Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O)=[O:4].O[CH:14]1[CH2:19]SC(O)C[S:15]1.[Br-].[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]([CH2:5][C:6]1[S:15][CH:14]=[CH:19][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:4]
Reactant: OC1CSC(O)CS1
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: [Br-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)Cc1sccc1C(=O)OC
Temperature: 25 °C
Yield: 82.4 %

Procedure:
100.0 g of dimethyl 1,3-acetonedicarboxylate was dissolved in 2,800 ml of dioxane, and added thereto were 52.5 g of 2,5-dihydroxy-1,4-dithiane and 5.0 g of lithium bromide. The resulting mixture was refluxed for 15 hours, cooled to room temperature, and concentrated by evaporation. To the residue, 1,000 ml of n-hexane was added, stirred, and the hexane layer was separated. This extraction procedure was repeated twice using 500 ml portions of n-hexane. The separated n-hexane layers were combined and concentrated under reduced pressure to obtain 60.9 g (yield of 49%) of the title compound as an oil, which was directly used in the next step without any purification. An analytical sample of the title compound could be obtained by vacuum distillation.
Reaction SMILES: [CH:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>O1CCCC1>[CH2:23]([O:22][CH2:21][C:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCCC1
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(COCc1ccccc1)(C(=O)OCC)C1CCCCC1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
Diethyl cyclohexylmalonate (18.7 g) (ref. Bailstein 9, 739) was added to a stirred suspension of sodium hydride (4.8 g., 50% dispersion in oil) in dry tetrahydrofuran (50 ml) under nitrogen. The mixture was refluxed, with stirring, for one hour. The mixture was cooled and benzyl chloromethyl ether (13.9 g.) (Sigma Chemical Company) in dry tetrahydrofuran (50 ml) was added and the mixture was refluxed, with stirring, for three hours. The mixture was cooled and poured into water. The aqueous mixture was extracted with ether. The ether extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. Diethyl 2-benzyloxymethyl-2cyclohexylmalonate (30 g.) was obtained as a brown oil and was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCCC2)c1
Reactant: O=C(Cl)OCc1ccccc1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OCc2ccccc2)C2CCCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclopentylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O.[CH3:23][N:24](C)[CH:25]=O.C(N(CC)C(C)C)(C)C.CNC>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH:11]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:12]([N:24]([CH3:25])[CH3:23])=[O:14]
Reactant: CC(C)(C)OC(=O)NC(Cc1nc2ccccc2s1)C(=O)O
Reactant: CN(C)C=O
Agent: CNC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(Cc1nc2ccccc2s1)NC(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 80 %

Procedure:
The 3-(benzo[d]thiazol-2-yl)-2-(tert-butoxycarbonylamino)propanoic acid (0.15 g, 0.465 mmol) was combined with N,N,N′,N′-tetramethyl-o-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.21 g, 0.558 mmol), N,N-dimethylformamide (3.0 mL), N,N-diisopropylethylamine (120 μl, 0.92 mmol) and the 2 M dimethylamine in THF (1.0 mL). The reaction was stirred for 2 h., partitioned between ethyl acetate and 1 N HCl. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as a semisolid. The product was purified by Flash chromatography on a silica gel column eluting hexane:ethyl acetate gradient to give tert-butyl 3-(benzo[d]thiazol-2-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.13 g, 80%). Analytical LCMS (M+H)+: m/z=350.1.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=N[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C>[Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([N:39]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)=[O:9]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Br
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(-c2ccccc2)sc1Br)N1CCCCC1
Temperature: 25 °C
Yield: 7.7 %

