Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[OH:12])=[O:5])[CH3:2].O.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH3:26])[N:9]([CH:21]([CH3:23])[CH3:22])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[CH3:20])[OH:12])=[O:5])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccccc2OC)n(C(C)C)c1C(O)c1ccc(Cl)cc1C
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-[(4-chloro-2-methyl-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate C, 3.5 g, 8.4 mmol) in dioxane (80 ml)/H2O (20 ml) were added 2-methoxy-phenyl boronic acid (2.0 g, 13.2 mmol), K2CO3 (3 g, 21.7 mmol). The mixture was degassed for 5 min and then Pd(PPh3)4 (1.7 g, 1.5 mmol) was added. The mixture was stirred at 100° C. for 2 h to give a complete conversion. Dioxane was removed under reduced pressure. The residual material was dissolved in EtOAc and extracted with brine. The aqueous layer was washed with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The product was fixed on silica gel and purified by flash chromatography (silica gel, solvent: CH2Cl2/EtOAc, 100:0→80:20) to give the title compound as a yellow foam. tR: 1.27 min (LC-MS 2); ESI-MS 433.3 [M+H]+ (LC-MS 2). 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.56-7.48 (m, 2H), 7.29-7.05 (m, 3H), 7.34-7.29 (m, 1H), 7.10-7.96 (m, 1H), 6.94-6.91 (m, 1H), 6.52 (d, 1H), 4.58-4.52 (m, 1H), 4.24 (q, 2H), 3.73/3.68 (s, 3H), 2.16 (s, 3H), 1.27 (t, 3H), 1.05 (d, 3H), 0.58 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C(O[N:41]=O)CC(C)C>C1C=CC=CC=1>[NH:1]1[C:2]2[C:3](=[C:4]([O:5][CH2:6][C@@H:7]3[CH2:11][CH2:10][CH2:9][N:8]3[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:19]=[CH:20][CH:21]=2)[CH:22]=[N:41]1
Reactant: Cc1c(N)cccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
A solution of t-butyl (2S)-2-[(3-amino-2-methylphenoxy) methyl]pyrrolidine-1-carboxylate (5.00 g, 16.33 mmol), potassium acetate (1.92 g, 19.6 mmol) and acetic anhydride (4.9 mL, 52.3 mmol) in benzene is treated dropwise with isoamylnitrite (4.3 mL, 32.7 mmol), heated at reflux temperature overnight, cooled to room temperature and filtered. The filtercake is washed with benzene. The filtrates are combined and concentrated in vacuo to give a yellow oil residue. The residue is purified by chromatography (silica gel, EtOAc:hexanes, 15:85). The purified oil (5.05 g) is dissolved in ethanol, treated with 40% aqueous NaOH, heated at reflux temperature for 45 min, cooled in an ice-water bath, neutralized to pH 8 with concentrated HCl and concentrated in vacuo to remove the ethanol. The resultant aqueous residue is extracted with EtOAc. The combined extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a yellow oil. This oil is purified by chromatography (silica gel, EtOAc:hexanes, 30:70) to give the title product as an off-white solid, 3.52 g, mp 125° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.C(O)(C)C.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[C:25]([C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1)[N:26]2[CH3:31]>C(N(CC)CC)C>[CH2:37]([N:35]1[CH:36]=[C:32]([C:25]2[N:26]([CH3:31])[C:27]3[C:23]([N:24]=2)=[C:22]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]2)[N:30]=[CH:29][N:28]=3)[CH:33]=[N:34]1)[CH3:38]
Reactant: CCn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCn1cc(-c2nc3c(N4CCC(n5c(=O)[nH]c6ccccc65)CC4)ncnc3n2C)cn1
Temperature: 80 °C
Yield: 96.5 %

Procedure:
To a solution of 1-piperidin-4-yl-1,3-dihydro-2H-benzimidazol-2-one (0.1 g, 0.33 mmol) in an anhydrous isopropanol (8 mL) and triethylamine (0.2 mL) was added 6-chloro-8-(1-ethyl-1H-pyrazol-4-yl)-9-methyl-9H-purine (65 mg, 0.25 mmol). The reaction mixture was heated to 80° C. for 16 hours, and cooled to room temperature. The resulting precipitates were collected by vacuum filtration, and triturated with 15 mL of ethanol at 75° C. for 30 min. The solids were collected by vacuum filtration to give 107 mg (97% yield) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 8.44 (s, 1H), 8.25 (s, 1H), 8.03 (d, 1H), 7.13 (dd, 1H), 6.93 (m, 3H), 5.61 (s, 2H), 4.53 (dd, 1H), 4.22 (q, 2H), 3.84 (s, 3H), 3.18 (s, 2H), 2.33 (m, 2H), 1.82 (d, 2H), 1.40 (t, 3H); MS (EI) for C23H25N9O: 444.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([OH:10])=[O:9].[CH2:22](O)[CH3:23]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15])[C:8]([O:10][CH2:22][CH3:23])=[O:9]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(Oc2ccc(F)cc2F)c1

