Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][C:10]([NH:13][CH:14]=O)([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][CH2:9][C:10]([CH3:12])([NH:13][CH3:14])[CH3:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(COC(c1ccccc1)c1ccccc1)NC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CNC(C)(C)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
A solution of 1-diphenylmethoxy-2-formylamino-2-methylpropane (8.2 g) in ether (50 ml) was added to a suspension of lithium aluminium hydride (2.2 g) in ether (100 ml) at a rate which maintained a gentle reflux. The mixture was stirred at room temperature for 18 hours, quenched by the sequential dropwise addition of water (2.2 ml), 5M aqueous sodium hydroxide solution (2.2 ml) and water (6.6 ml) and filtered. The filtrate was dried over sodium sulphate and evaporated to give the title compound as a colourless gum (7.5 g, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:23]=[CH:22][C:17]([CH2:18][NH:19][O:20][CH3:21])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:19]([CH2:18][C:17]2[CH:22]=[CH:23][C:14]([F:13])=[CH:15][C:16]=2[C:24]([F:27])([F:25])[F:26])[O:20][CH3:21])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCc1ccc(F)cc1C(F)(F)F
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(Cc1ccc(F)cc1C(F)(F)F)C(=O)C=C1OC(C)(C)OC1=O
Yield: 98 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-(4-fluoro-2-trifluoromethyl-benzyl)-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (98% yield): mp 129-130° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.76 (6H, s, CH3), 3.69 (3H, s, OCH3), 5.04 (2H, s, NCH2), 6.45 (1H, s, CH), 7.21 (1H, m, aromatic), 7.37 (1H, m, aromatic), 7.47 (1H, m, aromatic). Anal. calcd for C16H15F4NO5: C, 50.94; H, 4.01; N, 3.71. Found: C ,50.96; H, 4.07; N, 3.66.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]=[C:12]=[O:13]>C(OC(=O)C)C>[Cl:9][C:4]1[CH:3]=[C:2]([NH:1][C:12]([NH:11][CH3:10])=[O:13])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Product: CNC(=O)Nc1ccc(O)c(Cl)c1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 4-amino-2-chlorophenol (21.5 g; 0.15 mol) in ethylacetate (400 ml) is cooled to 0° C. and then methyl isocyanate (18.6 g; 0.15 mol) added slowly. The solution is stirred for one hour and then evaporated under vacuum to afford 30 g of title product, m.p. 188°-189° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]#[N:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C>[Br:1][C:2]1[C:3]([NH:9][C:15]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)=[NH:16])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: N#Cc1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: N=C(Nc1ncc(Br)nc1Br)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
A solution of 3,5-dibromo-pyrazin-2-ylamine (608 mg, 2.4 mmol), furan-2-carbonitrile (297 uL, 3.39 mmol) and AlCl3 (320 mg, 2.4 mmol) in dichloroethane (6 ml) was heated at 115° C. overnight. The reaction was cooled to room temperature and water (5 ml) was added. After 30 minutes, the resulting precipitate was collected and purified by column chromatography (SiO2, THF) to afford 595 mg (72%) of N-(3,5-dibromo-pyrazin-2-yl)-furan-2-carboxamidine as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J=3.4, 1.8 Hz, 1H), 7.3 (dd, J=3.1 Hz, 1H), 7.98 (s, 1H), 8.49(s, 1H), 8.69 (br. s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-n2ccnn2)cc1
Product: O=C/C=C/c1ccc(-n2ccnn2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1H-1,2,3-triazol-1-yl)-benzaldehyde (prepared as described in J. Med Chem. 1998, 41, 2390) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][N:8]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:16][CH2:15]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.C(=O)([O-])O.[Na+].C>O.C(#N)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][N:8]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:16][CH2:15]3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)N(C1CCN(Cc3ccccc3)CC1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: O=C1Nc2cc(O)ccc2CN1C1CCN(Cc2ccccc2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
A mixture of 18.0 g (0.0512 mol) of 3,4-dihydro-7-methoxy-3-(1-phenylmethyl-4-piperidinyl)-2(1H)-quinazolinone and 100 g of pyridine hydrochloride was heated to 160° C. with stirring for 3 hours. After cooling, the product was dissolved in 500 mL of water, the solution obtained was carefully treated with excess solid sodium hydrogen carbonate, whereupon a highly viscous oil was precipitated. This oil was taken up in 150 mL of methanol, the methanolic solution formed was clarified over activated charcoal, then freed from solvent in vacuo once more. The residue was stirred with 50 mL of acetonitrile and then brought to the boil. It was left to cool and the precipitate formed was suction filtered and dried in vacuo at ambient temperature. Yield: 10.8 g (63% of theoretical). Rf=0.32 (MP F). IR (KBr): 1649 (C═O) cm−1; MS: M+=337.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:11][CH2:12][CH:13]([CH2:20][CH2:21][CH3:22])[CH2:14][C:15](OCC)=[O:16].C(N(CC)CC)C.[BH4-].[Na+]>CCO>[NH2:1][C:2]1[C:3]([CH2:4][N:11]2[CH2:12][CH:13]([CH2:20][CH2:21][CH3:22])[CH2:14][C:15]2=[O:16])=[CH:6][CH:7]=[CH:8][N:9]=1
Reactant: Nc1ncccc1C=O
Reactant: CCCC(CN)CC(=O)OCC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCC1CC(=O)N(Cc2cccnc2N)C1
Temperature: 25 °C
Yield: 8 %

