Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][C:11]#[N:12])=[C:5]([CH3:13])[CH:4]=1.[H][H]>N.[Ni]>[NH3:12].[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH2:10][CH2:11][NH2:12])=[C:5]([CH3:13])[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc(C)c(CC#N)cc1C
Agent: [Ni]
Agent: N
Product: COc1cc(C)c(CCN)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (4-methoxy-2,5-dimethyl-phenyl)-acetonitrile (200 mg, 1.14 mmol) and Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was stirred under 60 psi of hydrogen gas at room temperature for 18 hours. Tlc analysis showed that not all of the starting material had been consumed and so further Raney® nickel (50 mg) in 2M methanolic ammonia (10 mL) was added. The reaction mixture was stirred under 60 psi of hydrogen gas for an additional 18 hours at room temperature and was then filtered through Arbocel®. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 90:10:1 to afford the title product as a pale brown solid in 38% yield, 98 mg. 1H NMR (400 MHz, CDCl3) δ: 6.87 (1H, s), 6.68 (1H, s), 3.77 (3H, s), 2.80 (2H, m), 2.69 (2H, m), 2.28 (3H, s), 2.10 (3H, s) ppm; LRMS APCI m/z 180 [M+H]+
Reaction SMILES: O.O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]=[C:19]([CH2:25][OH:26])[C:18]2=[O:27].O>C(O)(=O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[O:21][CH:20]=[C:19]([CH:25]=[O:26])[C:18]2=[O:27]
Reactant: O=c1c(CO)coc2ccc(Br)cc12
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1coc2ccc(Br)cc2c1=O
Temperature: 40 °C

Procedure:
A warm (40° C.) solution of 29.8 g. (0.1 mole) of sodium dichromate dihydrate in 80 ml of glacial acetic acid is added over a 5-minute period to a stirred, warm (60° C.) solution of 25.5 g. (0.1 mole) of 6-bromo-3-(hydroxymethyl)chromone in 300 ml of glacial acetic acid. The temperature rises to 72° C. After one-half hour, water (1400 ml) is added and the mixture is heated at 80° C. for a few minutes. The mixture is cooled and filtered to give 13.6 g. (54%) of good quality aldehyde. Recrystallization from ethyl acetate gives pure 6-bromo-3-formylchromone having mp 186°-188° C.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:11])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][C:7]([NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=1)=[O:11])([CH3:8])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 64.9 %

Procedure:
113 mg of 2-Methyl-2-{[4-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid tert-butyl ester were dissolved in 2 ml dichloromethane and treated with 2 ml trifluoroacetic acid. After 30 min at 60° C. the volatiles were evaporated. The residue was treated with ethanol and 2 M HCl and evaporated three times. The resulting residue was crystallized from diethylether/heptane to afford 65 mg of 2-Methyl-2-{[4-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[NH:18][CH:19]([C:36]2[C:41]([Cl:42])=[N:40][CH:39]=[CH:38][N:37]=2)[C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[N:27]3)=[CH:22][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:37]3[CH:38]=[CH:39][N:40]=[C:41]([Cl:42])[C:36]3=[C:19]([C:20]3[CH:29]=[C:28]4[C:23]([CH:24]=[CH:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[N:27]4)=[CH:22][CH:21]=3)[N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)CC1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
4-{[(3-Chloro-pyrazin-2-yl)-(2-phenyl-quinolin-7-yl)-methyl]-carbamoyl}-piperidine-1-carboxylic acid benzyl ester (2.1 g, 3.6 mmol) was dissolved in CH3CN (126.0 mL) and DMF (0.4 mL) in a round bottom flask equipped with a condenser. The reaction was charged with POCl3 (1.7 mL, 17.9 mmol) and stirred at 55° C. for 3 h. The reaction mixture was concentrated in vacuo, redissolved in DCM, cooled to 0° C., and charged with 2M NH3 in isopropanol to basic pH. Hydromatrix was added, the mixture was concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (Jones Flashmaster, 20 g/70 mL cartridge, eluting with 100% CH2Cl2 to 2% CH3CN/CH2Cl2) to afford 4-[8-chloro-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-3-yl]-piperidine-1-carboxylic acid benzyl ester as a yellow solid; MS (ES+): m/z 574 (100) [MH+]; HPLC: tR=4.2 min (OpenLynx, polar 5 min).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][O:7][C:8]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:12]([N+:22]([O-:24])=[O:23])=[CH:11][C:9]=1[NH2:10].[N:25]#[C:26][NH2:27].[OH-].[Na+]>C(O)CCC.O.CC1CCCO1.C(OCC)C>[CH3:6][O:7][C:8]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:12]([N+:22]([O-:24])=[O:23])=[CH:11][C:9]=1[NH:10][C:26]([NH2:27])=[NH:25]
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1N
Reactant: N#CN
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC1CCCO1
Solvent: CCCCO
Product: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1NC(=N)N
Temperature: 90 °C
Yield: 92.6 %