Procedure:
A mixture of 3-(2,4-difluorophenoxy)-4-nitrobenzoic acid (1.0 g) and sulfuric acid (3 drops) in ethanol (5 ml) was refluxed for 8 hours. Ethanol was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated to give pale brown needles of ethyl 3-(2,4-difluorophenoxy)-4-nitrobenzoate (1.1 g).
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=[C:4]2[CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]([C:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]=4)=[CH:21][C:20]=3[N:3]12>CO.[Pd]>[CH3:1][CH:2]1[C:7](=[O:8])[N:6]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=[C:4]2[CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[C:22]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:31][CH2:30]4)=[CH:21][C:20]=3[N:3]12
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Reaction time: 20 h
Yield: 99.9 %

Procedure:
To a solution of tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.07 g, 0.117 mmol) in MeOH (15 mL) was added Pd/C (10%, 0.010 g) and the reaction mixture was stirred under an atmosphere of H2 (1 atm) for 20 h. The reaction mixture was filtered, washing with methanol (3×5 mL). The filtrate was concentrated in vacuo to give tert-butyl 4-(1-methyl-2-oxo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)piperidine-1-carboxylate (0.07 g, 100%), which was used directly in the next step.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:24]([C:31]1[N:32]=[C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:34][C:35]=1[CH2:36]Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(C)=O>[CH2:24]([C:31]1[N:32]=[C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[O:34][C:35]=1[CH2:36][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[CH:10][NH:11]3)[CH2:6][CH2:5]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Reactant: ClCc1oc(C2CCCCC2)nc1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(Cc2nc(C3CCCCC3)oc2CN2CCN(c3cccc4[nH]ccc34)CC2)cc1
Yield: 94 %