Procedure:
2-Bromo-5-phenyl-thiophene-3-carboxylic acid (0.99 g, 3.5 mmol) was dissolved in DMF (20 mL). DIPEA (7.0 mmol), HATU (3.5 mmol) and piperidine (3.5 mmol) were added and the solution stirred at room temperature. The reaction mixture was partitioned between ethyl acetate and 1 N hydrochloric acid. The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated. The residue was purified by flash chromatography on silica, eluting with 0%-50% ethyl acetate in cyclohexane. The fractions containing the desired product were concentrated under vacuum to give a solid which was further purified by HPLC, eluting with 50%-90% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum then freeze-dried to give the title compound (95 mg). LCMS m/z 350.07 [M+H]+ R.T.=12.57 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.50 (d, 1H), 7.40 (t, 2H), 7.3 (m, 1H), 7.1 (s, 1H), 3.7 (m, 2H), 3.4 (t, 2H), 1.7 (m, 4H), 1.6 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>ClCCl>[Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:8][CH2:7]2
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(S(C)(=O)=O)CC3)cc1C(F)(F)F
Reaction time: 48 h

Procedure:
N-(8-Chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.193 g) in dichloromethane (10 ml) containing triethylamine (0.055 ml) was treated with methanesulfonyl chloride ((0.063 g) and the mixture stirred for 48 h. Water was added and the organic phase separated and solvent removed at reduced pressure. The residue was triturated with diethyl ether to give the title compound (0.19 g).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([OH:14])[CH:12]=[CH2:13].[CH3:18][O-:19].[Na+].[CH3:21][OH:22]>>[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([OH:14])[CH:12]=[CH2:13].[CH3:8][O:9][CH:10]([O:16][CH3:17])[C:11]([CH3:15])([O:14][C:18]([O:22][CH3:21])=[O:19])[CH:12]=[CH2:13]
Reactant: CO
Reactant: C[O-]
Agent: C=CC(C)(O)C(OC)OC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CC(C)(OC(=O)OC)C(OC)OC
Reaction time: 8 h

Procedure:
1,000 parts of toluene and 292 parts of 1,1-dimethoxy-2-methyl-2-hydroxy-3-butene are taken, 437 parts of a 30 percent strength solution of sodium methylate in methanol are then added slowly at from 90° to 100° C. and at the same time the methanol is distilled off, until the internal temperature reaches 107° C. 236 parts of methyl chlorocarbonate are subsequently added at 30° C. and stirring is continued for 8 hours. The mixture is then stirred with 500 parts of water, after which the organic phase is separated from the aqueous phase. Working up the organic phase by distillation gives, in addition to unconverted 1,1-dimethoxy-2-methyl-2-hydroxy-3-butene, 348 parts of 1,1-dimethoxy-2-methyl-2-(methoxycarbonyloxy)-3-butene, of boiling point/20 mm Hg=107°-110° C. The yield is 85% of theory.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[SiH](Cl)(Cl)Cl.[CH2:12]([Cl:16])[C:13](=[CH2:15])[CH3:14]>>[Si:1]([CH2:14][CH:13]([CH2:12][Cl:16])[CH3:15])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C=C(C)CCl
Reactant: CC[SiH](CC)CC
Agent: Cl[SiH](Cl)Cl
Product: CC[Si](CC)(CC)CC(C)CCl
Yield: 82.3 %