Procedure:
Methanesulfonic acid (0.508 mL, 7.83 mmol) was added to a slurry of 2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitroaniline (Intermediate 14, 1.39 g, 5.22 mmol) in butan-1-ol (10 mL) and water (0.5 mL) at r.t. The resulting slurry was heated to 90° C. and at that temperature a solution of cyanamide (0.439 g, 10.44 mmol) in water (0.22 mL) was added dropwise over a period of 1 minute. The mixture was heated at 90° C. for 0.5 h then methanesulfonic acid (0.339 mL, 5.22 mmol) was added dropwise. At 10-minute intervals more cyanamide (0.219 g, 5.22 mmol), more methanesulfonic acid (0.339 mL, 5.22 mmol) and more cyanamide (0.329 g, 7.83 mmol) and more methanesulfonic acid (0.339 mL, 5.22 mmol) were successively added. The mixture was allowed to cool and was diluted with 2-methyltetrahydrofuran (75 mL) and diethyl ether (75 mL). This solution was then basified using 5M NaOH to ˜pH 13. The resulting phases were separated and the aqueous solution was extracted with 2-methyltetrahydrofuran (3×50 mL). The combined organic solutions were washed with sat. brine and dried (MgSO4). The product precipitated onto the drying agent, so after filtration the MgSO4 was washed with hot CH2Cl2/CH3OH 5:1 (5×100 mL) and the combined filtrate was concentrated in vacuo. The residue was dissolved in hot 2-s propanol (80 mL), filtered while hot and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), filtered and the filtrate was concentrated in vacuo to give the title compound (1.49 g, 89%) as an orange foam. The product could only be deposited amorphously from the 2-propanol filtrate, but a 38 mg sample of the final product was crystallised from ethanol (˜100 μL) and was collected by filtration, washed with −70° C. ethanol and diethyl ether and dried under vacuum to give the title compound (11 mg, 28%) as a yellow powder; 1H NMR: 2.25 (3H, s), 2.44-2.49 (4H, m), 2.99-3.16 (4H, m), 3.91 (3H, s), 6.73 (1H, s), 7.38 (3H, s), 7.67 (1H, s); m/z: ES+ MH+ 309.
Reaction SMILES: [CH2:1]([N:8]([CH3:21])[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.Cl>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1
Yield: 100.1 %

Procedure:
To a stirred solution of N-benzyl-N-methyl-4-nitrophenylacetamide (step (b), 24.9 g, 87.6 mmol) in tetrahydrofuran (270 ml) under nitrogen, was added dropwise 1.0M borane-tetrahydrofuran (245 ml, 245 mmol). The reaction was heated at reflux for 2 hours, cooled, then methanol (53 ml) was added dropwise followed by the cautious addition of aqueous 2.5N hydrochloric acid (100 ml). The resulting mixture was refluxed for 1 hour and then concentrated on a rotary evaporator to remove the organic solvents. Water was added to the residue and the mixture was basified to pH 11 with 2.5N aqueous sodium hydroxide. The product was then extracted into three portions of methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to yield 23.7 g (100%) of N-benzyl-N-methyl[2-(4-nitrophenyl)ethyl]amine. The hydrochloride salt, prepared in methanol and recrystallized from 95% ethanol-ether, melted at 222°-4° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][CH2:14][CH:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].BrN1C(=O)CCC1=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[O:13][CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COC(=O)C1COC(c2ccc([N+](=O)[O-])c(OC)c2)=N1
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Product: COC(=O)c1coc(-c2ccc([N+](=O)[O-])c(OC)c2)n1
Yield: 85.5 %