Procedure:
A mixture containing 4-piperazinoindole (0.2 mmole), potassium carbonate (0.5 mmole), potassium iodide (0.08 mmole) and 4-benzyl-5-chloromethyl-2-cyclohexyl oxazole (0.19 mmole) from example 2 was stirred in acetone (2 ml) for 16 hr. The mixture was concentrated in vacuo, water (10 ml) added, and the product extracted into dichloromethane (2×10 ml). The combined organics was washed with water (5 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the required product as a beige solid (94% yield). An ethanolic solution (5 ml) of the product was treated with fumaric acid (1 equivalent), and the resulting salt crystallized from diethyl ether to afford the titled product as a light beige powder.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:24])=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)[CH:8]=1.[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[Cl:23][C:6]1[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([Cl:21])[CH:15]=3)[N:13]=2)=[CH:8][C:3]([CH2:2][NH:1][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:4]([F:24])[CH:5]=1
Reactant: Cc1ccc(-n2nc(-c3cc(CN)c(F)cc3Cl)[nH]c2=O)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(-c3cc(CNC(=O)C(C)(C)C)c(F)cc3Cl)[nH]c2=O)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chloro-4-fluorophenyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-88, 0.200 g), pivaloyl chloride (0.5 mL), TEA (2.0 mL), dry THF (5 mL) to afford 0.074 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 2.32 (s, 3H), 4.29 (d, J=8.8 Hz, 2H), 7.43 (d, J=11.6 Hz, 1H), 7.60-7.67 (m, 1H), 7.79 (d, J=10.4 Hz, 1H), 7.96 (s, 1H), 8.15 (m, 1H), 12.60 (s, 1H); MS (m/z): 451.52 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:11])([CH3:10])[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5].[H-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:21]([N+]([O-])=O)[C:18]=1[C:19]#[N:20])([O-:16])=[O:15]>C1COCC1>[C:19]([C:18]1[C:17]([N+:14]([O-:16])=[O:15])=[CH:24][CH:23]=[CH:22][C:21]=1[O:1][CH2:2][C:3]([CH3:10])([CH3:11])[C:4]([NH:6][CH2:7][CH2:8][CH3:9])=[O:5])#[N:20]
Reactant: CCCNC(=O)C(C)(C)CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 3-hydroxy-2,2-dimethyl-N-propylpropanamide (1.59 g, 10.0 mmol) (Example 215d) in dry THF (30 mL) was carefully added NaH (60% in mineral oil, 400 mg, 10.0 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2,6-dinitrobenzonitrile (1.93, 10.0 mmol), and the reaction solution was stirred at 0° C.—RT under nitrogen overnight. The reaction mixture was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 60% EtOAc in hexanes to give the title compound as a pale yellow solid (2.21 g, 72%). MS 306 (MH+).
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:6]([F:10])=[CH:5][C:3]=1[NH2:4].C([Li])(CC)C.[I:16]I>C1COCC1>[F:1][C:2]1[C:8]([F:9])=[C:7]([I:16])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4]
Reactant: II
Reactant: Nc1cc(F)cc(F)c1F
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: Nc1cc(F)c(I)c(F)c1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a stirred solution of 2,3,5-trifluoro aniline (2.0 g, 13.605 mmol, 1.0 eq) in dry THF (40 mL) at −78° C., was added sec-butyl lithium (10.88 mL, 13.6 mmol, 1.0 eq) over 30 minutes. Stirring was continued at −78° C. for 2 h. A solution of iodine (4.14 g, 16.32 mmol, 1.2 eq) was added dropwise and reaction was slowly warmed to 20° C. over 1 hour (h). The reaction was quenched with 10% aq. Na2S2O3 solution and extracted with methyl tert-butyl ether (MTBE) (3×50 mL). The combined organic extract was washed with saturated (sat.) brine solution, dried over anhydrous Na2SO4, filtered and evaporated to dryness under reduced pressure. The crude product was column purified over silica using 0-10% EtOAc with hexanes as eluent to afford 2,3,5-trifluoro-4-iodoaniline (1.3 g, 35%) as pink solid: 1H NMR (400 MHz, CDCl3) δ 6.43-6.39 (m, 1H), 3.99 (brs, 2H); ESIMS m/z 274 ([M+H]+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[C:26]=1[F:27])(=O)=O.[CH3:30][O:31][C:32]1[CH:41]=[C:40]([CH3:42])[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.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>[F:27][C:26]1[C:11]2[C:12]([C:22](=[O:25])[NH:23][CH3:24])=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[O:14][C:10]=2[CH:9]=[CH:8][C:7]=1[C:39]1[C:40]([CH3:42])=[CH:41][C:32]([O:31][CH3:30])=[C:33]([CH:38]=1)[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1OC
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OS(=O)(=O)C(F)(F)F)c(F)c12
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)c(F)c12
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
A mixture of the above prepared 4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl trifluoromethanesulfonate (assumed 0.211 mmol), methyl 2-methoxy-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.078 g, 0.253 mmol), (Ph3P)4Pd (0.024 g, 0.021 mmol) and cesium carbonate (0.103 g, 0.317 mmol) in a mixture of H2O (0.2 mL)/1,4-dioxane (1 mL) was stirred at 95° C. for 2 hours 30 min. The mixture was left standing at r.t. overnight. The mixture was diluted with 3.5 ml 1,4-dioxane, filtered through a Whatman PVDF 0.45 um disk (with 3×1 ml washing). The filtrate was concentrated. The mixture was added with 3.5 ml 1N HCl, and then 6 ml H2O (yellow solid deposited on the wall of the flask). The aqueous was decanted, and the residue washed with 3×2 ml H2O and dried. LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=466.27, HPLC Rt=1.708 min.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:16]=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][NH:14]3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:26]([O:30][C:31](=[O:55])[C@@H:32]([NH:44][C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH2:33][N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C)C=O>[C:26]([O:30][C:31](=[O:55])[C@@H:32]([NH:44][C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])[CH2:33][N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][CH:37]=[N:38][C:39]=2[N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][CH2:12][CH2:13][NH:14][C:15]=3[N:16]=2)[CH2:3][CH2:2]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(Cl)ncnc21)NC(=O)OCc1ccccc1
Reactant: c1cc2c(nc1C1CCNCC1)NCCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.44 g of the compound of step c) were dissolved in 5 ml of anhydrous dimethylformamide. 0.7 ml of N,N-diisopropylethylamine were added together with 0.58 g of (S)-2-benzyloxycarbonylamino-3-(6-chloro-purin-9-yl)-propionic acid tert-butyl ester, and the mixture was stirred at ambient temperature overnight. Thin layer chromatographic control exhibited only incomplete reaction. Stirring was therefore continued for 6 hours at 40° C. until the reaction was complete. The solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed twice with water. The organic phase was dried with anhydrous magnesium sulfate and, after filtration, concentrated in vacuo. The raw material was chromatographed on silica gel with ethyl acetate and ethyl acetate/methanol (1:10). Yield: 224 mg.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Br>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:2]
Reactant: BrCCOCCBr
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCOCC2)c1
Yield: 46.5 %

