 mL) was added bromine (200 mg). The reaction was stirred at 20° C. for 15 min, and was then poured directly into boiling acetic acid (50 mL) containing zinc powder (500 mg). The reaction was refluxed for 5 min and allowed to cool to room temperature. After dilution with 10% methanol/methylene chloride (100 mL), the mixture was filtered through silica gel the solvent was removed in vacuo, and the resulting solid was treated with boiling ethanol (25 mL) followed by dilution with water (100 mL). The mixture was cooled to 0° C. and the solid was filtered and dried to yield 8-Bromo-(4-methoxyphenyl)-imidazo[1,5,a]quinoxaline-1,3(2H,5H)-dione (Compound 26) as a yellow solid, m.p. 154° C. (dec).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.Br[CH2:14][CH2:15][CH2:16][Cl:17]>CN(C)C=O.O>[NH:8]1[C:9]2[C:5](=[C:4]([O:3][CH2:14][CH2:15][CH2:16][Cl:17])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cccc2[nH]ccc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 58.6 %

Procedure:
A suspension of 1.6 gm (39.7 mMol) sodium hydride (60% dispersion in mineral oil) in 80 mL dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. To this suspension were added 5.0 gm (37.6 mMol) 4-hydroxyindole in portions over 30 minutes. The reaction mixture was stirred at room temperature for 1.5 hours after this addition was complete. To the resulting mixture was then added dropwise a solution of 5.91 gm (37.6 mMol) 1-bromo-3-chloropropane in dimethylformamide and the reaction mixture stirred for 18 hours at room temperature. The reaction mixture was diluted with water and then extracted well with ethyl acetate. The ethyl acetate phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with 10% ethyl acetate in hexane. Fractions containing product were combined and concentrated under reduced pressure to provide 4.62 gm (59%) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH:40]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])(=[O:3])[CH3:2]>C(O)=O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:29]([NH:30][C:31](=[O:60])[C:32]([C:35]3[N:36]=[C:37]([NH2:40])[S:38][CH:39]=3)=[N:33][OH:34])[C:28](=[O:61])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=CO
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Temperature: 45 °C
Yield: 81.3 %

Procedure:
A mixture of 8.29 g of the diethylamine salt of Step A of Example 5 and 24 ml of 50% aqueous formic acid was heated at 45° C. for 15 minutes and was then vacuum filtered to remove triphenyl carbinol. The filtrate was evaporated to dryness under reduced pressure and the residue was taken up in ethanol several times to obtain 3.5 g of a product identical to that of Examples 5,6 and 7.
Reaction SMILES: [OH:1][C:2]([CH3:36])([CH3:35])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH2:12]C)[CH2:6][CH2:5]1.Br[C:38]1[S:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][N:42]=1>>[OH:1][C:2]([CH3:35])([CH3:36])[CH2:3][C@@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([C:38]3[S:39][C:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[CH:41][N:42]=3)=[CH:18][CH:19]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CN(C)C(=O)c1cnc(Br)s1
Reactant: CC[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncc(C(=O)N(C)C)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 2-bromo-N,N-dimethylthiazole-5-carboxamide following a procedure analogous to that described in Example 459 Step 4. LC-MS Method 2 tR=1.215 min, m/z=450.1; 1H NMR (CD3OD) 0.92 (s, 3H), 1.22 (s, 3H), 1.53 (d, 3H), 2.11 (s, 2H), 2.19-2.28 (m, 1H), 2.40-2.58 (m, 2H), 3.00-3.31 (m, 4H), 5.56 (m, 1H), 7.02 (d, 2H), 7.26-7.39 (m, 5H), 7.69 (d, 2H), 8.08 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 4-hydroxypyridine (0.57 g, 6.0 mmol) to give the titled compound as pale yellow solid substance(1.05 g, 75%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>O1CCCC1.[Ni].O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [Ni]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Reaction time: 24 h

Procedure:
A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) is added to a Parr bottle containing a mixture of Raney nickel (1 g) in water (15 mL) under N2, and the reaction mixture is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 24 hrs. The catalyst is removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate is diluted with water (50 mL) and EtOAc (50 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil is chromatographed on a Flash 40M 90 g silica gel cartridge eluting with EtOAc/heptane (15/85). Pooling and concentration of those fractions with an Rf=0.19 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 85–86° C.; MS (ESI+) for C10H12N2F2S m/z 231 (M+H)+.
Reaction SMILES: [Li+].[OH-].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:8]([CH:20]=1)[C:9]([O:11]CC1C=CC(F)=CC=1)=[O:10].Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:8]([CH:20]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Solid LiOH (0.23 g, 9.58 mmol) was added to a stirred solution of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (may be prepared as described in Description 86; 1 g, 1.92 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. After cooling to room temperature, the solvent was removed to obtain a solid, which was dissolved in water (20 ml) and stirred in an ice-water bath. 1N HCl (aq) was added to adjust the pH to 4. The solid was filtered, and dried in vacuo to yield the title compound as a grey solid. 674 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.F[C:10]1[CH:33]=[CH:32][C:13]([C:14]([C:16]2[CH:31]=[CH:30][C:19]([O:20][C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:32]1[CH:33]=[CH:10][CH:11]=[CH:12][C:13]=1[C:14]([C:16]1[CH:31]=[CH:30][C:19]([O:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(O)c1cccc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2)c1
Reactant: Nc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cccc(Oc2ccccc2C(=O)c2ccc(Oc3cccc(C(=O)O)c3)cc2)c1
Reaction time: 8 h
Yield: 14 %