Procedure:
To a solution of 2-aminonicotinaldehyde x282 (8.19 mmol, 1 eq, 1 g) in 10 ml of EtOH, is added ethyl 3-(aminomethyl)hexanoate hydrochloride x31 (9.83 mmol, 1.2 eq, 2.06 g) and the resulting solution is stirred at room temperature for 1 h30. Then, triethylamine (9.0 mmol, 1.1 eq, 909 mg) is added and the mixture is stirred during 0.5 hour. Sodium borohydride is then added (9.83 mmol, 1.2 eq, 372 mg). The resulting mixture is stirred at room temperature for 20 hours, heated at 55° C. for 21 hours and then overnight at room temperature. Volatiles are removed under vacuum and CH2Cl2 (50 ml) and water (25 ml) are added. The organic layer is washed with water (25 ml) and dried over MgSO4. After filtration, volatiles are removed under reduced pressure. The crude product is purified by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2 (v/v/v)) and recrystallized in AcOEt to afford 1-[(2-aminopyridin-3-yl)methyl]-4-propylpyrrolidin-2-one 230 as a white solid (152 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[CH:5]=[CH:6][C:7]=1F.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[O:15][CH2:14][C:13]([F:17])([F:16])[F:12]
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccc(OCC(F)(F)F)c(Br)c1
Temperature: 90 °C
Yield: 97 %

Procedure:
3-Bromo-4-fluoronitrobenzene (1.0 eq) was added to a stirring solution of 2,2,2-trifluoroethanol (1.1 eq) and potassium carbonate (2.0 eq) in DMF. The solution was heated for 18 hours at 90° C. at which time no starting material was apparent by LCMS. The solution was cooled and filtered through Celite and the plug washed with EtOAc. The organic layer is then washed with brine and water, dried over MgSO4, filtered and concentrated to yield the desired product 97% pure, 80% yield. LC Rt=2.975 min. MH+=302.0
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]2[C:19]3[N:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13](=O)[NH:12][CH:11]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O.Cl>C(#N)C.O1CCOCC1>[Cl:23][C:13]1[N:12]=[CH:11][C:10]([CH2:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: COc1ccc(Cc2c[nH]c(=O)c3cccnc23)cn1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: COc1ccc(Cc2cnc(Cl)c3cccnc23)cn1
Temperature: 25 °C

Procedure:
396 mg (1.48 mmol) of 8-[(6-methoxy-pyridin-3-yl)-methyl]-6H-[1,6]naphthyridin-5-one in 24 ml of acetonitrile are mixed, whilst excluding air, with 1.4 ml (15 mmol) of phosphorus oxychloride and 0.78 ml of 4 N HCl in dioxane and stirred for 96 h at 65° C. After cooling to RT, partial concentration by evaporation takes place on a RE, then 40 ml of ice water and 10 ml of NH3 solution are added and extraction carried out 3 times with EtOAc. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated by evaporation to form 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contaminated with a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine); FAB-MS: (M+H)+=286; HPLC(gradient20-100) tRet=10.2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: Nc1ccccc1B(O)O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1ccccc1N