Procedure:
Using methyl 3-(cyanomethyl)benzoate (1.0 g, 5.7 mmol), sodium hydride (60% in oil, 0.69 g, 17 mmol), bis(2-bromoethyl)ether (1.8 g, 6.9 mmol) and dimethyl sulfoxide (12 mL) as starting materials and in the same manner as in Reference Example 31, the title compound (650 mg, 46%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18]C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(Cl)(Cl)[Cl:29]>CCOC(C)=O>[ClH:29].[CH2:1]([O:8][C:9](=[O:26])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of trans-[4-(tert-butoxycarbonylamino-methyl)-cyclohexyl]-carbamic acid benzyl ester (4.00 g, 11.0 mmol) in EtOAc (40 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). To the reaction mixture was added CHCl3 (10 mL) and the mixture was stirred at ambient temperature for 3 hr. To the reaction mixture was 4 M hydrogen chloride in EtOAc (20 mL) and the mixture was stirred at ambient temperature for 1.5 hr, filtered, washed with EtOAc, and dried under reduced pressure to give trans-(4-aminomethyl-cyclohexyl)-carbamic acid benzyl ester hydrochloride (2.96 g, 90%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14](OCC)=[O:15])=[CH:10][C:9]=1[CH3:21])=[O:6])[CH3:3].C(=O)=O.CC(O)C.[CH3:30][NH:31][CH3:32]>C(Cl)(Cl)Cl>[CH3:30][N:31]([CH3:32])[C:14](=[O:15])[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([NH:7][C:5]([O:4][C:2]([CH3:22])([CH3:3])[CH3:1])=[O:6])=[C:9]([CH3:21])[CH:10]=1
Reactant: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)c(C)c1
Reactant: CNC
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: Cc1cc(OCC(=O)N(C)C)ccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 312 h
Yield: 100 %

Procedure:
To a 100 mL pressure vessel with a stirring bar was added ethyl 4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetate (1.00 g, 3.24 mmol). The vessel was cooled in a Dry Ice®/2-propanol bath to -78° C. and dimethylamine was condensed onto the solid to a final volume of ~30 mL. The reaction vessel was sealed, allowed to warm to ambient temperature and stirred for 13 days. The excess dimethylamine was vented and the residue was dissolved in CHCl3 and concentrated, twice to remove the last traces of dimethylamine. The crude product was chromatographed on 75 g of silica gel using 75/25 EtOAC-hexane as eluant to provide 1 g (100% yield) N,N-dimethyl-4-(1,1-dimethylethoxycarbonyl)amino-3-methylphenoxyacetamide as a white, crystalline solid. 1H NMR (CDCl3): d 1.50 (s, 9H), 2.22 (s, 3H), 2.96 (s, 3H), 3.07 (s, 3H), 4.63 (s, 2H), 6.09 (br s, 1H), 6.77, (s, 2H), 7.52 (br s, 1H). ##STR51## N,N-Dimethyl 4-amino-3-methylphenoxyacetamide (5-3)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][NH:24][CH3:25]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][N:24]([CH3:25])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 150 °C

Procedure:
A mixture of 1,4-bisbenzyl-2-(chloromethyl)piperazine (1 equivalent) and dimethylamine (5 equivalents) in ethanol, was heated at 150° C. for 36 hours in a sealed high pressure vessel. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was taken up in 1 N HCl, and the solution was washed with CH2Cl2. The water phase was made basic with a 30% aqueous NaOH solution (pH=12) and extracted with CH2Cl2. The organic extracts were collected and dried over Na2SO4. Evaporation of the solvent under reduced pressure afforded {[1,4-bisbenzylpiperazin-2-yl]methyl}dimethylamine. LC/MS (m/z): 324.3 (MH+), Rt 1.76 minutes.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:19][CH2:18][CH2:17][CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:13][CH:12]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(CN2CCCCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(CN2CCCCC2)nc1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A solution of 6-piperidin-1-ylmethyl-pyridin-3-ol (0.225 g, 1.17 mmol), 1-bromo-3-chloro propane (0.23 mL, 2.34 mmol), and K2CO3 (0.483 g, 3.50 mmol) in acetone (10 mL) was heated to reflux temperature. After 10 h the reaction mixture was cooled to rt, diluted with acetone (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated, giving the crude title compound as an oil (0.250 g, 80%).