Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:13][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: Cn1nc([N+](=O)[O-])cc1CO
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of (1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (496 mg, 3.16 mmol) in chloroform (10 mL) at 0° C. was added phosphorus tribromide (854 mg, 0.30 mL, 3.16 mmol) drop wise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo and the residue purified by flash chromatography (silica gel, 40 g, 20% to 40% ethyl acetate in hexanes) to give 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 63%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:12]([Cl:20])=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[Cl:20])[C:4]=1[F:21])=[O:29]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1Cl
Yield: 77.9 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.062 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.05 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. for 6 h with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 16 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling EtOH, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(2,5-dichloro-3-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.067 g, 0.141 mmol, 78% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br. s., 1H), 8.27 (s, 1H), 8.02 (d, J=2.06 Hz, 1H), 7.78 (s, 1H), 7.53 (d, J=8.38 Hz, 1H), 7.40 (t, J=7.69 Hz, 1H), 7.25 (d, J=1.65 Hz, 1H), 4.53 (d, 2H). LC-MS (ES−) m/z 471.01, 473.00, 474.99 [M−1]. LC-MS (ES+) m/z 472.91, 474.92, 476.90 [M+H].
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2C)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=1[O:19][CH3:18])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Reactant: COc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2ccccc2c1Nc1ccccc1OC
Yield: 86.8 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (2.33 g, 10 mmol), 2-methoxyaniline (1.69 ml, 15 mmol) and dioxan (10 ml) were heated at reflux for 30 minutes, then allowed to cool. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethanol to give 3-butyryl-4-(2-methoxy-phenylamino)quinoline (2.78 g), m.p. 167°-168°.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1>C(#N)C>[N:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)=[CH:16][CH:15]=3)=[CH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=c1cc(-c2ccc(O)cc2)oc(N2CCOCC2)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1cc(-c2ccc(OCc3ccc4ccccc4n3)cc2)oc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
2-Morpholinyl-6-(4-hydoxyphenyl)-4-pyrone, as prepared in Example 5, (273 mg, 1.0 mmole) was suspended in 8 ml acetonitrile in a 25 ml one neck round bottom flask under nitrogen. The suspension was treated successively with potassium carbonate (829 mg, 6.0 mmole) and 2-chloromethyl-quinoline (533 mg, 3.0 mmole). The reaction mixture was stirred at 70° C. overnight. The acetonitrile was removed in vacuo and the residue was washed with 1×25 ml dichloromethane. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo to a yellow solid. The crude material was washed with diethyl ether and was recrystallized from ethyl acetate to give 377 mg (91%) of Compound 8 as an orange solid.
Reaction SMILES: C(OC([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C@@H:12]([C@H:22]([O:34][Si](C(C)(C)C)(C)C)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=2)[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1)=O)C.C([O:44][C:45]([C:47]1C=CN[CH:48]=1)=[O:46])C.C(OC(C1C=NN(C[C@@H]([C@H](O[Si](C(C)(C)C)(C)C)C2C=C(OC)C(C)=C(OC)C=2)CCCC2C=CC=CC=2)C=1)=O)C>>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([C@@H:22]([OH:34])[C@@H:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][N:8]2[CH:9]=[CH:10][C:6]([CH2:48][CH2:47][C:45]([OH:46])=[O:44])=[CH:7]2)[CH:24]=[C:25]([O:32][CH3:33])[C:26]=1[CH3:31]
Reactant: CCOC(=O)c1ccn(C[C@H](CCCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2cc(OC)c(C)c(OC)c2)c1
Reactant: CCOC(=O)c1cc[nH]c1
Agent: CCOC(=O)c1cnn(C[C@H](CCCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2cc(OC)c(C)c(OC)c2)c1
Product: COc1cc([C@@H](O)[C@@H](CCCc2ccccc2)Cn2ccc(CCC(=O)O)c2)cc(OC)c1C

Procedure:
Using ethyl1-{(2S)-2-[(S)-{[tert-butyl(dimethyl)silyl]oxy}(3,5-dimethoxy-4-methylphenyl)methyl]-5-phenylpentyl}-1H-pyrrole-3-carboxylate (produced by carrying out procedures similar to Example 24 using the compound produced in Example 16 and ethyl1H-pyrrole-3-carboxylate) instead of ethyl1-{(2S)-2-[(S)-{[tert-butyl(dimethyl)silyl]oxy}(3,5-dimethoxy-4-methylphenyl)methyl]-5-phenylpentyl}-1H-pyrazole-4-carboxylate, procedures similar to Example 29→Example 33→Example 34→Example 36→Example 37 were carried out to give the title compound having the following physical properties.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCOCC1.