Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F:7][C:8]([F:17])([F:16])[C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.F[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CN(C=O)C>[F:7][C:8]([F:16])([F:17])[C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
K2CO3 (23.45 g, 170 mmol) was added to a solution of 3-(trifluoromethyl)phenol (25 g, 154 mmol) and 4-fluorobenzaldehyde (19.14 g, 154 mmol) in DMF (300 mL), and the reaction mixture was stirred at 140° C. for 4 h. After cooling down to room temperature, the reaction mixture was poured into ice water (2500 ml), extracted with ethyl acetate (500 ml×2), and washed with brine (200 mL×2). The organic phase was dried with sodium sulfate, filtered, and concentrated to give the title compound as a brown solid (35 g, 66.9% yield). LCMS: rt=1.62 min, [M+H+]=267
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12]>C(Cl)Cl>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(CN)OC
Solvent: ClCCl
Product: COC(CNC(C)=O)OC
Yield: 95.1 %

Procedure:
30.6 g (0.3 mol) of acetic anhydride are added to 315 g (0.3 mol) of aminoacetaldehyd dimethyl acetal in 50 ml of methylene chloride. When the exothermic reaction is complete, the methylene chloride is removed by distillation, the product is distilled, giving 42 g of colourless product (97% of theory), boiling point 110° C., 0.001 mbar. The product is a single compound according to GC
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].CN(C)C=O>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccc(O)c(Cl)c2oc2cccc(F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl
Reaction time: 4 h
Yield: 98.7 %

Procedure:
A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8 g of potassium carbonate, 3.3 g of ethyl bromoacetate and 40 ml of N,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. After cooling the mixture, water was added thereto and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 3.4 g of ethyl 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of this ester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxed for 30 minutes. After cooling, the mixture was rendered acidic with concentrated hydrochloric acid and the resulting crystal was recovered by filtration and dried. Recrystallization from DMF gave 2.5 g of 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11][CH3:12])=[O:10].[N+:18]([O-])([OH:20])=[O:19]>ClCCl.C(O)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([N+:18]([O-:20])=[O:19])=[C:8]([CH:7]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(OC)c(OCCCCl)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(OCCCCl)c(OC)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
The aforementioned J. Med. Chem., 44, 3965 (2001) further describes a process for preparing a 4-alkoxy-5-halogenoalkoxy-2-nitrobenzoic acid compound from a 4-alkoxy-3-hydroxybenzoic acid compound. For example, methyl 3-hydroxy-4-methoxybenzoate is reacted with 3-chloropropyl p-toluenesulfonate in an aqueous potassium carbonate solution in the presence of tricaprylmethyl ammonium chloride to produce methyl 3-(3-chloropropoxy)-4-methoxybenzoate, and the methyl 3-(3-chloropropoxy)-4-methoxybenzoate is reacted with 70% nitric acid in a mixture of dichloromethane and acetic acid, to give methyl 5-(3-chloropropoxy)-4-methoxy-2-nitrobenzoate in 61% yield (based on the amount of methyl 3-hydroxy-4-methoxybenzoate).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:11]([O-])=O.[Na+].O.O.[Sn](Cl)Cl>O.Cl>[F:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:11]
Reactant: O=N[O-]
Reactant: COc1ccc(N)c(F)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
With vigorous stirring, 9.15 g (0.065 mole) of 2-fluoro-4-methoxyaniline (Example 3, Step B) was added to 60 mL of concentrated hydrochloric acid that had been cooled to -10° C. A solution of 4.83 g (0.070 mole) of sodium nitrite in 30 mL of water was slowly added dropwise, while the temperature was kept at or below -10° C. Upon completion of addition, the reaction mixture was stirred at -10° C. for one hour, after which 33.85 (0.150 mole) of tin(II) chloride dihydrate in 50 mL of concentrated hydrochloric acid Was added slowly, dropwise, while the temperature was kept below -5° C. After the reaction mixture had stirred for one hour as it warmed to ambient temperature, the crude product was filtered from the mixture and dissolved in 250 mL of water. This solution was made basic with 4N sodium hydroxide and extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and filtered. The filtrate was placed on a silica gel column and eluted with methylene chloride to remove colored impurities and then with ethyl acetate to obtain the desired product. The solvent was evaporated under reduced pressure to yield 6.30 g of 2-fluoro-4-methoxyphenylhydrazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:13])[CH3:12].O>ClCCCl>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: ClCCCl
Solvent: O
Product: CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 50 °C
Yield: 73 %

