Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]([F:10])=[N:8][CH:9]=1)[CH3:3].[CH3:11][C@@H:12]1[NH:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:10][C:7]1[N:8]=[CH:9][C:4]([C@H:2]([N:17]2[CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C@@H:12]2[CH3:11])[CH3:3])=[CH:5][CH:6]=1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC(Br)c1ccc(F)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A mixture of 5-(1-bromoethyl)-2-fluoropyridine (Example 146, Step 2; 8.95 g, 43.9 mmol) and (S)-tert-butyl 3-methylpiperazine-1-carboxylate (9.22 g, 46.1 mmol) (CNH Technologies Inc.) in acetonitrile (200 mL) was treated with K2CO3 (7.27 g, 52.6 mmol) and KI (1.456 g, 8.77 mmol). The mixture was placed into a pre-heated (70° C.)oil bath and allowed to stir under an inert atmosphere overnight. The heating bath was then removed and the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with chloroform (200 mL) and water (300 mL). The organic layer was separated, and the aqueous layer was extracted with chloroform (1×100 mL). The combined organic layers were then washed with a saturated brine solution, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (120 g silica gel, 0% to 40% EtOAc/hexanes) to provide tert-butyl (3S)-4-((1R)-1-(6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (5.02 g, 15.52 mmol, 35.4% yield) (lower Rf diastereomer) as a viscous yellow-orange oil. m/z (ESI, +ve) 324.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.09-8.14 (m, 1H); 7.75 (td, J=8.0, 2.2 Hz, 1H); 6.90 (dd, J=8.5, 2.8 Hz, 1H); 3.94 (br. s., 1H, =); 3.55 (br. s., 1H); 3.37 (br. s., 2H); 3.20 (br. s., 1H); 2.71 (ddd, J=11.3, 7.6, 3.5 Hz, 1H); 2.43 (dd, J=9.6, 5.5 Hz, 2H); 1.43 (s, 9H); 1.38 (d, J=6.8 Hz, 3H); 0.99 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][NH:14][CH2:15][CH2:16][C:6]=3[C:5]=2[CH:4]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:14]2[CH2:15][CH2:16][C:6]3[C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[C:12]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13]2)=[O:28])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccc(OC)cc21
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CCc2c1[nH]c1ccc(OC)cc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 9-methoxy-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.42 (1H, br s), 7.98 (1H, s), 7.62 (2H, m), 7.28 (1H, m), 7.16 (2H, m), 6.93 (1H, d), 6.88 (1H, dd), 4.24 (4H, m), 3.88 (3H, s), 3.23 (2H, m), 1.23 (3H, t); MS (ES): 409 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11](Cl)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:32](=[O:39])[NH:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11]([N:36]3[CH2:35][CH2:34][C:33]4([N:29]([C:26]5[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][CH:27]=5)[CH2:30][NH:31][C:32]4=[O:39])[CH2:38][CH2:37]3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C1NCN(c2ccc(Br)cc2)C12CCNCC2
Reactant: Fc1ccc(C2(c3ccc(F)cc3)C=CC(Cl)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCN(c2ccc(Br)cc2)C12CCN(C1C=CC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 3.5 h

Procedure:
A mixture of 3.7 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene, 3.1 g of 1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 204°-207° C), 1.7 g of potassium carbonate, 2 g of potassium iodide and 25 ml of dimethylformamide is stirred at 65°-75° C for 3.5 hours. The reaction mixture is then poured into water. The precipitated powder is collected by filtration and dissolved in methanol. The solution is concentrated to some degree, and acetone is added thereto, and the whole mixture is cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 219°-221° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].F[C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1>O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccnc(F)c1
Reactant: OCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(OCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 58.8 %