[NH3:26]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17](=[O:19])[NH2:26])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2sc(C(N)=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-t-Butoxycarbonyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine-2-carboxylic acid (570 mg, 2.0 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml), and the solution was mixed with 1,1-carbonyldiimidazole (320 mg, 2.0 mmol) and stirred at room temperature for 1 hour. The reaction solution was mixed with ammonia dioxane solution (0.5 M, 8.0 ml, 4.0 mmol) and the stirring was continued for 16 hours. The solvent was removed by evaporation from the reaction solution under a reduced pressure, and the residue was mixed with ethyl acetate and washed with water, hydrochloric acid (1 N), sodium hydroxide aqueous solution (1 N) and saturated brine. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed by evaporation under a reduced pressure to obtain 450 mg (1.6 mmol, 80% in yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.N1C=CC=CC=1.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35](Cl)=[O:36]>C(Cl)Cl>[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH2:34][C:35]([N:19]1[CH2:18][CH2:17][C:16](=[C:15]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]3[CH:22]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1)=[O:36]
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Reactant: O=C(Cl)Cc1cccs1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cc1cccs1)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
To a solution of 1.0 gm (3.22 mmole) of 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta [1,2-b]pyridin-11-ylidene) piperidine and 0.29 mL of pyridine in 20 mL of dry CH2Cl2 at 0° C. and under an argon atmosphere was added dropwise 0.438 mL (3.55 mmol) of 2-thiopheneacetyl chloride. After 30 minutes the mixture was washed with 1.0N aqueous NaOH and then brine. The organic portion was dried over Na2SO4, filtered and converted in vacuo to provide a residue which was purified via flash chromatography (3% MeOH in CH2Cl2) and treated with activated carbon to provide the title compound as a glass.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1F
Reactant: NC(=S)C1CC1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccccc1F

Procedure:
prepared by reaction of 3-chloro-3-(2-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.00 min; [M+H]+=278.3.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][N:33]=[C:32]2[O:41][C:42]1[CH:43]=[C:44]([CH:46]=[CH:47][CH:48]=1)[NH2:45]>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:45][C:44]2[CH:46]=[CH:47][CH:48]=[C:42]([O:41][C:32]3[C:31]4[C:36](=[CH:37][C:38]([O:39][CH3:40])=[C:29]([O:28][CH3:27])[CH:30]=4)[N:35]=[CH:34][N:33]=3)[CH:43]=2)=[O:19])[N:7]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
A mixture of phenyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.14 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113 (0.119 g, 0.4 mmol) and DMAP (0.025 g) in THF (6 mL) was stirred at room temperature overnight. The reaction was quenched by adding DCM and concentrated. To the residue was added Et2O to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea as solid (0.181 g, 82%). 1H NMR (300 MHz, DMSO-d6) δ 1.25 (s, 9H), 2.37 (s, 3H), 3.98 (s, 3H), 3.99 (s, 3H), 6.33 (s, 1H), 6.93 (d, 1H), 7.16 (d, 1H), 7.32-7.40 (m, 6H), 7.55 (d, 2H), 8.41 (s, 1H), 8.55 (s, 1H), 9.23 (s, 1H); LC-MS (ESI) m/z 553 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH:6]=[C:5]([O:32][CH3:33])[N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][C:10]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=[C:5]([O:32][CH3:33])[N:4]=1
Reactant: COc1cc(Oc2cccc(-c3ccccc3)c2C(=O)OCc2ccccc2)nc(OC)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(Oc2cccc(-c3ccccc3)c2C(=O)O)nc(OC)n1

Procedure:
To 10.3 Grams of benzyl 2-(2,6-dimethoxypyrimidine-4-yloxy)-6-phenylbenzoate dissolved in 100 ml of ethyl acetate was added 0.5 g of 10% palladium on activated carbon (water content: about 50%) and the resulting mixture was subjected to catalytic reduction at room temperature under normal pressure (hydrogen pressure) for 3 hours. The palladium on carbon was filtered off and the filtrate obtained was concentrated under reduced pressure to obtain 2-(2,6-dimethoxypyrimidine-4-yloxy)-6-phenylbenzoic acid (the present compound (1)) in quantitative yield.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)(=[O:19])=[O:20])[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2cccc(C)c2)c1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(S(=O)(=O)n2c(-c3ccccc3)cc(C=O)c2C)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution (10 mL) of ethyl 2-methyl-1-[(3-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrole-3-carboxylate (588 mg) in tetrahydrofuran was cooled to −78° C., a 1.5 mol/L toluene solution (3.00 mL) of diisobutylaluminum hydride was added dropwise. After completion of the dropwise addition, the mixture was stirred at −78° C. for 30 min, and at room temperature for 30 min. 1 mol/l Hydrochloric acid (10 mL) was added to the reaction mixture and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. A solution (10 mL) of the residue in acetonitrile was cooled to 0° C., tetra-n-propylammonium perruthenate (53 mg), N-methylmorpholine N-oxide (358 mg) and molecular sieves 4A powder (1.0 g) were added, and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (30 mL) and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1) to give the title compound as a pale-yellow oil (yield 250 mg, 48%).