Procedure:
The same operation as in Example (96a) was performed using methyl 2-(3-methoxy-4-nitrophenyl)-4,5-dihydro-1,3-oxazole-4-carboxylate obtained in Example (102b) (1.72 g, 6.14 mmol), α,α-bisisobutyronitrile (50 mg, 0.3 mmol), N-bromosuccinimide (1.20 g, 6.75 mmol) and benzene (30 mL). Purification by silica gel column chromatography (elution solvent: chloroform/methanol=99/1, 98/2, 95/5) gave 1.46 g of the title compound as a light yellow solid (85%).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH:9]=O.C([BH3-])#N.[Na+].Cl.[CH3:18][O:19][C:20]([C@@H:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH2:29])=[O:21]>CO>[CH3:18][O:19][C:20]([C@@H:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[NH:29][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH3:6])=[O:21]
Reactant: CC(C)(C)CC=O
Reactant: COC(=O)[C@@H]1CCCCC[C@@H]1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)[C@@H]1CCCCC[C@@H]1NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
Sodium acetate (0.197 g, 2.40 mmol), powdered 4 Å molecular sieves (0.60 g), 3,3-dimethylbutyraldehyde (0.151 mL, 1.20 mmol) and sodium cyanoborohydride (0.151 mg, 2.40 mmol) were added sequentially to a solution of cis-2-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 2a, 0.250 g, 1.20 mmol) in methanol (10 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (2×150 mL). The organic layers were washed sequentially with half-saturated aqueous sodium bicarbonate solution (100 mL) and saturated aqueous brine solution (100 mL), then were dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 0-25% ethyl acetate in hexanes) to afford the desired product, cis-2-(3,3-dimethyl-butylamino)-cycloheptanecarboxylic acid methyl ester (0.090 g, 0.352 mmol, 29%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.90 (s, 9H), 1.33-1.37 (m, 2H), 1.43-1.50 (m, 3H), 1.58-1.87 (m, 7H), 2.46-2.53 (m, 1H), 2.58-2.65 (m, 1H), 2.81-2.85 (m, 1H), 2.95-2.99 (m, 1H), 3.67 (s, 3H). LC-MS (ESI) calcd for C15H29NO2 255.22, found 256.3 [M+H+].
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:7](=[O:19])[N:6]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26])=[O:4].[OH-].[Na+]>>[C:13]1([S:10]([N:8]2[CH2:9][CH:5]([C:3]([OH:4])=[O:2])[N:6]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:7]2=[O:19])(=[O:11])=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1c1ccccc1Cl

Procedure:
1-Benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed with NaOH solution to give 1-benzenesulfonyl-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH2:7]([O:9][C:10]1[C:11]([B:19]2[O:23][C:22](C)(C)C(C)(C)[O:20]2)=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])C=O)[CH3:8].Cl>O.C1COCC1>[CH2:7]([O:9][C:10]1[C:11]2[B:19]([OH:20])[O:23][CH:22]([CH2:6][N+:3]([O-:5])=[O:4])[C:12]=2[CH:15]=[CH:16][C:17]=1[F:18])[CH3:8]
Reactant: C[N+](=O)[O-]
Reactant: CCOc1c(F)ccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(F)ccc2c1B(O)OC2C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a cooled solution of sodium hydroxide (80 mg, 2.0 mmol) in water (3.0 mL), nitromethane (244.0 mg, 4.0 mmol) was added at 0° C. and stirred for 10 min. Then 3-ethoxy-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (588.0 mg, 2.0 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at for 1 h at 0° C. and for 2 h at room temperature. The reaction mixture was acidified with 2.5 M HCl (1.0 mL) and the product was extracted with ethyl acetate (2×20 mL). The organic extracts were combined and washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and product was chromatographed on a column of silica gel(CH2Cl2:MeOH=95:5) to give the title compound as a solid (350 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (dd, J=11.3, 8.2 Hz, 1H), 7.16 (dd, J=8.0, 3.3 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.30 (dd, J=13.5, 2.2 Hz, 1H), 4.62 (dd, J=13.5, 9.2 Hz, 1H), 4.35 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS (ESI) m/z=254 (M−1, negative).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)C=O.[OH:11]O>[OH-].[Na+]>[Br:1][C:2]1[CH:9]=[C:6]([OH:11])[C:5]([OH:10])=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc(Br)cc1O
Reaction time: 2 h
Yield: 74 %

