Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C[Al](C)C.O(C1C=C(N(CC2C=CC=C(OC(F)(F)C(F)F)C=2)CC(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1.[O:44]([C:51]1[CH:52]=[C:53]([N:57]([CH2:65][C:66]2[CH:67]=[C:68]([CH:73]=[CH:74][CH:75]=2)[C:69](OC)=[O:70])[CH2:58][CH:59]([OH:64])[C:60]([F:63])([F:62])[F:61])[CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.CN([Al]CCl)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:2][N:3]([CH3:4])[C:69](=[O:70])[C:68]1[CH:73]=[CH:74][CH:75]=[C:66]([CH2:65][N:57]([C:53]2[CH:54]=[CH:55][CH:56]=[C:51]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:52]=2)[CH2:58][CH:59]([OH:64])[C:60]([F:63])([F:62])[F:61])[CH:67]=1
Reactant: CNC
Reactant: COC(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Agent: CN(C)[Al]CCl
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of N,N-dimethylamine hydrochloride (525 mg, 0.0064 mol) in 3.0 mL of toluene at −40° C. was added dropwise a 2.0 M solution of 20 trimethylaluminum in toluene (3:2 mL, 0.0064 mol) over 15 min. The reaction mixture was warmed to room temperature and stirred for 2 h. To a solution of methyl 3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]benzoate (209 mg, 0.00047 mol) from EX-612B in 2.5 mL of toluene at −10° C. was slowly added the (N,N-dimethylamino)-chloromethylaluminum reagent (850 μL, 0.00085 mol). The reaction mixture was warmed to room temperature then heated at 40° C. overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate and quenched with 10% aqueous potassium hydrogen phosphate. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 2:3 ethyl acetate in hexane to afford 195 mg (91%) of the desired N,N-dimethyl-3-[[(3-phenoxyphenyl)(3,3,3-trifluoro-2-hydroxypropyl)amino]methyl]-benzamide product as a pale yellow solid. Anal. calcd. for C25H25F3N2O3.0.5 H2O: C, 64.23; H, 5.61; N, 5.99. Found: C, 64.49; H, 5.77; N, 5.85. HRMS calcd. 459.1896 [M+H]+, found: 458.1887. 1H NMR (C6D6) δ7.01-6.95 (m, 3H), 6.92-6.87 (m, 5H), 6.79 (t, 1H), 6.46 (s, 1H), 6.37 (t, 2H), 4.91 (bs, 1H), 4.26 (s, 2H), 4.10 (bq, 1H), 3.84 (dd, 1H), 3.38 (dd, 1H), 2.53 (bs, 3H), 2.14 (bs, 3H). 19F NMR (C6D6) δ−78.69 (d, 3F).
Reaction SMILES: I/[CH:2]=[CH:3]/[CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C([Li])(C)(C)C.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[C:25](=[O:29])[CH2:26][CH2:27][CH:28]=1.C(O)(=O)C.O.C1COCC1>CCOCC.CCCCC.C#CCCC.[Cu+]>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C@@H:24]1[C@@H:28](/[CH:2]=[CH:3]/[CH2:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:27][CH2:26][C:25]1=[O:29]
Reactant: O=C1CCC=C1CCCCCCCBr
Reactant: I/C=C/CC1CCCCC1
Agent: [Cu+]
Agent: C#CCCC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: CC(=O)O
Product: O=C1CC[C@H](/C=C/CC2CCCCC2)[C@H]1CCCCCCCBr
Reaction time: 0.17 h
Yield: 104.7 %