Procedure:
To a mixture of 4-bromobenzyl alcohol (4.54 g, 24.3 mmol) and N,N-dimethylformamide (50.0 mL) were added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) was added at 0° C. under nitrogen atmosphere, which was stirred for 50 minutes at room temperature. 2-Fluoro-4-methylpyridine (1.80 g, 16.2 mmol) was then added thereto at 0° C., and stirred for 2 hours and 30 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, and filtered. The filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (2.65 g, 58.8%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[CH2:27]([N:29]([CH2:36][CH3:37])[CH:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:28]>>[CH2:36]([N:29]([CH2:27][CH3:28])[CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:31]1)[CH3:37]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN(CC)C1CCCNC1
Agent: Cl
Product: CCN(CC)C1CCCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and N,N-diethylpiperidin-3-amine dihydrochloride. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.26 (br. s., 6 H) 1.57 (br. s., 2 H) 1.76-2.17 (m, 2 H) 2.36-2.90 (m, 9 H) 3.02 (br. s., 1 H) 3.70 (br. s., 1 H) 4.52-4.92 (m, 1 H) 7.48-7.60 (m, 3 H) 7.63-7.73 (m, 1 H) 7.95-8.10 (m, 2 H) 8.43 (s, 1 H); ESI-MS m/z [M+H]+ 459.3.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:38]=[N:39][NH:40][CH:41]=5)[CH:28]=[CH:27][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Product: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)c(F)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 144. MS (ESI+) 449.0. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.90-7.83 (m, 1H), 7.74-7.66 (m, 1H), 7.45-7.35 (m, 2H), 7.26 (d, J=1.5, 1H), 7.16 (dd, J=8.3, 1.6, 1H), 4.33 (t, J=4.9, 2H), 3.41 (t, J=4.9, 2H)
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1>CN(C)C=O>[O:22]1[CH2:23][CH2:24][O:25][CH:21]1[CH2:20][CH2:19][O:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][CH:7]2[S:11][C:10](=[O:12])[NH:9][C:8]2=[O:13])=[CH:4][CH:3]=1
Reactant: BrCCC1OCCO1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(OCCC3OCCO3)cc2)S1

Procedure:
A procedure similar to that described in Preparation 46 was repeated, except that 15.0 g of 5-(4-hydroxy-benzyl)thiazolidine-2,4-dione, 8.80 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 17 ml of 2-(2-bromoethyl)-1,3-dioxolane and 80 ml of dimethylformamide were used, and that the product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 6.67 g of the title compound, melting at 102-104° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:47])[CH2:17][NH:18][C:19](=[O:46])[CH2:20][CH:21]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]2[S:35]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)(=[O:37])=[O:36])[CH2:10][CH2:9]1)=O)(C)(C)C>C(OCC)(=O)C.C(OCC)C>[ClH:44].[Cl:45][C:40]1[CH:39]=[C:38]([S:35]([N:22]2[CH:21]([CH2:20][C:19]([NH:18][CH2:17][C:16](=[O:47])[NH:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:46])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=3)(=[O:37])=[O:36])[CH:43]=[CH:42][C:41]=1[Cl:44]
Reactant: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)CC2c3ccccc3-c3ccccc3N2S(=O)(=O)c2ccc(Cl)c(Cl)c2)CC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cl
Product: O=C(CNC(=O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)NCC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 199.1 %

Procedure:
To a solution of 4-[(2-{2-[5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetylamino}-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.2 mmol) in ethyl acetate (5 mL) 2.4M hydrogen chloride in ethyl acetate (4 mL, 9.6 mmol) was added. The reaction mixture was stirred at room temperature overnight, then diluted with diethyl ether (25 mL). The precipitated product was filtered off and washed with diethyl ether to yield 127 mg (87%) of the title compound as white crystals. MS (EI) 602.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:20]=1[F:34].C(Cl)Cl>CO.Cl[Pd]Cl.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:21][C:20]=1[F:34]
Reactant: CC1(C)OB(c2ccc(Cl)c(F)c2)OC1(C)C
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccnc(-c2ccc(Cl)c(F)c2)c1
Temperature: 100 °C
Yield: 79.3 %