Procedure:
In a 100 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH, 13.6 g (0.1 mol) of Cl3SiH, and 9.1 g of methallyl chloride, followed by addition of 0.05 ml Pt catalyst solution at 21° C. There was a rapid and exothermic reaction to 61° C. in 2 min. Reaction appeared to have stopped and was heated to reflux over 4 hrs. when VPC showed complete reaction. Vacuum distillation yielded 17.03 g (82.5%) of Et3SiCH2CHMeCH2Cl, indicating that Cl3SiH is an effective promoter for the reaction of Et3SiH with methallyl chloride.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:60]=[CH:59][C:23]([CH2:24][C:25]2[S:29][C:28]([C:30]3[C:35]([Br:36])=[CH:34][N:33]=[C:32]([NH:37][CH2:38][CH2:39][N:40]4[C:44]([CH3:46])([CH3:45])[C:43](=[O:47])[NH:42][C:41]4=[O:48])[N:31]=3)=[CH:27][C:26]=2[CH2:49][CH2:50][O:51][Si](C(C)(C)C)(C)C)=[CH:22][CH:21]=1.O>O1CCCC1>[F:19][C:20]1[CH:60]=[CH:59][C:23]([CH2:24][C:25]2[S:29][C:28]([C:30]3[C:35]([Br:36])=[CH:34][N:33]=[C:32]([NH:37][CH2:38][CH2:39][N:40]4[C:44]([CH3:46])([CH3:45])[C:43](=[O:47])[NH:42][C:41]4=[O:48])[N:31]=3)=[CH:27][C:26]=2[CH2:49][CH2:50][OH:51])=[CH:22][CH:21]=1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCO[Si](C)(C)C(C)(C)C)c(Cc3ccc(F)cc3)s2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(Br)c(-c2cc(CCO)c(Cc3ccc(F)cc3)s2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Tetrabutylammonium fluoride (5 mL, 1M in tetrahydrofuran, 5.00 mmol) was added slowly to a solution of 1-(2-(4-(5-(4-fluorobenzyl)-4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)-5-bromopyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (1.8 g, 2.66 mmol) in tetrahydrofuran (40 mL) at rt. After stirring at rt for 4 h, 100 mL of water was added. The mixture was extracted with ethyl acetate 3×100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with methanol/dichloromethane (1:30) to give the title compound as a slightly yellow solid (1.2 g, 80%).
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)OCC
Reaction time: 2 h

Procedure:
To a solution of sodium (0.95 g) in ethanol (80 ml) are added diethyl malonate (7.2 g) and 5-(1-benzyloxycarbonyl-4-piperidyl)pentylp-toluenesulfonate (13.7 g). The mixture is refluxed for 2 hours with stirring. After the further addition of a mixture of sodium (0.25 g), ethanol (25 ml) and diethyl malonate (1.8 g), the reflux is continued for further 2 hours. After evaporation of ethanol, the residue is diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract is dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-ethoxycarbonylheptanoate as an oil. To a mixture of this ester and ethanol (30 ml) is added dropwise a solution of sodium hydroxide (6 g) in water (50 ml). After the addition is complete, the mixture is diluted with water (150 ml) and extracted with a mixture of ether and petroleum ether (1:1, 150 ml). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (300 ml). The organic extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 7-(1-benzyloxycarbonyl-4-piperidyl)-2-carboxyheptanoic acid as an oil. This acid is heated for 1 hour at 160°-165° C. with stirring. The resulting oil is purified by silica gel column chromatography using hexane-ethyl acetate (3:1-1:1) as an eluent to yield 7-(1-benzyloxycarbonyl-4-piperidyl)heptanoic acid (6.4 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:22])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:25].[CH2:36]([N:38]([CH2:41]C)[CH2:39]C)C.CNC>O1CCCC1>[C:12]1([CH3:19])[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([CH3:17])[C:11]=1[C:10]1[C:5]2[C:4](=[O:21])[N:3]([CH3:22])[C:2]([NH:1][C:36](=[O:25])[N:38]([CH3:41])[CH3:39])=[N:7][C:6]=2[N:8]([CH3:20])[CH:9]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C)c(-c2cn(C)c3nc(N)n(C)c(=O)c23)c(C)c1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cn(C)c3nc(NC(=O)N(C)C)n(C)c(=O)c23)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
To a solution of 2-amino-5-mesityl-3,7-dimethyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (0.040 g, 0.135 mmol) in tetrahydrofuran (1 mL) were added p-nitrophenyl chloroformate (0.073 g, 0.361 mmol) and triethylamine (0.050 mL, 0.361 mmol), and the mixture was allowed to stir at 60° C. for 2 hours. A 2M solution of dimethylamine in tetrahydrofuran (0.4 mL) was added to the mixture, followed by stirring at 60° C. for 15 hours. After cooling, the reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with hexane/ethyl acetate (4:1-1:2). The desired fractions were concentrated in vacuo, and the residual crystals were washed with diisopropyl ether-diethyl ether to give 0.012 g (24%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14](Cl)=[N:15][OH:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.O1CCCC1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:26]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=4)[O:16][N:15]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(Oc2ccc(F)cc2)nc1
Reactant: C#Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4ccc(F)cc4)nc3)no2)cn1
Temperature: 50 °C
Reaction time: 5 h
Yield: 18.9 %