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodopyridin-3-yl)-N-methyl-3,5-bis(trifluoromethyl)benzamide (example 98, intermediate a) and 2-amino-phenylboronic acid after a reaction time of 4 hours. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Further purification by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (19%). MS (ESI): m/z=440.119 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH:5]=[CH:6][C:7](OCC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[CH2:5][CH2:6][CH2:7][OH:8]
Reactant: CCOC(=O)C=Cc1ccccc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1CCCO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
A solution of 980 mg of ethyl 2-methoxycinnamate in 15 ml of tetrahydrofuran was added dropwise to a dispersion of 290 mg of lithium aluminum hydride and 10 ml of tetrahydrofuran, whilst ice-cooling. After the addition was complete, the reaction mixture was stirred at room temperature for 1.5 hours, and then sufficient sodium sulfate decahydrate was slowly added, whilst ice-cooling, to the mixture in order to decompose any excess of the hydride. Insoluble materials were filtered off, and the filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 640 mg of 3-(2-methoxyphenyl)propanol as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:12])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:12][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Br:13])=[CH:15][CH:16]=2)=[CH:16][CH:15]=1
Reactant: OCCOCCOCCO
Reactant: BrCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Brc1ccc(COCCOCCOCCOCc2ccc(Br)cc2)cc1
Yield: 90.7 %

Procedure:
To a solution of 355 mg (8.88 mmol) of sodium hydride contained at 60% in mineral oil in dry dimethylformamide (60 ml) was added 851 mg (5.67 mmol) of triethylene glycol in an atmosphere of argon, and the mixture was reacted at 40°-50° C. for 30 min. followed by addition of 3.37 g (13.5 mmol) of 4-bromobenzyl bromide. The mixture was allowed to react at room temperature for 18 hours. To the reaction mixture at 0° C. was added a saturated aqueous solution of ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane yielded 2.51 g (5.14 mmol) of 1,12-bis(4-bromophenyl)-2,5,8,11-tetraoxadodecane.
Reaction SMILES: [C:1]1([C:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][C:9]([N:11]2[CH2:15][C:14]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]=5[C:13]=3[CH2:12]2)[CH:19]=[CH:18][CH:17]=4)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:32]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:8][CH2:9][N:11]2[CH2:15][C:14]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][C:24]=5[C:13]=3[CH2:12]2)[CH:19]=[CH:18][CH:17]=4)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CC(c1ccccc1)(c1ccccc1)c1ccccc1)N1CC2=C(C1)c1cccc3cccc2c13
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C(CCN2CC3=C(C2)c2cccc4cccc3c24)(c2ccccc2)c2ccccc2)cc1

Procedure:
Following the procedures set out in Example 1, 3.0 parts of 3,3,3-triphenylpropionyl chloride and 2.0 parts of acenaphto[1,2-C]pyrrolidene are reacted to provide 8-(3,3,3-triphenylpropionyl)acenaphto[1,2-C]pyrrolidine, melting at 159°-168°. 3.5 Parts of this amide are reacted with 3.6 parts of lithium aluminum hydride in tetrahydrofuran to provide 8-(3,3,3-triphenylpropyl)acenaphtho[1,2-C]pyrrolidine. This compound has the following structural formula. ##STR45##
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O.[CH3:26]O>>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O:14][CH3:26])=[O:13])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1Nc1cccc(C(F)(F)F)c1
Yield: 71 %