Procedure:
Methyl 2-chloroisonicotinate (1.2 g, 6.99 mmol), potassium carbonate (0.580 g, 4.20 mmol) and PdCl2 (dppf) (0.122 g, 0.17 mmol) were combined in a microwave vial. 2-(4-Chloro-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1 g, 8.19 mmol) dissolved in MeOH (15 mL) was added. The reaction mixture was heated in a single node microwave reactor at 100° C. for 15 min. DCM (125 mL) and water (125 mL) were added, shaken and the phases separated. The aqueous phase was extracted with DCM (125 mL). The combined organic phases were washed with brine (250 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient of 10% EtOAc in heptane over 3 CV and then 10 to 50% EtOAc in heptane over 12 CV was used as mobile phase. The product was collected using the wavelength 253 nm. Methyl 2-(4-chloro-3-fluorophenyl)isonicotinate (1.473 g, 79%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 4.00 (s, 3H), 7.48-7.54 (m, 1H), 7.76-7.83 (m, 2H), 7.88-7.94 (m, 1H), 8.24-8.27 (m, 1H), 8.83 (dd, 1H).
Reaction SMILES: O.[CH3:2][C:3]1O[C:5]([CH3:14])=[CH:6][C:7](=[O:13])[C:8]=1[C:9]([O:11][CH3:12])=[O:10].[NH2:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]1>C1(C)C=CC=CC=1>[CH3:2][C:3]1[N:15]([CH:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]([CH3:14])=[CH:6][C:7](=[O:13])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1c(C)oc(C)cc1=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(C)n(C2CC(C)(C)NC(C)(C)C2)c(C)cc1=O
Temperature: 25 °C

Procedure:
A 500 ml, 3-neck, round-bottom flask is equipped with a mechanical stirrer, thermometer and a Dean-Stark water trap topped with a water cooled condenser. The flask is charged with a mixture of 45.5 g (0.25 moles) of the methyl 2,6-dimethyl-4-oxopyran-3-carboxylate prepared as described above, 39.1 g (0.25 m) 4-amino-2,2,6,6-tetramethylpiperidine, and 300 ml toluene. The stirred mixture in the flask is heated to boiling by means of an oil bath and the water formed during the reaction is collected in the trap. After 4 hours of reflux a total of 3.8 ml water is collected and the flask and its contents are cooled to room temperature. The toluene is removed by means of a rotary evaporator. On standing and cooling the residue deposits crystals of the title product which are further purified by fractional crystallization.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[O:18][C@@H:17]([CH2:19][O:20]C(=O)C3C=CC=CC=3)[C@:15](C(=O)C3C=CC=CC=3)([OH:16])[C@:13]2(C(=O)C2C=CC=CC=2)[OH:14])[N:3]=1.[NH3:45]>CO.[Cu]>[NH2:45][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[N:4]([C@H:12]2[O:18][C@@H:17]([CH2:19][OH:20])[C@H:15]([OH:16])[C@@H:13]2[OH:14])[N:3]=1
Reactant: O=C(OC[C@@H]1O[C@H](n2nc(Br)c3c(=O)[nH]cnc32)[C@](O)(C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1)c1ccccc1
Reactant: N
Agent: [Cu]
Solvent: CO
Product: Nc1nn([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)c2nc[nH]c(=O)c12
Yield: 36 %

Procedure:
3-Bromo-1-(2′,3′,5′-O-tribenzoyl-β-L-ribofdranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one 24 (714 mg, 1.08 mmoles) was dissolved in MeOH saturated with NH3 at 0 C (30 mL). Thin copper wire (21 mg, 0.33 mmole) and cuprous chloride.(33 mg, 0.33 mmole) were added. The mixture in a sealed, stainless steel bomb was heated at 100 C for 16 h. After cooling, silica gel (2 g) was added to the reaction mixture and, the solvent evaporated. The silica gel absorbed with the crude product was loaded onto a silica column and eluted with 5% Et3N, 17% MeOH in CH2Cl2). The product was further purified by recrystallization (95% EtOH) to afford 3-amino-1-β-L-ribofuranosylpyrazolo[3,4-d]pyrirnidin-4(5H)-one 26 as a white needles (110 mg, 36%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38]Cl)=[O:28])([CH3:25])([CH3:24])[CH3:23].CCN(C(C)C)C(C)C>CC#N>[C:22]([O:26][C:27]([N:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[N:31]=[C:30]1[CH2:38][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[CH3:14])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(NCCCCNC(=O)OC(C)(C)C)c1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccccn1)N(CCCCNC(=O)OC(C)(C)C)Cc1nc2ccccc2n1C(=O)OC(C)(C)C

