Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:22])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>C1COCC1>[CH3:9][O:10][C:11](=[O:22])[CH:12]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH3:14]
Reactant: COC(=O)CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC=C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A 2M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0.1279 mol) in 40 ml of dry THF at -78° C. under nitrogen and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4-bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at -78° C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with 6 ml of saturated ammonium chloride solution at -78° C., 20 ml of water was added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 22.1 g (63.7%) of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine methyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: Cc1cc(F)cc(B(O)O)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1cc(F)cc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of (3-fluoro-5-methylphenyl)boronic acid (824 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.0 g) in MeCN (18 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with EtOAc in hexane then MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (267 mg) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13](Cl)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:22]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[N:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([N:29]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[NH:30][C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]1[N:22]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[N:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2ccccc2)n1
Temperature: 110 °C

Procedure:
1-Benzyl-5-chloro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[3,2-b]pyridine (0.075 g, 0.19 mmol, from Step 3), di-tert-butyl hydrazine-1,2-dicarboxylate (0.049 g, 0.21 mmol, Aldrich) and Cs2CO3 (0.062 g, 0.19 mmol, Aldrich) were combined in toluene (1.7 mL) and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.015 g, 0.019 mmol, Aldrich) was added. The mixture was degassed by a stream of nitrogen through the solution for 10 minutes. The vial was sealed and heated to 110° C. for 3 hours. Additional reagents and catalyst (same of each as the initial quantities) were added, the mixture was degassed again and the reaction mixture was then heated in the microwave to 140° C. for 10 minutes. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted three times, and the combined extracts were dried over sodium sulfate, filtered and concentrated. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (45 mg, 40%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[CH3:15].Cl[C:17]([O:19][CH3:20])=[O:18]>CC(C)=O>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:17](=[O:18])[O:19][CH3:20])=[C:9]([CH3:15])[CH:10]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(O)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)Nc1ccc(O)cc1C
Reaction time: 3 h
Yield: 100 %

Procedure:
12.0 g of potassium carbonate were added to a solution of 100 g of 4-amino-3-methylphenol in 400 ml of acetone cooled in an ice-water bath, followed by the addition of 80 ml of methyl chloroformate at the same temperature. The resulting mixture was stirred at the same temperature for 3 hours, at the end of which time the reaction mixture was filtered. The resulting filtrate was concentrated under reduced pressure to give 151 g (yield 100%) of the title compound as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.5 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate (28 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 36 mg of the titled compound (yield, 94%). 1H NMR (300 MHz, CDCl3): δ 3.30 (s, 4H), 3.77 (s, 4H), 4.15 (s, 3H), 6.90-6.97 (m, 3H), 7.28-7.45 (m, 4H), 7.75-7.76 (m, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:43][C:44]2[CH:64]=[CH:63][C:47]3[N:48]([CH3:62])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][CH:55]=[C:54]([C:58]([CH3:61])([CH3:60])[CH3:59])[CH:53]=4)=[N:50][C:46]=3[CH:45]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[C:58]([C:54]1[CH:53]=[C:52]([NH:51][C:49]2[N:48]([CH3:62])[C:47]3[CH:63]=[CH:64][C:44]([O:43][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:45][C:46]=3[N:50]=2)[CH:57]=[CH:56][CH:55]=1)([CH3:60])([CH3:59])[CH3:61]
Reactant: Cn1c(Nc2cccc(C(C)(C)C)c2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cn1c(Nc2cccc(C(C)(C)C)c2)nc2cc(OC3(C(=O)O)C=CC=CN3)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 3-(tert-butyl)benzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[3-(tert-butyl)phenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[3-(tert-butyl)phenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=416.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]=[C:10]=[O:11].[NH2:12][C@H:13]([C:15]([NH:17][C@H:18]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:16])[CH3:14]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][CH:18]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=2[N:20]([CH3:35])[C:19]1=[O:36])=[O:16])[CH3:14])=[O:11]
Reactant: C[C@H](N)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: O=C=Nc1c(F)cccc1F
Product: C[C@H](NC(=O)Nc1c(F)cccc1F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
Following General Procedure (5-A1) using 2,6-difluorophenyl isocyanate and (S)-3-[(L-alaninyl)]amino-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2-one, as described in Example 8-B above, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 491 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:10])=[CH:6][CH:7]=1
Reactant: CNC1CCCC1
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C1CCCC1
Temperature: 80 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (318 mg, 1.96 mmole) in 4 mL of dry acetonitrile is 395 mg (3.92 mmol) of N-methylcyclopentylamine followed by 270 mg (1.96 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 340 mg (77% yield) of (6-Chloro-pyridin-3-ylmethyl)-cyclopentyl-methyl-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.40–1.90 (m, 4H), 2.15 (s, 3H), 2.78–2.89 (m, 1H), 3.56 (s, 2H), 7.29 (d, 1H, J=8.3 Hz), 7.70–7.80 (m, 1H), 8.28 (d, 1H, J=2.1 Hz); MS 225.3 (M+H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[C:1]([C:5]1[N:10]=[C:9]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cnc(C(C)(C)C)nc1Cl
Reactant: Cn1ccc2cc(B(O)O)ccc21
Product: COC(=O)c1cnc(C(C)(C)C)nc1-c1ccc2c(ccn2C)c1
Yield: 74.8 %