Procedure:
A solution of 5-bromo-2-hydroxybenzaldehyde (10 g, 50 mmol) was dissolved in a 1 N aqeuous NaOH solution (55 mL). To this yellow solution was added hydrogen peroxide (36%, 12 mL) dropwise via addition funnel at room temperature. After stirring for 2 h, the reaction was quenched by adding saturated solution of Na2S2O3, and extracted with EtOAc. The organic extract was washed with 1N HCl, water, brine, and passed through a short pad of silica gel to obtain 4-bromobenzene-1,2-diol (7.0 g, 74%) as a brown solid. 1H NMR (300 MHz, CDCl3) 7.02 (d, J=2.1, 1H), 6.91 (dd, J=8.8, 2.1, 1H), 6.73 (d, J=8.8, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].B(Cl)(Cl)Cl>>[CH:11]1[C:10]([C@H:7]2[CH2:8][O:9][C:4]3[CH:3]=[C:2]([OH:1])[CH:19]=[CH:18][C:5]=3[CH2:6]2)=[CH:15][CH:14]=[C:13]([OH:16])[CH:12]=1
Reactant: COc1ccc(C2=Cc3ccc(O)cc3OC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)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: Cl.[C:2](C1C=CC(O)=CC=1)(C)=C.[CH3:12][C:13]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[CH3:14].[OH-].[Na+].C1(C)C(O)=CC=CC=1>>[CH3:2][C:17]1[CH:16]=[C:15]([C:13]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)([CH3:12])[CH3:14])[CH:20]=[CH:19][C:18]=1[OH:21]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=C(C)c1ccc(O)cc1
Agent: Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Product: Cc1cc(C(C)(C)c2ccc(O)cc2)ccc1O
Reaction time: 4 h

Procedure:
Anhydrous HCl was introduced, with adequate cooling, into a mixture of 134 g (1.0 mole) of freshly prepared 4-isopropenylphenol (made by thermally cracking BPA in the presence of catalytic amounts of sodium hydroxide and separating it from the coproduct phenol by fractional vacuum distillation) and 540 g (5.0 moles) of o-cresol, while maintaining the temperature of the ensuing exothermic reaction below 50° C. After 4 hours, the red colored reaction mixture was stripped of HCl and excess cresol under water aspirator vacuum and the resultant straw colored melt was purified by recrystallization from cyclohexane. The 98.7% pure MMEP had a mp of 112°-113° C.
Reaction SMILES: [OH:1][N:2]1[CH:7]([C:8]([Cl:11])([Cl:10])[Cl:9])[C:6]([Cl:13])([Cl:12])[C:5](=[O:14])[O:4][C:3]1([CH3:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(N(CC)CC)C.ClCCl>[C:22]1([NH:28][C:29]([O:1][N:2]2[CH:7]([C:8]([Cl:9])([Cl:10])[Cl:11])[C:6]([Cl:13])([Cl:12])[C:5](=[O:14])[O:4][C:3]2([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(c2ccccc2)OC(=O)C(Cl)(Cl)C(C(Cl)(Cl)Cl)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccccc2)OC(=O)C(Cl)(Cl)C(C(Cl)(Cl)Cl)N1OC(=O)Nc1ccccc1
Yield: 39 %