Procedure:
A solution of 1.13 gm of 1-iodo-3-cyclohexyl-1-transpropene (4.50 mmol) in 22 ml dry ether was cooled to -78° with stirring under argon and treated with 8.60 ml of 1.07 M t-butyllithium in pentane. The reaction mixture was stirred for 2 hours at -78°, and transferred into a stirred, -78° solution of 532 mg of copper(I)pentyne in 12 ml dry ether (solubilized at 25° by addition of 1.50 ml hexamethylphosphorus triamide). The resultant complex was stirred for 0.5 hour at 1.0 gm (3.86 mmol) of the material prepared in Example XVI in 4.5 ml dry ether was injected dropwise over 10 minutes. The reaction mixture was stirred for 0.5 hours at -78°, 1.5 hours at -10° and 0.5 hour at 0°. The reaction mixture was processed as described, infra, in Example XVIII, excluding the treatment with acetic acid/water/THF to yield 1.55 gm of a yellow oil. Chromatography (85:15 silicic acid-Celite, benzene→ethyl acetate gradient elution) afforded 1.19 gm of a yellow oil, Rf (system II) 0.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15]1([C:20](Cl)=[O:21])[S:19][CH:18]=[CH:17][CH:16]=1.Cl.O>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH:5]2[C:20](=[O:21])[C:15]1[S:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)N1C(=O)C(C(=O)c2cccs2)c2cc(Cl)ccc21
Temperature: 8 °C
Reaction time: 0.5 h
Yield: 103.3 %

Procedure:
To a stirred solution of 429.9 g (2.04 mole) of 5-chloro-2-oxindole-1-carboxamide in 4 liters of N,N-dimethylformamide was added 547.9g (4.48 mole) of 4-(N,N-dimethylamino)pyridine, and then the mixture was cooled to 8° C. To this mixture was added, with stirring, a solution of 328 g (2.23 mole) of thenoyl chloride in 800 ml N,N-dimethylformamide over a 30 minute period, with the temperature being maintained between 8° and 15° C. Stirring was continued for 30 minutes, and then the reaction mixture was poured with stirring into a mixture of 510 ml of concentrated hydrochloric acid and 12 liters of water. Stirring was continued for 2 hours, and then the solid was collected by filtration and washed with water followed by methanol. The solid was dried to give 675.6 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([O:13][C:14](=[O:30])CC(C1C=CC(C2CCCCC2)=CC=1)=O)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:30])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:10])[CH3:12]
Reactant: CC(=O)c1cccc(F)c1
Reactant: CCOC(=O)CC(=O)c1ccc(C2CCCCC2)cc1
Product: CCOC(=O)CC(=O)c1cccc(F)c1
Yield: 91 %

Procedure:
The title compound was prepared from m-fluoro acetophenone, by a method analogous to the preparation of 3-(4-cyclohexylphenyl)-3-oxo-propionic acid ethyl ester in step A1 of Method A, except that the product was purified by vacuum distillation (bp 114-117° C. at 0.8-0.9 mm Hg) in 91% yield.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[C@@H:3]1[C:10]([O:12][CH:13]1[CH:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][CH:15]([CH3:22])[CH2:14]1)=[O:11].[C:23](=O)([O-])[O-].[K+].[K+]>CO.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:23][O:8][C:6]1[CH2:7][C@H:2]([CH3:1])[C@@H:3]([C:10]([O:12][C@H:13]2[C@H:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][C@@H:15]([CH3:22])[CH2:14]2)=[O:11])[C:4](=[O:9])[CH:5]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)[C@H]2C(=O)CC(=O)C[C@@H]2C)C1
Reactant: O=C([O-])[O-]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [K+]
Solvent: CO
Product: COC1=CC(=O)[C@H](C(=O)O[C@@H]2C[C@H](C)CC[C@H]2C(C)C)[C@@H](C)C1
Temperature: 23 °C
Reaction time: 12 h
Yield: 713.6 %