Procedure:
Using General Procedure A, [4-(1-pyridin-2-ylethylamino)-butyl]-carbamic acid tert-butyl ester, N-(t-butoxycarbonyl)-2-chloromethylbenzimidazole, and KI in anhydrous CH3CN were reacted with DIPEA to obtain 2-{[(4-tert-butoxycarbonylaminobutyl)-(1-pyridin-2-ylethyl)-amino]-methyl}benzimidazole-1-carboxylic acid tert-butyl ester. Conversion to the HBr salt gave COMPOUND 219 as a white solid. 1H NMR (D2O) δ 1.55 (br, 4H), 1.63 (d, 3H, 6.9 Hz), 2.62 (m, 1H), 2.80 (m, 1H), 2.88 (br, 2H), 4.43 (d, 2H, J=2.4 Hz), 4.58 (m, 1H), 7.60 (m, 2H), 7.78 (m, 2H), 7.97 (t, 1H, J=6.6 Hz), 8.12 (d, 1H, J=8.1 Hz), 8.56 (t, 1H, J=8.0 Hz), 8.77 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 13.17, 24.44, 24.97, 39.57, 47.46, 52.31, 59.31, 114.26 (2C), 126.57, 126.74, 126.92 (2C), 130.92 (2C), 141.83, 148.12, 152.04, 156.52. ES-MS m/z 324 (M+H). Anal. Calcd. for C19H25N5.3.1HBr.1.8H2O.0.2C4H10O: C, 38.26; H, 5.47; N, 11.27; Br, 39.85. Found: C, 38.22; H, 5.13; N, 11.16; Br, 40.00.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]2[N:9]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:10]([Cl:12])=[N:11][C:7]=2[CH:6]=1)=[O:4].C1COCC1.O[Li].O>O>[Cl:12][C:10]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[C:8]2[CH:19]=[CH:20][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=1
Reactant: COCCOCn1c(Cl)nc2cc(C(=O)OC)ccc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COCCOCn1c(Cl)nc2cc(C(=O)O)ccc21
Temperature: 23 °C
Reaction time: 18 h
Yield: 860.6 %