Procedure:
To a mixture of (6-(4-fluoro-phenoxy)-pyridin-3-yl)-acetohydroximoyl chloride (25 mg) described in Manufacturing Example 75-1-4 and tetrahydrofuran (1 mL) were added 5-ethynyl-pyridin-2-ylamine (6.0 mg, 0.051 mmol) described in Manufacturing Example 28-1-3 and triethylamine (14 μL, 0.10 mmol), which was stirred for 5 hours at 50° C. The reaction mixture was allowed to room temperature, water was added at the same temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (3.5 mg, 19%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[C:7](Cl)Cl)=[CH:4][CH:3]=1.[OH-:12].[Na+].Cl.C[OH:16]>>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][C:7]([OH:16])=[O:12])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: Oc1ccc(C=C(Cl)Cl)cc1
Reactant: CO
Agent: Cl
Agent: [Na+]
Product: O=C(O)Cc1ccc(O)cc1
Yield: 94.5 %

Procedure:
In an autoclave were placed 0.5 g of p-hydroxy-β,β-dichlorostyrene ##STR12## 1.0 g of sodium hydroxide and 5 ml of methanol. The mixture was heated at 120°-130° C. for 4 hours. Then the methanol was distilled off. To the residue was added 10 ml of water and the mixture was refluxed for 30 minutes. After completion of the reaction, the reaction mixture was acidified by concentrated hydrochloric acid and was extracted three times with 10 ml of ether. The extract was dried over anhydrous magnesium sulfate and the ether was distilled off. The residue was purified by silica gel column chromatography by using benzene, n-hexane and ethyl acetate (10:10:3) as a developer solvent to afford 0.3 g of p-hydroxyphenylacetic acid ##STR13## Yield 94.5%, m.p. 151°-152° C. NMR (CDCl3, δ, ppm) 3.50 (s, 2H), 4.25 (b.s., 2H), 6.92 (m, 4H)
Reaction SMILES: Cl.[CH2:2]([C:8]1[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[N:14]([CH2:17][C:18]([CH3:26])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:15]=[N-:16]>>[CH3:26][C:18](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][N:14]1[CH:7]=[C:6]([CH2:5][CH2:4][CH2:3][CH2:2][C:8]2[N:9]=[C:10]([NH2:13])[NH:11][CH:12]=2)[N:16]=[N:15]1
Reactant: C#CCCCCc1c[nH]c(N)n1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(CCCCc2c[nH]c(N)n2)nn1
Yield: 88 %

