Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:33][CH:32]=3)=[O:30])[CH2:22][CH2:21]2)([OH:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[BH4-].[K+]>CO>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([CH:20]2[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][CH:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:35][CH:36]=3)[OH:30])[CH2:24][CH2:25]2)([OH:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccc(C(C)(C)C)cc3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)c1ccc(C(O)CCCN2CCC(C(O)(c3ccccc3)c3ccc(C(C)(C)C)cc3)CC2)cc1

Procedure:
To 8.0 g (0.0143 mole) of 4-[4-[α-(p-tert-butylphenyl) α-hydroxybenzyl]piperidino]-4'-tert-butylbutyrophenone hydrochloride dissolved in 50 ml of methanol is added with stirring a solution of 0.9 g (10% molar excess) of potassium hydroxide in methanol after which 1.54 g of potassium borohydride is added with stirring. The reaction mixture is allowed to react for about 3 hours at room temperature, after which the methanol is removed. Water is added to the remaining residue which is then extracted with ether, dried over magnesium sulfate, and filtered through celite. The filtrate is evaporated under vacuum, and the remaining solid is recrystallized several times from ethanol-water filtering while hot to give 4-[α-(p-tert-butylphenyl)-α-hydroxybenzyl]-α-(p-tert-butylphenyl)-1-piperidinebutanol, M.P. 179°-181.5°C.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:14]([NH:19][C:20](=[O:39])[O:21][C@H:22]([CH2:27][N:28]1[C:32]2[CH:33]=[C:34]([Cl:38])[C:35]([Cl:37])=[CH:36][C:31]=2[N:30]=[CH:29]1)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].O[C@H]([C@@H](NC(=O)O[C@H](CN1C2C=C(Cl)C(Cl)=CC=2N=C1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][C:2]([C@@H:14]([NH:19][C:20](=[O:39])[O:21][C@H:22]([CH2:27][N:28]1[C:32]2[CH:33]=[C:34]([Cl:38])[C:35]([Cl:37])=[CH:36][C:31]=2[N:30]=[CH:29]1)[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])(=[O:7])=[O:6]
Reactant: CCCC[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCCC[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 37.8 %

Procedure:
To a solution of 50.5 mg (0.084 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate in 2.2 mL of chloroform was added 44.6 mg (0.105 mmol) of Dess-Martin periodinane. The mixture was stirred at room temperature for 1.25 h, and then diluted with ethyl acetate. A saturated aqueous sodium thiosulfate solution was added, and the two layers were mixed vigorously before a saturated aqueous solution of sodium bicarbonate was added. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography eluting with a hexane:acetone solution (1:1) to yield 19 mg (38%) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate. ES-LCMS m/z 598 (M+H)+ retention time=4.00 min. HRMS C26H33Cl2NS5O5S m/z 598.1658 (M+H)Cal; 598.1674 (M+H)Obs.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37]>>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: COc1ccccc1Br
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromoanisole
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>CCOCC>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cccc(Br)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(Br)c1)Oc1ccccc1

Procedure:
A solution of 1.56 g. of phenyl chloroformate in 50 ml. of ether is added dropwise to a stirred solution of 3.44 g. of 3-bromoaniline in 35 ml. of ether, the mixture is stirred for one hour at room temperature and then filtered. The filtrate is evaporated and the residue is crystallized from hexane to yield phenyl N-(3-bromophenyl)carbamate, m.p. 88°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:29])[CH:10]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.NO.[N:33]1C=CC=CC=1>C(O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:10]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[N:33][O:29][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)C(C(=O)c2ccc(OC)cc2)c2ccc(OC)cc2)cc1
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: COc1ccc(-c2noc(-c3ccc(OC)cc3)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C

Procedure:
A mixture of the 1,3-diketone obtained in step 3 (1.0 equiv.), hydroxylamine hydrochloride (1.5 equiv.), pyridine (2.0 equiv.) and ethanol was heated to reflux overnight. Cooled to rt and removed solvent in vacuo. Water and ethyl acetate were added. The organic layer was separated, washed with dil. HCl, brine, dried, filtered and the solvent was concentrated in vacuo. The product 1-[4,5-bis(4-methoxyphenyl)isoxazol-3-yl]-4-methoxybenzene was obtained was an off white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 192 h
Yield: 66.8 %