Procedure:
To a mixture of 2-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-5-carboxylic acid methyl ester (0.600 g, 0.200 mmol), THF (10 mL), and water (3.33 mL), was added LiOH.H2O (47.0 mg, 1.96 mmol). The mixture was stirred 18 h at 23° C. The solvent was evaporated, water (5 mL) was added and the mixture acidified to with 1M HCl. The resulting white precipitate was filtered and dried to yield the titled compound (0.490 g, 86%). MS (ESI/CI): mass calcd. for C12H13ClN2O4, 284.1; m/z found, 285.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.93 (s, 2H), 8.30 (s, 1H), 8.18 (d, J=1.4 Hz, 1H), 7.96 (dd, J=8.6, 1.5 Hz, 1H), 7.90 (dd, J=8.5, 1.6 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 5.74 (d, J=17.5 Hz, 4H), 3.64-3.60 (m, 4H), 3.43-3.39 (m, 4H), 3.18 (d, J=0.6 Hz, 6H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:9][CH3:10])[C:4]([O:6]CC)=O)[CH3:2].[CH:11]([N-]C(C)C)(C)[CH3:12].[Li+].C([NH:22]C(C)C)(C)C.C([Li])CCC.BrCC#N>C1COCC1>[CH2:11]([C:3]1([CH2:1][CH3:2])[CH2:9][CH2:10][NH:22][C:4]1=[O:6])[CH3:12]
Reactant: CC(C)NC(C)C
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(CC)CC
Agent: N#CCBr
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC1(CC)CCNC1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 2-ethylbutyrate (21.60 g, 150 mmol) in THF (25 mL) was added dropwise to a solution of lithium diisopropylamide prepared by treating diisopropylamine (16.67 g, 165 mmol) in dry THF (150 mL) with butyllithium in hexanes (2.5M, 66 mL, 165 mmol) at −78° C. for 1 h in a nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 1 h, then a solution of bromoacetonitrile (21.60 g, 180 mmol) in THF (50 mL) was introduced slowly over a period of 30 minutes (the reaction mixture starts getting darker as the addition progresses). The resulting dark mixture was stirred overnight (ca. 16 h) and allowed to warm from −78° C. to room temperature. The reaction was quenched by addition of HCI (1 N, 250 mL) at 0° C. The layers were separated, and the aqueous phase was further extracted with ether (3×100 mL). The combined organic extract was washed sequentially with 75 mL portions of saturated NaHCO.sub.3, water (several times), and brine, and dried over MgSO.sub.4. The solvent was removed in vacuo to give 27.77 g of dark colored liquid. After two vacuum distillations, the nitrile (12.35 g, 45%) was obtained as a colorless liquid: bp 84-85° C. (1.3 mm Hg). An analytical sample was prepared by column chromatography over silica gel (hexanes-EtOAc, 19:1) followed by bulb-to-bulb distillation (pot temp. 80° C. (1 mm Hg)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:17][CH:18]([CH3:20])[CH3:19])[C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][NH:8][CH2:9][CH:10]([O:13][CH3:14])[O:11][CH3:12].C([O-])([O-])=O.[Na+].[Na+].[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([O:17][CH:18]([CH3:20])[CH3:19])[C:5]([CH3:16])=[C:6]([CH:15]=1)[CH2:7][N:8]([CH2:9][CH:10]([O:11][CH3:12])[O:13][CH3:14])[S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: COC(CNCc1cc(Br)cc(OC(C)C)c1C)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(CN(Cc1cc(Br)cc(OC(C)C)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.9 %

Procedure:
To a mixture of N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-2,2-dimethoxyethanamine (108c, 3.5 g, 10 mmol) and Na2CO3 (1.6 g, 15 mmol) in THF (40 mL) and H2O (20 mL) was added TsCl (2.0 g, 11 mmol). The reaction mixture was stirred at room temperature for 5 hours, then extracted with EtOAc (4×40 mL). The combined organic layers were washed with H2O (2×30 mL) and brine (2×100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc=5:1) to give N-[5-bromo-2-methyl-3-(propan-2-yloxy)benzyl]-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide (108d, 4.7 g, 93%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)[CH:2]=[CH2:3].[CH2:9]([Br:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C(#N)C>[Br-:17].[CH2:9]([N+:6]1[CH:7]=[CH:8][N:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCn1ccnc1
Reactant: CCCCCCCCBr
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=CCn1cc[n+](CCCCCCCC)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
1-Allylimidazole (1.0 mL: 0.009 mol) was ice-cooled, and octyl bromide (4.8 mL: 0.028 mol) was added thereto dropwise. After the dropwise addition, the temperature was gradually increased to 25° C., and subsequently stirring was carried out continuously for 24 hours. The product was a pale brown viscous liquid. This was added dropwise to 100 mL of toluene, and a viscous liquid that separated out was recovered and dried. The same procedure was repeated once more. The viscous liquid thus obtained was made into an acetonitrile solution, active carbon that had been heated and vacuum-dried was added thereto, and stirring was carried out for about 24 hours. After the acetonitrile was distilled off, the viscous liquid was recovered with dichloromethane, and the solvent was distilled off. The 1-octyl-3-allylimidazolium bromide thus obtained was a liquid at room temperature, the amount collected was 2.47 g (yield; 89%), the glass transition temperature (Tg) was −64.5° C., and the ionic conductivity at 30° C. was 0.0926 (mS/cm). The results are given in Table 1. The structure was confirmed by 1H-NMR measurement. The results are shown below.