Procedure:
2-Oxindole (3 g) was suspended in 1,2-dichloroethane and 3.2 mL acetyl chloride were slowly added. The resulting suspension was heated to 50° C. for 5 hours, cooled, and poured into water. The resulting precipitate was collected by vacuum filtration, washed copiously with water and dried under vacuum to give 2.9 g (73% yield) of the title compound as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].C[O-].[Na+].CO.Cl>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 4.5 h

Procedure:
A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (0.40 g), methyl 3-mercaptopropionate (1.42 ml) and 28% sodium methylate methanolic solution (1.25 ml) in methanol (10 ml) was refluxed for 4.5 hours in an oil bath under heating. To the reaction mixture was added methyl 3-mercaptopropionate (0.53 ml, 0.32 ml) respectively after 2 hours and 3.5 hours of heating. Further, 28% sodium methylate-methanol solution (0.63 ml) was added after 2.5 hours. After 4.5 hours, the reaction mixture was cooled, neutralized with 1N hydrochloric acid (9.6 ml) and extracted with dichloromethane (100 ml). The extract was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and distilled off the solvent under reduced pressure. The residue was subjected to a silica gel column chromatography (hexane:ethyl acetate=1:3) for purification. The objective fractions were concentrated. Then, the collected precipitate was washed with isopropyl ether to afford (2R, 3R)-2-(2,4-difluorophenyl )-3-mercapto-1-(1-H-1,2,4-triazol-1-yl)-2-butanol (0.22 g) as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: Oc1ccc(F)cc1Cl
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Cl
Yield: 125.6 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:2]1.[CH2:15](O)[CH3:16]>S(=O)(=O)(O)O>[CH2:15]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:16]
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1c[nH]c2ccccc12
Yield: 95 %

Procedure:
To a mixture of 3-indolepropionic acid (4.00 g, 1 eq) in ethanol (70 ml), 1 ml of sulphuric acid is added dropwise and the mixture is first refluxed overnight and then evaporated to dryness. The resulting crude residue is dissolved in ethyl acetate and the organic solution is washed with 5% aqueous sodium bicarbonate, water, dried over MgSO4, filtered and finally evaporated to dryness, to afford the title compound as a yellow solid (4.30 g, 95% yield), which is used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:22])[C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].C([O-])(=O)C.[NH4+]>>[Cl:23][C:24]1[N:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:22][C:13]1[C:14]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)=[C:2]([Cl:1])[CH:3]=[C:4]2[C:12]=1[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1)=[O:27]
Reactant: O=C(O)c1cccnc1Cl
Reactant: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2N)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CN1CCN(c2c(Cl)cc3c([nH]c4cnccc43)c2NC(=O)c2cccnc2Cl)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to Method A from 6-chloro-7-(4-methyl-piperazin-1-yl)-8-amino-9H-β-carboline and 2-chloro-nicotinic acid in 25% yield. 1H-NMR (300 MHz, DMSO-d6): δ 2.21 (s, 3H), 2.33 (m, 2H), 2.54(m, 2H), 3.24 (m, 4H), 7.73 (dd, 1H), 8.12 (d, 1H), 8.35 (d, 1H), 8.37 (s, 1H), 8.48 (dd, 1H), 8.61 (dd, 1H), 8.91 (s, 1H), 10.40 (s, 1H), 11.33 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.46 min. MS (M+H+): 455.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].I[CH2:15][CH3:16]>CN(C)C=O>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[CH3:16]
Reactant: CCI
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccnc1C=O
Temperature: 50 °C
Yield: 83.8 %

Procedure:
To a suspension of 1H-imidazole-2-carbaldehyde (480 mg, 5 mmol) and potassium carbonate (936 mg, 6 mmol) in N,N-dimethylformamide (7 mL) was added iodoethane (829 mg, 6 mmol) and the mixture was heated at 50° C. for 5 hrs. Solvent was removed under reduced pressure. The residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 1-ethyl-1H-imidazole-2-carbaldehyde as light yellow oil (520 mg, yield 84%). 1H NMR (400 MHz, CDCl3) δ (ppm): 1.42-1.46 (t, J=7.2 Hz, 3H), 4.42-4.47 (q, 2H), 7.19 (s, 1H), 7.29 (s, 1H), 9.82 (s, 1H). LC-MS (ESI) m/z: 125 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>C(#N)C.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>[OH:29][CH2:25][CH2:26][C:27]#[C:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Cc1ccn2cc(-c3ccc(Br)cc3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccn2cc(-c3ccc(C#CCCO)cc3)nc2c1
Temperature: 60 °C
Yield: 71.7 %