Procedure:
A suspension of 3-(4-[4-ethoxycarbonylphenyl]piperazin-1-yl)methyl-1H-pyrrolo[2,3-b]pyridine (0.6594 g, 1.81 mmol) in ethanol (50 ml) containing 1M aqueous sodium hydroxide (10.5 ml, 10.8 mmol) was stirred at room temperature for eight days, during which time the solid slowly dissolved. The reaction mixture was concentrated to a small volume, diluted with water and neutralised (pH 6-7) with acetic acid to give a gum which solidified on standing. The solid was collected, washed with water and dried in vacuo. Recrystallisation from dimethylformamide/water gave the title compound (0.4069 g, 67%) as a white solid, m.p. >250° C. (dec.); (Found: C, 66.96; H, 5.88; N, 16.30. C19H20N4O2.0.25H2O requires C, 66.94; H, 6.06; N, 16.44); δH (DMSO-d6) 2.51 (4H, m, 2×piperazinyl CH2), 3.27 (4H, m, 2×piperazinyl CH2), 3.68 (2H, s, CH2N), 6.93 (2H, d, J 9.0 Hz, ArH), 7.04 (1H, dd, J 7.8, 4.7 Hz, 5-H), 7.38 (1H, d, J 2.2 Hz, 2-H), 7.57 (2H, d, J 9.0 Hz, ArH), 8.06 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.20 (1H, dd, J 4.7, 1.4 Hz, 6-H), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 337 (M+1)+.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][CH:48]1[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]1=[O:62].Br[C:64]1[CH:65]=[C:66]([CH3:70])[CH:67]=[CH:68][CH:69]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:66]1([CH3:70])[CH:67]=[CH:68][CH:69]=[C:64]([C:48]2([CH3:47])[CH2:52][CH2:51][C:50](=[CH:53][N:54]([CH3:61])[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]2=[O:62])[CH:65]=1
Reactant: CC1CCC(=CN(C)c2ccccc2)C1=O
Reactant: Cc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(C2(C)CCC(=CN(C)c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 77.3 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with tris(dibenylideneacetone)dipalladium (0) (1.5 mg, 0.0125 mmol, 5 mol % Pd), (S)-BINAP (31.4 mg, 0.05 mmol, 10 mol %) and 2-methyl-5-(N-methyl-anilinomethylene)cyclopentanone (108 mg, 0.5 mmol). Toluene (2 mL) was added and the mixture was stirred for 1 min at room temperature. 3-Bromotoluene (171 mg, 1.0 mmol) and sodium t-butoxide (96 mg, 1.0 mmol) were added to the tube. The tube was capped with the septum, purged with argon, and additional toluene (4 mL) was added through the septum. The mixture was heated to 100° C. with stirring until the starting ketone had been completely consumed as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material; was purified by flash chromatography on silica gel to afford 118 mg (77%) of the title compound. The ee was determined to be 80% by chiral HPLC analysis.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][C:16](Br)=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.CCCCCCC>C(COC)OC.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>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3cc(Br)ccc3c2CC1
Reactant: OB(O)c1ccccc1
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: CCCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(c1ccccc1)N1CCc2[nH]c3cc(-c4ccccc4)ccc3c2CC1
Yield: 36.2 %