Procedure:
A solution of (1R, 3R, 4S)-p-menth-3-yl (1R, 2S)-2-methyl-4,6- dioxocyclohexanecarboxylate (2, 24.0 g, 77.8 mmol, 1 equiv) in methanol (300 mL) was treated with camphorsulfonic acid (ca. 800 mg, 3.9 mmol, 0.05 equiv) and the resulting solution was stirred at 23° C. for 12 h. The reaction mixture was neutralized by the addition of solid potassium carbonate (1.08 g, 7.78 mmol, 0.10 equiv) and the resulting suspension was filtered and the filtrate was concentrated. The residue was concentrated from toluene (2×15 mL) and then was purified by flash column chromatography (20% ethyl acetate-hexanes) to afford (1R, 3R, 4S)-p-menth-3-yl (1R, 6S)-4-methoxy-6-methyl-2-oxo-3-cyclohexene-1-carboxylate (4) as a white solid (mp 78°-80° C., 17.9 g, 71%). The regioisomeric enone, (1R, 3R, 4S)-p-menth-3-yl (1R, 6S)-2-methoxy-6-methyl-4-oxo-2-cyclohexene-1-carboxylate (5) was isolated in separate fractions and was resubjected to the reaction conditions to establish the equilibrium mixture of enones, in which the desired product 4 is strongly favored.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([NH2:21])[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:21][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:16]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccc(Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid 9 (150 g, 0.744 mol), 1,4-phenylenediamine 8 (150.0 g, 1.387 mol), anhydrous potassium carbonate (309 g, 2.236 mol), copper powder (2.0 g, 31.5 mol), cupric sulfate (10 mg) and water (2.25 l) was heated to reflux with stirring for 5 hr. It was then filtered hot through a fluted paper and allowed to stand overnight at room temperature. The potassium salt of the product was collected on a glass sinter and washed with ice-cold water (2×250 mL) followed by ice-cold ethanol (250 mL). The product was dissolved in boiling water (1250 mL) and acetic acid was then added until there was no further precipitation. The mixture was cooled with an external ice water bath and the product collected. The product was washed with ice-cold water (3×500 mL) followed by ice-cold ethanol (2×500 mL), dry ether (250 mL) and finally hexane (2×500 mL). The product was dried over P2O5 under vacuum to yield a light brown solid 10 (130.52 g 64%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33](O)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[C@H:41]([OH:42])[CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]4)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:16]=23)[CH2:2][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Product: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@H]4O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl (3R*,4R*)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Br:21]N1C(=O)CCC1=O.O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:21][CH:10]1[CH:5]2[CH2:4][CH:3]3[CH2:9][CH:7]([CH2:8][CH:1]1[C:2]3=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: BrC1C2CC3CC(C2)C(=C2C4CC5CC(C4)CC2C5)C1C3
Reaction time: 12 h

Procedure:
High selectivity for ketone introduction adjacent to double bonds can also be accomplished by selective bromination as shown in this example. 4-Bromoadamantylideneadamantane is prepared as follows. To a solution of 3 mmol (804 mg) of adamantylideneadamantane (X) in 40 ml of CH2Cl2 is added 6.6 mmol (1.175 g) of N-bromosuccinimide. The reaction mixture is refluxed and stirred for 12 hr. The reaction mixture is diluted with CH2Cl2 and ished twice with water and a saturated Na2S2O3 solution. The organic layer is dried over MgSO4 and evaporated. The yield of 4-bromoadamantylideneadamantane (XI) is over 95%). An analytically pure sample is obtained by crystallization from acetone and sublimation [115° C. (0.002 mm)]. Conversion of this intermediate to 4-ketoadamantilideneadamanatne (XII) is accomplished using the same procedure as in Example 4.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][Br:13])=[CH:7][C:6]=1[CH2:15][O:16]C(=O)C)(=O)C.Br.O>CO>[Br:13][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([CH2:15][OH:16])[CH:7]=1)=[O:14]
Reactant: CC(=O)OCc1cc(C(=O)CBr)ccc1OC(C)=O
Agent: Br
Solvent: O
Solvent: CO
Product: O=C(CBr)c1ccc(O)c(CO)c1
Yield: 68.9 %