Procedure:
The product of Step A (1.8 g) in dry acetonitrile (40 mL) was treated sequentially with tetrakis(triphenylphosphine)palladium(0) (0.1 g), triethylamine (1.27 g), and Cul (10 mg) then heated at 60° C. for 30 minutes. The mixture was cooled to ambient temperature, treated with 3-butyn-1-ol (0.361 g) and heated at reflux temperature for 18 hours. The mixture was cooled to ambient temperature and evaporated to dryness. The residue was crystallized, twice, from acetone to afford the title compound (1.02 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60% in oil, 55 mg, 1.22 mM) in dry THF (10 ml) stirring at 0° C. was added a solution of methyl indazole-3-carboxylate (von Auwers et al, Ber., 52, pg 1345 (1919), 210 mg, 1.22 mM) in dry THF (10 ml). After 10 min benzyl bromide (0.15 ml, 1.22 mM) was added and the solution left stirring at room temperature overnight. Water (2 ml) was added and the solvent removed in vacuo. The residue was partitioned between water and ethyl acetate and the combined organic dried over magnesium sulfate and evaporated. Column chromatography (ethyl acetate/cyclohexane 1:4) provided methyl 1 benzyl-indazole-3-carboxylate as a yellow powder (250 mg, 77%). M.pt. 181° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:25].[OH:17][C@@H:16]1[CH2:15][NH:14][CH2:13][C@H:12]1[NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O=C(N[C@@H]1CNC[C@H]1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl (3R,4R)-3-benzyloxycarbonylamino-4-hydroxypyrrolidine-1-carboxylate (16 g) was dissolved in chloroform (143 mL), followed by addition of a solution (72 mL) of 4 M HCl in 1,4-dioxane, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure to obtain benzyl ((3R,4R)-4-hydroxypyrrolidin-3-yl)carbamate mono hydrochloride. This compound was used in the subsequent step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:3]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: CCOC(=O)c1ccc(OC)cc1
Product: COc1ccc(C(=O)Cc2cc(Cl)ccn2)cc1

Procedure:
2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone was synthesized from 4-chloro-2-picoline (10 g, 78.4 mmol) and ethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) as described in Example 12 to give the product as a mixture of enol and keto tautomers. MS m/z 262 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:20]=[O:21]>C(#N)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:20]=[O:21]
Reactant: C=O
Reactant: COc1ccc(O)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(O)c(C=O)c1
Temperature: 45 °C
Yield: 74 %

Procedure:
A mixture of 600 g of acetonitrile, 186.2 g of 4-methoxyphenol (1.5 moles) and 214 g (2.25 moles) of anhydrous magnesium chloride was warmed to 45° C. and 227.4 g (2.25 moles) of triethylamine was added dropwise at that temperature. Paraformaldehyde (150 g, 4.75 moles) was then added and the reaction was heated to reflux. Methanol was removed over 3 hours by distillation, using a 10-inch column packed with Penn-State packing. The weight of the methanol removed (vapor temperature 60-65° C.) was 130 g. The solution was cooled to 60° C. and added to 900 mL of water. The solution was acidified with 240 mL of conc. HCl and extracted with 150 g of ethyl acetate. The ethyl acetate solution was washed once with 300 mL of tap water, clarified through diatomaceous earth, and stripped on a rotary evaporator at 10 mm pressure and 85° C. bath temperature. The weight of the product was 206.5 g, the liquid chromatograph area percent was 86%, and liquid chromatograph weight percent was 82%. The overall assay yield was 74%.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9][C:8]=2[CH2:7][CH2:6]1.N>C(O)(=O)C.O>[CH2:5]1[CH:16]2[CH:8]([NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=32)[CH2:7][CH2:6]1
Reactant: c1ccc2c3c([nH]c2c1)CCC3
Agent: N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: c1ccc2c(c1)NC1CCCC21
Temperature: 15 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
1.9 g of sodium cyanoborohydride are added in portions to a solution of 1.5 g of 1,2,3,4-tetrahydrocyclopenta[b]indole in 40 ml of acetic acid cooled to 15° C. The reaction medium is stirred for 20 hours while allowing it to rise to ambient temperature and then the pH is brought to neutrality with a 28% aqueous ammonia solution. The reaction mixture is diluted with water and then extracted with dichloromethane, and the organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (95/05), so as to give 1.3 g of 1,2,3,3a,4,8b-hexahydrocyclopenta[b]indole in the form of a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1)C1C=CC=CC=1.C1CCCCC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:8][C:9]1[CH:26]=[CH:25][C:12]2[CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: COc1ccc(C2=Cc3ccc(OCc4ccccc4)cc3OC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1ccc(C2=Cc3ccc(O)cc3OC2)cc1