Procedure:
A solution of 8 g (0.02 mol) N-hydroxy-2-methyl-2-phenyl-4-trichloromethyl-5,5-dichloro-6-oxotetrahydro-1,3-oxazine, 2.4 g (0.02 mol) phenylisocyanate and several drops triethylamine in 90 ml dichloromethane was stirred at about 10° C. for about 2 days. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give a yellow oil. The oil crystallized from ethanol/hexane to give 4 g of product, m.p. 154°-157° C. The product is tabulated in Table I as Compound No. 8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11](=[O:17])OC(C)(C)C)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.CCN(CC)CC.[CH2:26]([N:28]1[C:32]2=[N:33][C:34]([CH2:57][CH3:58])=[C:35]([CH2:44][NH:45][C:46]([C:48]3[CH:49]=[C:50]([CH:54]=[CH:55][CH:56]=3)C(O)=O)=[O:47])[C:36]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:31]2[CH:30]=[N:29]1)[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:55]2[CH:54]=[CH:50][CH:49]=[C:48]([C:46]([NH:45][CH2:44][C:35]3[C:36]([NH:37][CH:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[C:31]4[CH:30]=[N:29][N:28]([CH2:26][CH3:27])[C:32]4=[N:33][C:34]=3[CH2:57][CH3:58])=[O:47])[CH:56]=2)=[O:17])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)cc(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(F)cc(Br)c2)c1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
To a clear solution of 1,1-dimethylethyl [(3-bromo-5-fluorophenyl)methyl]carbamate (280 mg, 1.11 mmol) 207310-29 in DCM (1 mL) was added 4N HCl in dioxane (1 mL). Solid precipitated out from the solution after 30 min. but the mixture was stirred at RT for another hour. It was then concentrated under vacuum to get rid of solvent. Then the residue was re-dissolved in DCM. Et3N (0.5 mL, 3.07 mmol) was added followed by 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (300 mg, 0.62 mmol) and HBTU (311 mg, 3.07 mmol). The mixture was stirred at RT overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The organic layer was then washed with water followed by the brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was purified with CombiFlash chromatography, eluting with 0 to 10% methanol in DCM to obtain N-[(3-bromo-5-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (307 mg, 78%). LC-MS m/z 637 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH:16]2[CH2:18][CH2:17]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=1.[C:24]([C:27]1[S:28][C:29](B(O)O)=[CH:30][CH:31]=1)([OH:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC.CCO>[C:11]([O:10][C:9]([N:8]([CH:16]1[CH2:18][CH2:17]1)[C:6]1[N:5]2[N:19]=[CH:20][C:21]([CH:22]=[O:23])=[C:4]2[N:3]=[C:2]([C:29]2[S:28][C:27]([C:24]([OH:26])=[O:25])=[CH:31][CH:30]=2)[CH:7]=1)=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N(c1cc(Cl)nc2c(C=O)cnn12)C1CC1
Reactant: O=C(O)c1ccc(B(O)O)s1
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: CCO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(c1cc(-c2ccc(C(=O)O)s2)nc2c(C=O)cnn12)C1CC1
Temperature: 95 °C
Reaction time: 3 h
Yield: 35.4 %

Procedure:
To tert-butyl 5-chloro-3-formylpyrazolo[1,5-a]pyrimidin-7-yl(cyclopropyl)carbamate (1 g, 2.97 mmol) in 30 mL of a 2:1 mixture of 1,2-dimethoxyethane/EtOH was added 2-carboxythiophene-5-boronic acid (766 mg, 4.45 mmol), tetrakis(triphenylphosphine)palladium(0) (171 mg, 0.148 mmol), and 2M aqueous solution of Na2CO3 (4.45 mL, 8.91 mmol). The mixture was stirred at 95° C. for 3 hours then cooled to room temperature and partitioned between 2N NaOH and ethyl acetate. The layers were separated and the aqueous layer was acidified to pH<3 with conc. HCl. The aqueous layer was extracted (3×) with methylene chloride. The combined organic layers was washed with brine, dried over MgSO4, filtered, and evaporated to dryness to provide 450 mg of 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid. Some additional material which was in the first ethyl acetate layer was purified by silica gel chromatography (0%-20% MeOH/CH2Cl2) to provide another 550 mg of 5-(7-(tert-butoxycarbonyl(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (79%). LCMS (M+1=429)