Procedure:
Reaction of 2-[[3-(trifluoromethyl)phenyl]amino] benzoic acid with methanol and sulfuric acid according to the procedure of Example 26 gives a 71% yield of 2-[[3-(trifluoromethyl)phenyl]amino]benzoic acid, methyl ester as a colorless oil.
Reaction SMILES: [Br-:1].[OH:2][C:3]([C:30]1[CH:35]=[CH:34][C:33](OC)=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:4]([O:6][C@@H:7]1[CH:12]2[CH2:13][CH2:14][N+:9]([CH2:15][C:16](=[O:23])[NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)([CH2:10][CH2:11]2)[CH2:8]1)=[O:5].N12CCC(CC1)[C@@H](OC(=O)C(O)(C1C=CC(OC)=CC=1)C1C=CC=CC=1)[CH2:39]2.N12CCC(CC1)[C@@H](OC(=O)C(O)(C1C=CC=CC=1)C1C=CC=CC=1C)C2>>[Br-:1].[OH:2][C:3]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:39])[C:4]([O:6][C@@H:7]1[CH:12]2[CH2:11][CH2:10][N+:9]([CH2:15][C:16](=[O:23])[NH:17][C:18]3[CH:22]=[CH:21][O:20][N:19]=3)([CH2:14][CH2:13]2)[CH2:8]1)=[O:5]
Reactant: COc1ccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Reactant: COc1ccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccccc2)cc1
Agent: Cc1ccccc1C(O)(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: [Br-]
Product: Cc1ccccc1C(O)(C(=O)O[C@H]1C[N+]2(CC(=O)Nc3ccon3)CCC1CC2)c1ccccc1

Procedure:
This compound is prepared using an method analogous to (R)-3-[2-hydroxy-2-(4-methoxy-phenyl)-2-phenyl-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]-octane bromide (Example 22) by replacing hydroxy-(4-methoxy-phenyl)-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate O) with hydroxy-phenyl-o-tolyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Intermediate P).
Reaction SMILES: C(O[C:4]([C:6]1[NH:7][N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C(OC(=O)[NH:25][CH2:26][C:27](O)([CH3:29])[CH3:28])(C)(C)C.C(OC(C1N(CC(NC(OC(C)(C)C)=O)C)N=C(COC2C=CC=CC=2)C=1)=O)C.CC1CN2N=C(COC3C=CC=CC=3)C=C2C(=O)N1.CC1CN2N=C(COC3C=CC=CC=3)C=C2CN1>>[CH3:28][C:27]1([CH3:29])[N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:6]2[CH2:4][NH:25][CH2:26]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)n[nH]1
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Agent: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Agent: CC1Cn2nc(COc3ccccc3)cc2CN1
Agent: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Product: CC1(C)CNCc2cc(COc3ccccc3)nn21

Procedure:
The compound was prepared from 5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester and 2-hydroxy-2-methyl-propyl-carbamic acid tert-butyl ester using the methods described in the preceding examples 11 (rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester), 12 (rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one), and 13 (rac-6-methyl-2-phenoxymethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine).
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][C@@H:21]([CH2:26][O:27][CH2:28][CH3:29])[C:22](OC)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Si:13]([O:20][C@@H:21]([CH2:26][O:27][CH2:28][CH3:29])[C:22]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:23])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)OC
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC[C@H](O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65.1 %

Procedure:
A solution of trimethylaluminium (2M in hexane, 2.75 mL, 5.49 mmol) was added dropwise to a stirred solution of 5-methylpyridin-2-amine (0.594 g, 5.49 mmol) in toluene (10 mL) cooled to 0° C., over a period of 5 minutes under nitrogen. The resulting solution was stirred for 15 minutes. A solution of (S)-methyl 2-(tert-butyldimethylsilyloxy)-3-ethoxypropanoate (Intermediate G3) (1.31 g, 4.99 mmol) in toluene (5 mL) was added dropwise over a period of 2 minutes. The resulting solution was allowed to warm to ambient temperature and then heated to reflux for 7 hours then allowed to cool to room temperature and 1M citric acid (20 mL) added, diluted with water (25 mL) and the mixture extracted with ethyl acetate (25 mL). The aqueous was re-extracted with ethyl acetate (25 mL), the organic phases combined, washed with water (5 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 10 to 100% EtOAc in isohexane to give (2S)-2-(tert-butyl-dimethylsilyl)oxy-3-ethoxy-N-(5-methylpyridin-2-yl)propanamide (1.1 g, 65%). 1H NMR (400 MHz, CDCl3) δ 0.18 (3H, s), 2.00 (3H, s), 0.99 (9H, s), 1.18 (3H, t), 2.30 (3H, s), 3.51-3.61 (2H, m), 3.63-3.67 (1H, m), 3.78-3.81 (1H, m), 4.41-4.43 (1H, m), 7.51 (1H, dd), 8.13-8.18 (2H, m), 9.03 (1H, s); m/z (ESI+) (M+H)+=339; HPLC tR=3.31 min.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:8]#[N:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][C:19]([O:21][CH3:22])=[O:20].ClC(Cl)(Cl)C(O)=O>CCOCC>[C:8]([C:6]([OH:7])([C:5]1[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:17]1[N:13]([CH3:12])[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)#[N:9]
Reactant: COC(=O)Cc1cccn1C
Reactant: Cc1ccc(C(=O)C#N)cc1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)Cc1ccc(C(O)(C#N)c2ccc(C)cc2)n1C
Yield: 15.4 %