Procedure:
4-Hex-5-ynyl-1H-imidazol-2-ylamine hydrochloride (0.089 g, 0.4.47 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.085 g, 0.491 mmol) following the general procedure for click reactions outlined above to produce 4-{4-[1-(2-Methyl-3-phenyl-allyl)-1H-[1,2,3]triazol-4-yl]-butyl}-1H-imidazol-2-ylamine (0.132 g, 79%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 8.36 (s, 1H), 7.03 (m, 5H), 6.49 (s, 1H), 6.25 (s, 1H), 5.05 (s, 2H), 2.67 (t, 2H), δ 2.73 (t, 2H), δ 1.56 (s, 3H), δ 1.42 (m, 4H) ppm; 13C (75 MHz, CD3OD) δ 147.3, 144.7, 136.4, 132.7, 129.9, 128.9, 128.6, 128.5, 128.3, 127.5, 127.2, 126.9, 108.7, 61.2, 27.4, 27.3, 23.8, 22.8, 14.8 bpm; HRMS (ESI) calcd for C19H24N6(M+) 336.2135, found 336.2134.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.[ClH:18].[Cl:19][CH2:20][CH2:21][N:22]1[CH2:28][CH:27]2[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]2)[CH2:23]1.C(N(CC)CC)C>C(O)C>[ClH:19].[ClH:18].[CH:27]12[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([CH2:21][CH2:20][N:12]1[CH2:13][CH2:14][C:9]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:28]2
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 51.4 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.31 g, 0.01 mole), 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (2.49 g, 0.01 mole) and triethylamine (3.03 g) in absolute ethanol (50 ml) is refluxed for 24 hours. The reaction mixture is filtered. Hydrogen chloride gas is bubbled through the filtrate. The product is filtered off, washed with ethanol and sucked dry. Recrystallization from methanol gave the product (2.34 g), mp 265°-270° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=[O:12])=[CH:6][CH:5]=1.[OH2:14].[CH3:15][CH2:16][O:17][C:18]([CH3:20])=[O:19]>C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([CH:20]([C:6](=[O:14])[CH:7]([CH3:10])[CH3:8])[C:18]([O:17][CH2:16][CH3:15])=[O:19])=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CCOC(C)=O
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)Cc1ccc(Br)cc1)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a suspension of NaH (7.6 g, 158 mmol) in toluene (142 mL) at 0° C. was added dropwise a solution of ethyl isobutylylacetate (20 g, 126 mmol) in toluene (52 mL) and the resulting solution was stirred under an argon atmosphere for 30 min. Then, a solution of 4-bromophenylacetyl chloride (29.4 g, 126 mmol, prepared as described in reference example 1) in toluene (98 mL) was slowly added and the reaction mixture stirred at room temperature overnight. The resulting solution was poured into H2O-EtOAc and extracted with H2O (2×). The organic phase was washed with brine, the aqueous phase was acidified and extracted with EtOAc, and the combined organic phases were dried and concentrated. The residue was chromatographed on silica gel (hexane-EtOAc, 5%) to afford the title compound (29 g, 65%).
Reaction SMILES: [N-]=[N+]=[N-].O.[CH2:5]([N:7]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C:12]1=[O:17])[CH2:8][CH3:9])[CH3:6].[N-:18]=[N+]=[N-].[Na+].[ClH:22]>C(OCC)(=O)C.CO>[ClH:22].[CH2:5]([N:7]([CH2:10][CH:11]1[NH:18][C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:8][CH3:9])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN(CC)CC1CCCCC1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)CC1CCCCC(=O)N1
Temperature: 25 °C
Reaction time: 0.8 h

Procedure:
While maintaining a reaction temperature of from -10° to -5° C., a solution azide (10.0 g, 0.154 mol) in as little water as possible is added dropwise to a solution of 2-[(diethylamino)methyl]-cyclohexanone (22.0 g, 0.1 mol) in concentrated hydrochloric acid (200 ml). After the cooling has been stopped, the mixture is stirred (48 minutes) at ambient temperature. After further cooling to -10° to -5° C., sodium azide, (5.0 g, 0.77 mol) is added in the same way as described above, after which the mixture is stirred for a further 24 hours at ambient temperature. Then, the reaction mixture is concentrated under water jet vacuum, the syrupy residue is taken up in 10 ml of water, mixed with substantially anhydrous sodium carbonate and stirred thoroughly with ethyl acetate (200 ml). After removal of the solvent the organic phase leaves an oily residue which can be converted into a hydrochloride by treatment with ethereal hydrogen chloride solution. M.p. 171° C. (ethyl acetate/methanol 3:1 v/v). Yield: 10.1 g.