Reaction SMILES: C([Si]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:10]\[CH3:11])(C)C)(C)(C)C.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:39]C)C=C4)N(CC2)C1.CS(N)(=O)=O>C(O)(C)(C)C.O>[C:12]1([C:9](=[O:8])[C@H:10]([OH:39])[CH3:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: CS(N)(=O)=O
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](O)C(=O)c1ccccc1
Yield: 57.2 %

Procedure:
Compound 10b was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-phenprop-1-enyloxy)dimethylsilane (9b, 7.2 g, 0.029 mol), AD-mix-β (40.7 g), and CH3SO2NH2 (2.8 g, 0.0294 mol) in tert-butyl alcohol-water (110 mL:110 mL) The reaction was quenched with sodium sulfite (29.1 g). After purification, 2.49 g (80%) of the title product was isolated: [α]20D +84.9° (c 1.6, CHCl3); 1H NMR (CDCl3) δ 7.96-7.90 (m, 2H), 7.66-7.58 (m, 1H), 7.54-7.47 (m, 2H), 5.23-5.12 (m, 1H), 3.84 (d, 1H, J=6.3 Hz), 1.45 (d, 3H, J=7.05 Hz); 13C NMR (CDCl3) δ 202.4, 134.0, 133.4, 128.9, 128.7, 69.3, 22.3. C9H10O2.
Reaction SMILES: C(=O)([O-])O.[Na+].[N+:6]([C:9]1[CH:10]=[C:11]([OH:16])[C:12](=[CH:14][CH:15]=1)[OH:13])([O-:8])=[O:7].[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl>CN(C=O)C.O>[N+:6]([C:9]1[CH:15]=[CH:14][C:12]2[O:13][CH2:17][CH:19]([CH2:20][OH:21])[O:16][C:11]=2[CH:10]=1)([O-:8])=[O:7]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: ClCC1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Yield: 39.9 %

Procedure:
3.0 g of sodium hydrogen carbonate was suspended in 90 mL DMF. At 0° C. a solution of 5.15 g of 4-nitrocatechol was added dropwise over 15 min. Subsequently, 3.9 g of epichlorohydrin in 10 mL DMF were added over 15 min. Stirring was continued at room temperature, then at 80° C. overnight. The mixture was diluted with water and extracted three times with ethyl acetate, dried (anhyd. Na2SO4), filtered and concentrated under vacuum to give a yellow oil. The oil was purified by column chromatography on silica gel using EtOAc-hexanes (0-100% gradient) to give the product (2.8 g) as a yellow solid.