Procedure:
2-Acetoxymethyl-4-bromoacetylphenyl acetate (18.6 g) was dissolved in methanol (90 ml), and 47% hydrobromic acid (100 ml) was added to the solution under ice-cooling with stirring. After reaction for 16 hours at room temperature, water was added to the reaction mixture under ice-cooling with stirring, and the precipitates were collected by filtration and washed with water and hexane to give 2-bromo-4'-hydroxy-3'-hydroxymethylacetophenone (9.54 g) having a melting point of 117-119° C.
Reaction SMILES: [C:1]([CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5]([O:7][CH3:8])=O)#[N:2].[Li+].[BH4-].[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)CBr.[H-].[Na+]>C1COCC1.CN(C=O)C>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:26]=1)[CH2:8][O:7][CH2:5][CH:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:1]#[N:2]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: COC(=O)C(CC#N)c1ccccc1
Agent: [BH4-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CCC(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
Methyl 3-cyano-2-phenylpropanoate (350 mg, 1.90 mmol) was treated with LiBH4 (2.28 mmol) in THF (20 ml) at 50° C. for 2 hours until completion of the reaction. It was quenched with water and extracted with ethyl acetate. The organic phase was washed with water, brine and dried with Na2SO4 before being concentrated to dryness. The crude product was then mixed with 3,5-bis(trifluoromethyl)benzyl bromide in DMF (20 ml) and sodium hydride (91 mg, 2.28 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and quenched with water, and extracted with ethyl acetate. The organic phase was washed with water, brine and concentrated. The crude residue was purified by silica flash chromatography (15% ethyl acetate in hexanes) to afford the desired product (405 mg, 55% in two steps). 1H NMR (500 MHz, CDCl3) δ ppm 2.78 (dd, J=116.79, 7.32 Hz, 1 H) 2.88 (m, 1 H) 3.33 (m, 1 H) 3.81 (m, 2 H) 4.65 (s, 2 H) 7.27 (m, 2 H) 7.31 (m, 1 H) 7.37 (m, 2 H) 7.73 (s, 2 H) 7.80 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][NH:27][CH2:28][C:29]3[NH:30][CH:31]=[CH:32][N:33]=3)=[CH:22][CH:21]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH:47]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[N:10]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:34])[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:27]([CH2:47][C:43]3[NH:42][CH:46]=[CH:45][N:44]=3)[CH2:28][C:29]3[NH:33][CH:32]=[CH:31][N:30]=3)=[CH:22][CH:21]=2)=[CH:16][CH:17]=1)[CH:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CNCc2ncc[nH]2)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(Nc1ccc(CN(C(=O)OCc2ccccc2)C2CCCCC2)cc1)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 101.8 %

Procedure:
The compound (242 mg) obtained in Example 87-4 and 2-imidazole carboxaldehyde (63.4 mg) were dissolved in anhydrous methanol (7.2 ml). Then, the solution was added with sodium cyanoborohydride (96.9 mg) and adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. Subsequently, the extract was washed with saturated saline solution and the residue was then dried with anhydrous magnesium sulfate, followed by distilling the solvent off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (282 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.OO.C([O-])([O-])=[O:12].[K+].[K+]>C(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N+:6]([O-:12])[CH:7]=1
Reactant: Cc1ccc(Br)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(Br)c[n+]1[O-]
Temperature: 50 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2-methyl-pyridine (1.47 g, 8.54 mmol) in CH2Cl2 (5 mL) was treated with a cold solution of 30% aqueous hydrogen peroxide (4.6 mL) in acetic acid (13.8 mL) at 0° C. The reaction mixture was then stirred at 50° C. for 18 h and poured into ice water (5 mL). The resulting mixture was adjusted to pH=9 by addition of K2CO3. The mixture was stirred at rt for 15 min and diluted with CH2Cl2 (10 mL). The aqueous layer was extracted three tomes with CH2Cl2. The combined extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 5-bromo-2-methyl-pyridine N-oxide as a white solid (1.6 g, 99%) which was used without further purification.
Reaction SMILES: CO.[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=2[N+:20]([O-])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O=[Pt]=O.CC(O)C>[C:3]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=2[NH2:20])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(C)O
Product: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Reaction time: 8 h