Procedure:
As shown in Scheme 2, 7-benzyloxy-3-(4-methoxyphenyl)-2H-1-benzopyran (compound 1) was reacted with n-Bu4NI/BCl3 and BCl3 to give haginin E (compound 2a) at a yield of 79% and 7-hydroxy-3-(4-methoxyphenyl)-2H-1-benzopyran (4′-O-methyl haginin E, compound 2b) at a yield of 81%, respectively. Treatment of compound 1 with Pd(OH)2/C (Pearlman's reagent) and cyclohexene in refluxing ethanol promoted O-debenzylation and reduction of the chromene ring in one step, giving 7-hydroxy-3-(4-methoxyphenyl)-1-benzopyran (compound 3a) at a yield of 94%. Compound 3a was subsequently demethylated by use of n-Bu4NI/BCl3 to give equol (compound 3b) at a yield of 95%.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.Cl[CH2:12][C:13]([NH:15][C:16]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:17]=1[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)=[O:14].N>CO>[Cl:30][C:27]1[CH:28]=[CH:29][C:16]2[NH:15][C:13](=[O:14])[CH2:12][N:2]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]=2[CH:26]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: N
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 624.3 %

Procedure:
A mixture of methanol (550 mls), hexamethylenetetramine (14.1 g., 0.1 mol) and 2-chloroacetamido-5-chlorobenzophenone (308.2 g., 1.0 mol) was stirred and saturated with ammonia at room temperature. The mixture was heated slowly to reflux with a steady stream of ammonia bubbling through the solution. Refluxing was continued for 24 hours. The flow of ammonia was interrupted and the crystal slurry obtained was cooled to room temperature. The product, filtered, washed with methanol (2 × 125 ml) and hot water (4 × 500 ml), and dried gave 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (169 g., 62.3%) melting at 213° to 215° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([NH2:15])=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1ncc(Br)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
3-(Benzyloxy)pyridin-2-amine (25.0 g, 124.9 mmol) was added to acetonitrile (300 mL) and cooled to 0° C. 1-Bromopyrrolidine-2,5-dione (22.22 g, 124.9 mmol) was added portionwise and the reaction mixture was stirred for 15 minutes, then concentrated to dryness. The residue was dissolved in EtOAc and partitioned with water. The organic layer was washed twice with saturated sodium bicarbonate and once with brine. Activated charcoal was added to the organic layer, and the organic layer was warmed to reflux, then cooled, filtered through a plug of celite, and concentrated to give 9.4 g of the title compound. The celite and charcoal were resuspended in EtOAc and filtered through a celite plug to give an additional 3.6 g of the title compound, to provide a total of 12.0 g (34.3% yield). 1H NMR (CDCl3) δ 7.74 (d, 1H), 7.41 (m, 5H), 7.08 (d, 1H), 5.04 (s, 2H), 4.74 (bs, 2H). Mass spectrum (apci) m/z=279.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16]C.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:14])([CH3:13])[CH3:15])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16]
Reactant: COc1ccc2c(nnn2CC(C)(C)C)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-bromo-1-(2,2-dimethylpropyl)-5-methoxy-1H-1,2,3-benzotriazole (1-5) (8.97 g, 30.1 mmol, 1.0 equiv.) in dichloromethane (150 ml) at 0° C., was added slowly a 1M solution of BBr3 (60.2 ml, 60.2 mmol, 2.0 equiv.) in dichloromethane. The reaction mixture was allowed to warm up to room temperature and was stirred for an additional 14 hours. LCMS showed completion. The reaction mixture was treated with water, neutralized to pH=7, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to give provide 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (1-6). 1H NMR (500 MHz, CDCl3) 7.36 (d, 1H, J=9.0 Hz), 7.24 (d, 1H, J=9.0 Hz), 4.37 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 283.9 and 285.9 (intensity ratio ˜1:1) found, 284.0 and 286.0 required.