Procedure:
A mixture of m-aminophenol (0.64 g, 5.87 mmol), 3-[4-(4-fluorobenzoyl)phenoxy]benzoic acid (2.0 g, 5.95 mmol), and anhydrous potassium carbonate (4.0 g) was stirred in dry dimethylsulfoxide (20 ml) at 120° C. under nitrogen for 48 hours. The cooled reaction mixture was poured into water and carefully neutralized with conc. hydrochloric acid to precipitate 2.58 g of a white solid. The crude product was digested in hot toluene, and the toluene solution (after decanting from a large quantity of gum) was allowed to stand overnight at 0° C. The crystals thus obtained were recrystallized to give 0.35 g of product, m.p. 144°-150° C. dec. (14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][C@H:10]([C@H:13]([CH2:24]O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][OH:12])[CH:6]=[CH:5][C:4]=1[OH:26].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:9]([CH:10]1[CH:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:24][O:12][CH2:11]1)[C:7]1[CH:6]=[CH:5][C:4]([OH:26])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C[C@@H](CO)[C@H](CO)Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COc1cc(CC2COCC2Cc2ccc(O)c(OC)c2)ccc1O
Temperature: 40 °C
Reaction time: 5.5 h
Yield: 82.1 %

Procedure:
(−) secoisolariciresinol (100 mg) was dissolved in acetonitrile (5 ml) and to it was added a solution of triphenyl phosphine bromide in acetonitrile (1 ml) and the mixture was stirred at 0-80° C. for 1-10 hours. After completion of the reaction, the reaction mixture was concentrated under vacuum and the residue thus obtained was chromatographed over silica gel column. Elution of the column with 30% EtOAC in pet. ether gave (−) 3,4-divanillyl tetrahydrofuran (78 mg), m.p. 114-116° C.
Reaction SMILES: C([Mg]Cl)(C)(C)C.CO[C:9](=[O:34])[CH2:10][C@H:11]([O:23][C:24](=[O:33])[CH:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Mg]Cl)(C)(C)C.C1COCC1>C(OCC)(=O)C>[CH2:26]([C:25]1[C:24](=[O:33])[O:23][C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:9]=1[OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
In a 500 mL 3-necked round bottom flask fitted with a Claisen head with N2 inlet, a West condenser, a thermocouple-J-KEM controller and an addition funnel was added a solution of tert-butylmagnesium chloride (341 mL of a 1.0 M solution, 341 mmole, 3 equiv.) at about 60° C. Methyl-(R)-3-(2′-bromo-1′-oxooctyloxy)tetradecanoate (52.6.0 g, 113.5 mmole, 1 equiv.) (“bromodiester”) and 25 mL of dry THE were added to an addition funnel. The bromodiester mixture was slowly added to the t-BuMgCl/THF mixture at reflux over about one hour. The reaction mixture was sampled at 1 and 2 hours at about 60° C. (resulting in 90 and 91% area normalized gas chromatography (AN GC) analysis, respectively). After 2 hours the resulting reaction mixture was cooled and concentrated on a roto-evaporator to about ⅓ to about ½ the original volume. The resulting syrupy mixture was taken up in about 250 mL of toluene (or an ether, such as methyl tert-butyl ether and the like; a hydrocarbon, such as hexane, heptane, and the like; or mixtures thereof) and added to a mixture containing 250 mL of toluene, 75 mL of 10% HCl in a 1 L jacketed flask keeping the quenched solution below 30° C. The aqueous layer was removed. The organic layer washed one time with 50 mL of 1.0 N HCl solution. The aqueous layer was removed, the organic layer washed one time with 50 mL of water, dried over magnesium sulfate, filtered and concentrated. This resulted in a gel-like solid residue. The residue was dissolved in 250 mL of ethyl acetate at 40° C. The ethyl acetate was removed on the roto-evaporator. The resulting crude off-white solid (42.4 g) was slurried up in about 100 mL of hexane and cooled to 0° C., filtered and rinsed with 50 mL of cold hexane followed by another 25 mL of cold hexane. The isolated white solids were air dried under vacuum for about 1 to 2 hours resulting in 31.4 g of (6R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-pyran-2-one (78.4% yield).