Procedure:
A mixture of 3-benzoyl-8-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.48 g, 4.00 mmol) and tetrakis(triphenylphosphine)palladium (0.46 g, 0.40 mmol) in dimethoxyethane (10.0 mL) and a solution of phenylboronic acid (0.60 g, 4.80 mmol) in dimethoxyethane (10.0 mL) and sodium carbonate (2 M, 12.0 mL) were reacted in a manner similar to Preparation 1 to give a brown foam. Column chromatography (silica gel, 20-50% EtOAc/heptane) afforded 0.53 g (36%) of the title compound as a solid: mp 213-232° C.; 1H NMR (400 MHz, CDCl3) δ 8.13, 7.61, 7.44-7.40, 7.34-7.29, 4.07-3.98, 3.70-3.63, 3.21-3.13, 2.92-2.83; 13C NMR (100 MHz, CDCl3) δ 171.7, 142.3, 137.0, 135.9, 135.3, 134.9, 129.3, 128.7, 128.6, 128.3, 127.3, 126.5, 126.4, 119.3, 117.7, 110.3, 109.0, 51.4, 45.8, 29.1, 26.2; IR (drift) 3262, 1602, 1466, 1432, 1323, 1291, 1243, 811, 781, 763, 751, 743, 707, 699, 627 cm−1; MS (El) m/z 366 (M+); HRMS (FAB) calcd for C25H22N2O+H: 367.1810, found: 367.1813; Anal. Calcd for C25H22N2O: C, 81.94; H, 6.05; N, 7.64. Found: C, 81.43; H, 6.20; N, 7.42.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:11].C1(C)C=CC=CC=1.N>C(O)(C)(C)C.O>[CH3:9][C:8]1[C:3]([C:1]([NH2:2])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccnc1C#N
Agent: N
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cccnc1C(N)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Suspend 2-cyano-3-methyl pyridine (400 g) in t-butanol (800 mL) and heat to 70° C. Add concentrated sulphuric acid (400 mL) dropwise over 45 minutes. Maintain the temperature at 75° C., until the reaction is complete, and for an additional 30 minutes. Dilute the mixture with water (400 mL), charge with toluene (600 mL) and bring to pH 10 with concentrated aqueous ammonia. Maintain the temperature at 50°-55° C. during the work up. Separate the toluene phase, and reextract the aqueous layer. Combine toluene phases and wash with water. Remove the toluene to yield the title compound N-(1,1-dimethylethyl-(3-methyl-2-pyridine carboxamide, as an oil, from which solid product is crystallized. (Yield 97%, as determined by an internal standard assay with gas chromatography).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(N1C=CC=CC1N)C.[CH3:16][N:17]1[CH2:34][C:32]2=[C:33]3[C:28](=[C:29]([O:35][CH3:36])[CH:30]=[CH:31]2)[O:27][C@H:26]2[C@@:20]3([CH:21]=[CH:22][C:23]([CH2:25]2)=[O:24])[CH2:19][CH2:18]1.CN1CC2C=CC(OC)=C3C=2[C@]2([C@@H](O3)C[C@@H](O)C=C2)CC1.CN1CC2=C3C(=C(OC)C=C2)OC2C3(C=CC(O)C2)CC1>CCOCC.ClCCl.CO>[CH3:16][N:17]1[CH2:34][C:32]2=[C:33]3[C:28](=[C:29]([O:35][CH3:36])[CH:30]=[CH:31]2)[O:27][C@H:26]2[C@@:20]3([CH:21]=[CH:22][C@@H:23]([OH:24])[CH2:25]2)[CH2:19][CH2:18]1
Reactant: COc1ccc2c3c1O[C@@H]1CC(=O)C=C[C@]31CCN(C)C2
Agent: CCN1C=CC=CC1N
Agent: COc1ccc2c3c1OC1CC(O)C=CC31CCN(C)C2
Agent: COc1ccc2c3c1O[C@H]1C[C@@H](O)C=C[C@@]31CCN(C)C2
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2c3c1O[C@@H]1C[C@H](O)C=C[C@]31CCN(C)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
Lithium aluminium hydride (1M in ether, 1.2 ml, 1.20 mmol) was placed in a two necked round bottom flask fitted with a reflux condenser and nitrogen inlet. (-)-N-methy-ephedrine (0.23 g, 1.26 mmol) in ether (1 ml) was added dropwise and the solution was heated at reflux for 1 hour then cooled to room temperature. N-Ethyl-2-aminopyridine (0.31g, 2.52 mmol) in ether (1 ml) was added and the bright yellow solution was heated under reflux for a further 1 hour. The solution was cooled to -78° C. and solid (+) narwedine (97% e.e) (0.10 g, 0.35 mmol) was added. The suspension was warmed to 0° C., stirred for 20 hours and then allowed to warm to room temperature over 1 hour. The reaction was quenched 2M potassium carbonate (10 ml). The mixture was extracted into ethyl acetate (2×10 ml) and then the combined organic layer was washed with water (5 ml) and brine (5 ml) and dried over magnesium sulphate. Filtration and evaporation gave an orange oil which was shown by NMR and GC-MS to contain galanthamine and epigalanthamine in a 1:1 mixture. Flash chromatography on silica in dichloromethane-methanol 10:1 yielded (+) galanthamine (98% e.e.) (30% yield) and (+)-epigalanthamine (95% e.e) (26% yield). ##STR3##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=3)[C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]1=2
Reactant: Brc1ccccc1I
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2Br)cc1
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 1.0 g, 2.392 mmol), 1-bromo-2-iodobenzene (1.0 g, 3.588 mmol, Aldrich), Pd2(dba3)2 (138 mg, 0.239 mmol), Xantphos (437 mg, 0.478 mmol) and sodium-tert-butoxide (459 mg, 4.784 mmol) in toluene (20 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 12% ethyl acetate in hexane) to get 4-(2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a yellow coloured solid (1.2 g, 88.2%). m/z (ESI) 571.9 (M+H)+.
Reaction SMILES: [C:1]([OH:13])(=[O:12])/[CH:2]=[CH:3]/[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:14]1([CH2:20][CH2:21]O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:14]1([CH2:20][CH2:21][O:12][C:1](=[O:13])/[CH:2]=[CH:3]/[C:4]2[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCc1ccccc1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)OCCc1ccccc1