Procedure:
A mechanically stirred MeOH (3.8 L) suspension containing 1-[4-phenylmethoxy-3-nitrophenyl]ethanone (76.5 g, 282 mmol) was degassed with argon for 40 minutes at ~10° C. prior to addition of PtO2 (2.34 g, 10 mmol). Hydrogen was sparged into the reaction mixture at 8°-10° C. via a subsurface gas inlet. After eight hours, the completed reaction was degassed with Ar while being warmed to ~15° C., diluted with CHCl3 (250 mL) and filtered. The filtrate was stripped to give 70 g crude product which, after trituration for ten minutes with i-PrOH (450 mL) at 60° C., yielded 57.4 (84%) of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.CN(C)C=O.[Br:17][CH2:18][CH2:19][CH2:20]Br>O>[Br:17][CH2:18][CH2:19][CH2:20][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrCCCn1ccc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 25 %

Procedure:
To sodium hydride (0.9 g, 30 mmol, 80% oil dispersion) and indole (2.81 g, 24 mmoles) was added anhydrous dimethylformamide (50 mL). The resultant mixture was stirred at room temperature under argon for 1 h. Then neat 1,3-dibromopropane (7.3 mL, 72 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into water (120 mL) and the resultant slurry was extracted with diethyl ether (3×100 mL). After the organic extracts were combined and concentrated in vacuo, the crude material was purified by dry column chromatography (350 mL funnel filled with Silica 10–40μ, Sigma cat. S-6628) using as eluent a mixture of ethyl acetate and hexanes (1:49 v/v, containing 0.2% v/v isopropylamine) to yield 1.43 g of N-(3-bromopropyl)indole.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([O:29]C)=[O:28].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)Cc1ccccc1OCc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(COc2ccccc2CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a mixture of methyl 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.50 g), tetrahydrofuran (2 mL) and methanol (2 mL) was added a 1N aqueous sodium hydroxide solution (2.0 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (2 mL) and water were added to acidify the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated: to give crystals (0.41 g, 87%) of 2-[2-[3-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from methyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1.C1(C)C(S(O[CH:35]2[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]2)(=O)=O)=CC=CC=1>>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([O:14][C:11]2[CH:10]=[CH:9][C:8]([CH:7]3[CH2:6][CH2:5][N:4]([C:15]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[O:16])[CH2:3][CH:2]3[OH:1])=[CH:13][CH:12]=2)[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: Cc1ccccc1S(=O)(=O)OC1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C3CCN(C(=O)OCc4ccccc4)CC3O)cc2)C1

Procedure:
Analogously to Method I, 9.170 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidinecarboxylate and 11.00 g of tert-butyl 3-(toluenesulphonyloxy)azetidine-1-carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=0.23 (3:1 EtOAc-heptane); Rt=5.01.
Reaction SMILES: [C:1]12([O:11][C:12](=[O:26])[C@@H:13]([CH3:25])[NH:14]C(OCC3C=CC=CC=3)=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[ClH:27].CCOCC>CO.[Pd]>[ClH:27].[C:1]12([O:11][C:12](=[O:26])[C@@H:13]([CH3:25])[NH2:14])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: C[C@@H](N)C(=O)OC12CC3CC(CC(C3)C1)C2

Procedure:
N-Benzyloxycarbonyl-D-alanine 1-adamantyl ester (7.35 g, 20.6 mmol) was dissolved in 100 mL MeOH and 14.5 mL 1.25N HCl/ether. The solution was hydrogenated over 1.09 g of 10% Pd/C at 40 psi in a Parr apparatus at room temperature for 40 minutes. The solution was filtered through a Celite pad and the clear filtrate was evaporated to dryness to give a yellow oil, which was crystallized from EtOAc. A light yellow salt (4.2 g) was obtained. The crude product was recrystallized from MeOH-EtOAc; yielded 7.85 g (72%), mp 218°-219° (dec), 250 MHz nmr (CD3OD, ppm) 1.50 (d, 3H, J=7.35 Hz, β--CH3 of Ala), 1.72 (m, 6H, 1-adamantyl aliphatic protons of C's 2, 8 and 9), 2.18 (m, 9H, adamantyl aliphatic protons), 3.95 (q, 1H, J=7.35 Hz, α--H of Ala).