Procedure:
A solution of 1.45 g (0.01 mole) of 4-methylbenzoylcyanide, 1.5 g (0.01 mole) of methyl 1-methylpyrrole-2-acetate and 40 mg (0.25 mmoles) of trichloroacetic acid in 4 ml of ether was stirred at 25° under nitrogen for 21 days. The precipitated solid was collected by filtration and washed with cold ether, than hexane. The combined filtrates were evaporated in vacuo. A second crop of crystals was taken from hexane. After recrystallization from toluene:hexane was obtained, 0.46 g (16 percent yield) of methyl 5-[cyanohydroxy(4-methylphenyl)-methyl]-1-methylpyrrole-2-acetate mp 117°-118°. H1NMR CDCl3 2.35 (s, 3 H); 3.35 (s, 3 H); 3.55 (s, 2H); 3.65 (s, 3 H); 5.90 (d, 1 H); 6.05 (d, 1H); 7.15 (d, 2H); 7.35 (d, 2H). MS m/e 281, 280, 266, 212 IRnujol 3425, 1700 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[OH:14])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH2:21]([N:11]1[CH2:12][CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]([OH:14])[CH2:10]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: OC1CNCCC1c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OC1CN(Cc2ccccc2)CCC1c1ccc(F)cc1
Yield: 74.2 %

Procedure:
A solution of 4.00 g (20.5 mmol) of (3RS,4RS)-4-(4-fluorophenyl)-piperidin-3-ol in 150 ml of ethanol was treated with 2.80 g (26.4 mmol) of sodium carbonate and refluxed. A solution of 2.50 ml (21.1 mmol) of benzyl bromide in 50 ml of ethanol was added dropwise within one hour and thereafter the mixture was held at reflux temperature for 2 hours. The pale brownish suspension was filtered and the filtrate was concentrated under reduced pressure. Subsequently, the residue was partitioned between methylene chloride and water, the organic phase was dried over magnesium sulphate and finally the solvent was distilled off under reduced pressure. The crude product was chromatographed on silica gel using a 2:3 mixture of ethyl acetate and hexane as the eluent. There were obtained 4.34 g (74% of theory) of (3RS,4RS)-1-benzyl-4-(4-fluoro-phenyl)-piperidin-3-ol as a colourless solid; MS: 285 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C(S([CH2:23][N+:24]#[C-:25])(=O)=O)=CC=CC=1.C[O-].[Na+]>CO>[CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([CH3:13])=[CH:6][C:3]=1[C:4]1[O:5][CH:25]=[N:24][CH:23]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])c(C)cc1-c1cnco1
Temperature: 90 °C

Procedure:
To a mixture of 2,5-dimethyl-4-nitrobenzaldehyde (75 mg, 0.42 mmol) and toluenesulfonylmethyl isocyanide (TOSMIC) (98 mg, 0.5 mmol) in methanol (2 mL), was added sodium methoxide (68 mg, 1.26 mmol). The mixture was sealed and heated at 90° C. for 15 hr. The reaction mixture was concentrated and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated. The 5-(2,5-Dimethyl-4-nitrophenyl)oxazole obtained was used in the next step without purification.