Procedure:
A solution of 1.80 g (10.0 mmol) of caffeic acid, 17.9 mL (150 mmol) of β-phenylethyl alcohol and 100 mg of p-toluenesulfonic acid in benzene (100 mL) were stirred overnight at reflux with a Dean Stark trap. Solvent and excess alcohol were removed by distillation and residue purified by silica gel chromatography (petroleum ether/CHCl3). Product was crystallized (ether/petroleum ether) to provide 67H-42-A as snow-white crystals, 1.0 g (35%): mp 128.0° C. 126°-128° C.) (Grunberger, D. et al., Experimentia, (1988) 44:230-2).
Reaction SMILES: [CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH2:5]1)[CH:2]=[CH2:3].[Na].CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[O:23]1)(=O)=O>C(O)C>[CH2:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:21][CH:22]3[CH2:26][O:25][C:24]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=4[Cl:40])([CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[CH:29]4)[O:23]3)[CH:10]=2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCc2cc(O)ccc2C1
Reactant: CS(=O)(=O)OCC1COC(Cn2ccnc2)(c2ccc(Cl)cc2Cl)O1
Agent: [Na]
Solvent: CCO
Product: C=CCN1CCc2cc(OCC3COC(Cn4ccnc4)(c4ccc(Cl)cc4Cl)O3)ccc2C1
Reaction time: 0.25 h

Procedure:
1.89 g of 2-allyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline are added to a freshly prepared solution of alcoholate from 0.23 g of sodium in 30 ml of dry ethanol, the mixture is stirred for 15 minutes, 4.07 g of (2RS,4SR)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate are added, and the mixture is then heated under reflux for 8 hours. After cooling, the ethanol is removed in a rotary evaporator, and the residue is taken up with a mixture of 50 ml of water and 50 ml of methylene chloride. The organic phase is shaken twice more with water, dried over magnesium sulfate and evaporated in a rotary evaporator. The residue is purified by column chromatography on silica gel using a mixture of ethyl acetate/methanol 4:1. 1.3 g of a colorless resin (26% of theory) which gradually crystallizes is obtained. Melting point 94°-95° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35](OCC)=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:41][CH2:42][CH:43]([OH:45])[CH3:44]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:40])=[C:14]([C:35]([NH:41][CH2:42][CH:43]([OH:45])[CH3:44])=[O:36])[C:15](=[O:34])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]([CH3:33])[C:23](=[O:24])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O
Product: CC(O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN(C)C(=O)OCc2ccccc2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methyl{[(phenylmethyl)oxy]carbonyl}amino)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-amino-2-propanol using conditions similar to Step 5 from Example 497 and obtained as a white solid: ES+ MS: 577 (M+H+).
Reaction SMILES: [CH2:1](P(=O)(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:37][C:38]1[N:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][CH:39]=1>CN(C)C=O.C(O)C>[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42](/[CH:44]=[CH:1]/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:43]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=Cc1cccc(Br)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1cccc(/C=C/c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl benzylphosphonate (4.57 mL, 21.91 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.367 g, 43.8 mmol) and 18-Crown-6 (2.316 g, 8.76 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with 6-bromopicolinaldehyde (4.89 g, 26.3 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 1 h. The reaction was gradually warmed to 120° C. and held there for 2 h. The reaction was cooled to room temperature and poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to an oil. The oil was dissolved in hexanes and reconcentrated to give something that appeared to be crashing out as a solid. The resulting residue (solid in oil) was suspended in ethanol, concentrated, and pumped under high vacuum to give a dark-colored, moist solid. The resulting residue was suspended in ethanol (total volume (solid+solution)=20 ml). The resulting suspension was placed in the freezer and held there overnight. The resulting precipitate was collected by filtration to give 2.46 g (43%) as a faint tan powder. 1H-NMR (CDCl3, 500 MHz) δ 7.69 (d, J=16.2, 1H), 7.60 (d, J=8.9, 2H), 7.53 (dd, J=7.9, 7.6, 1H), 7.41 (dd, J=7.6, 7.3, 2H), 7.31-7.38 (m, 3H), 7.11 (d, J=16.2, 1H). 13C-NMR (CDCl3, 126 MHz) δ 157.2, 142.3, 138.8, 136.3, 134.5, 128.9, 128.8, 127.4, 126.4, 126.2, 120.7.