Reaction SMILES: [Mg].II.Cl[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:38])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:37])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C@:24]([C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:19]1)([OH:38])[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2-c2ccccc2Cl)C1
Reactant: COCCCCCl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1-c1ccccc1Cl)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A 250-mL three-necked flask was charged with magnesium turning (2.88 g, 0.12 mol) and a small crystal of iodine. The flask was evacuated and refilled with N2. A solution of 1-chloro-4-methoxybutane (15 g, 0.12 mol) in THF (60 mL) was added dropwise to the above mixture. After heating under reflux for 2 h most of magnesium had been consumed and the Grignard solution was cooled to rt. A 250-mL three-necked flask was charged with (3R)-1-(tert-butoxycarbonyl)-3-((2-(2-chlorophenyl))benzoyl)piperidine (4.43 g, 11 mmol) and THF (50 ml), evacuated and refilled with N2. The mixture was cooled in a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. The mixture was quenched with sat'd aq NH4Cl (100 mL) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give the crude product which was purified by flash column chromatography to afford pure (3R)-tert-butyl 3-((S)-1-(2-(2-chlorophenyl)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (2.5 g, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[CH2:8][Br:10]
Reactant: Cc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a solution of 9.45 g (50 mmol) of 5-bromo-2-fluorotoluene in 30 ml of carbon tetrachloride were added 9.08 g (50 mmol) of N-bromosuccinimide and 0.26 g (1 mmol) of 1,1′-azobis(cyclohexane-1-carbonitrile) and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to obtain 13.54 g of crude 5-bromo-2-fluorobenzylbromide as liquid.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([NH:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:4]=2[CH:3]=1)(=[O:25])[CH3:24]
Reactant: Nc1cc2c([nH]c1=O)OCc1ccccc1-2
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
To 2.0 gm of 2-amino-4,6-dihydro-3H-[2]benzopyrano[3,4-b]pyridin-3-one, in 100 ml of chloroform containing 1 ml of pyridine, add 0.80 gm of acetyl chloride. Stir the reaction at room temperature for 5 hours. Filter and wash the solution with water. Remove the solvent by stripping to give the title compound.
Reaction SMILES: [BH4-].[Na+].CCO.[CH3:6][CH:7]([O:21][C:22]([O:24][C:25]1[C:32]([CH3:33])=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][C:26]=1[CH3:34])=[O:23])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]>C(Cl)Cl>[CH3:6][CH:7]([O:21][C:22]([O:24][C:25]1[C:26]([CH3:34])=[CH:27][C:28]([CH2:29][OH:30])=[CH:31][C:32]=1[CH3:33])=[O:23])[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N+:18]([O-:20])=[O:19]
Reactant: COc1cc(C(C)OC(=O)Oc2c(C)cc(C=O)cc2C)c([N+](=O)[O-])cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C(C)OC(=O)Oc2c(C)cc(CO)cc2C)c([N+](=O)[O-])cc1OC
Yield: 74 %

Procedure:
Sodium borohydride (9 ing, 0.25 inmol) followed by EtOH (0.5 mL) was added to 7k (100 mg, 0.25 mmol) in CH2Cl2 (2 mL) at r.t. and then refluxed for 30 minutes. Aqueous workup (CH2Cl2, MgSO4) followed by concentration in vacuo yielded 8k (75 mg, 75%) as a light yellow solid: 1H NMR (270 MHz, CDCl3) d 1.68 (d, J=6.4 Hz, 3H), 2.03 (s, 6H), 3.86 (s, 3H), 3.91 (s, 3H), 4.45 (s, 2H), 6.39 (q, J=6.4 Hz, 1H), 6.92 (s, 2H), 7.06 (s, 1H), 7.52 (s, 1H); 13C NMR (68 MHz, CDCl3) d 16.0, 21.9, 56.3, 56.4, 64.4, 73.0, 107.4, 107.6, 127.2, 129.9, 132.3, 138.7, 139.8, 147.4, 148.1, 151.7, 153.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N+:19]=1[O-])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:26]#[N:27])[N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CN(C)C(=O)Cl
Reactant: CC(c1cccc[n+]1[O-])C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: C[Si](C)(C)C#N
Solvent: ClCCl
Product: CC(c1cccc(C#N)n1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of the product of part (i) (0.90 g), N,N-dimethylcarbamoyl chloride (0.80 g) and trimethylsilyl cyanide (0.80 g) in dichloromethane (10 ml) was stirred at room temperature for 7 days and the resulting solution was evaporated. The residue was treated with 5N hydrochloric acid (10 ml) and the mixture was agitated in an ultrasonic bath for 0.05 hour to give a clear solution. A solid formed on standing which was filtered off, washed with acetone followed by ether, and dried to give the title compound as the hydrochloride salt, (0.28 g), m.p. 219° (with decomposition).