Procedure:
Using a procedure analogous to Example B32, methyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (0.849 g, 3.71 mmol), N-methylindole-5-boronic acid (1.30 g, 7.43 mmol) and tetrakis-(triphenylphosphine)palladium(0) (86 mg) were combined to give methyl 2-tert-butyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylate (898 mg, 74% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.40 (s, 9 H), 3.70 (s, 3 H), 3.82 (s, 3 H), 6.57 (s, 1 H), 7.41-7.44 (m, 2 H), 7.53 (d, J=8.6 Hz, 1 H), 7.92 (s, 1 H), 8.94 (s, 1 H); MS (ESI) m/z: 324.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:16][CH3:17])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: Cc1cc[nH]c1-c1ccc(Cl)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A solution of 2-(4-chlorophenyl)-3-methyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.0 g, 5.22 mmol) in DMF (10 ml) was added dropwise to a stirred suspension of Sodium hydride (0.23 g, 5.74 mmol, 60% dispersion in mineral oil) in 20 ml DMF at 0° C. under a nitrogen atmosphere. The reaction mixture was then stirred at about 0° C. for 30 min. Ethyl iodide (0.89 g, 0.47 ml, 5.74 mmol) was then added to the reaction mixture maintaining the temperature at 0° C. The reaction mixture was then stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was slowly quenched with cold water (30 ml) and the resulting mixture was then extracted with ethyl acetate (2×30 ml). The combined organic layer was then washed with brine (1× 30 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain crude product as semi-solid mass (0.8 g), which was then purified by flash column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.6 g, 52.3%).
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:6]([O:5][C:3](=[O:4])[C:2]([CH3:17])([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[CH3:7]
Reactant: CCOC(=O)C(C)(C)CCCCCCCCBr
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)(C)CCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 47.8 %

Procedure:
Ethyl 2,2-dimethyl-10-bromodecanoate (2.2 g, 0.007 mol) was treated with 4-chlorobenzenesulphonamide (2.6 g, 0.014 mol) and potassium carbonate by the method described in Example 5(ii) to give title compound (1.4 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:20])[C:13](F)=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:31]([CH2:33][NH2:34])[OH:32]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:20])[C:13]([NH:34][CH2:33][CH2:31][OH:32])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:21]([CH3:22])[CH3:23])=[CH:6][CH:7]=1
Reactant: CC(C)c1oc2c(F)c(F)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: NCCO
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)c1oc2c(F)c(NCCO)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A stirred solution of 3-(4-chlorophenyl)-7,8-difluoro-2-isopropyl-chromen-4-one (3.94 g, 11.8 mmol), triethylamine (2.4 g, 3.2 ml, 23.6 mmol, 2 eq.) and ethanolamine (0.72 g, 0.71 ml, 11.8 mmol, 1 eq.) in N,N-dimethylacetamide (200 ml) is heated at 150° C. overnight. The reaction mixture is allowed to cool to room temperature and the solvent is removed by evaporation in vacuo. The residue is dissolved in ethyl acetate and washed with 2M HCl solution. The organic layer is washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to afford a brown oil. The oil is purified by flash chromatography (cyclohexane/ethyl acetate=9:1 to 4:6) to afford the title compound.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[O:17][C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)=[O:19]>>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([CH2:24][C:23]3[CH:26]=[CH:27][C:20]([C:18]([OH:19])=[O:17])=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Product: O=C(O)c1ccc(CN2Cc3ccccc3Cc3ccccc32)cc1
Yield: 45 %

Procedure:
Using similar procedures to those described in Example 1, 5,6-dihydro-11H-dibenzo[b,e]azepine (Tetrahedron, 1981, 37, 4159) was reacted with 4-methoxycarbonylbenzyl bromide to give 4-(5,6-dihydro-11H-dibenzo[b,e]azepin-5-ylmethyl)benzoic acid in 45% yield, m.p. 198° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4=[C:13]2[C:4](=[CH:5][CH:6]=[C:7]4[CH:8]=[C:9]([Br:17])[CH:10]=3)[CH:3]=1.CC([O-])(C)C.[K+].CS(C)=O.CI>C(Cl)Cl.O.CN(P(N(C)C)(N(C)C)=O)C>[Br:1][C:2]1[CH:15]=[C:14]2[CH2:16][C:11]3[C:12]4[C:13]2=[C:4]([CH2:5][CH2:6][C:7]=4[CH:8]=[C:9]([Br:17])[CH:10]=3)[CH:3]=1
Reactant: Brc1cc2c3c(ccc4cc(Br)cc(c43)C2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Brc1cc2c3c(c1)Cc1cc(Br)cc(c1-3)CC2
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 133.6 %

Procedure:
2,6-dibromo-4H-cyclopenta[def]phenanthrene (2.6 g, 7.7 mmol), t-BuOK (20.8 g, 61.6 mmol), DMSO (20 ml), and HMPA (20 ml) was placed in 50 ml round bottom flask with a syringe. The mixture was stirred for 50 minutes at room temperature and cooled to 0° C. CH3I (3.75 ml, 61.6 mmol) was dropped to the mixture with a syringe and the resultant solution was stirred for 30 minutes at 0° C. Then, water (50 ml) and methylene chloride (50 ml) were added to the solution to separate an organic layer. The organic layer was purified by silica gel column chromatography to obtain compound 2 (3.6 g, 80%). 1H NMR (300 MHz, CDCl3, δ): 7.98 (2H, s), 7.79 (2H, s), 7.73 (2H, s), 1.93 (m, 6H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C(Cl)Cl.[OH-].[Na+]>O>[CH2:8]1[CH2:9][CH2:10][N:5]([C:1]([N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:2])[CH2:6][CH2:7]1
Reactant: O=C(Cl)Cl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(N1CCCCC1)N1CCCCC1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
Phosgene was passed for 17 minutes, at the rate of 3 grams per minute, through a mixture of 84 grams (1 mole) of piperidine, 500 ml. of methylene chloride and 100 ml. of water. The pH was maintained in the range of 8-11 by the addition of 50% aqueous sodium hydroxide solution during the latter portion of the phosgene passage. An exothermic reaction occurred which caused refluxing of the mixture. After phosgenation was complete, additional base was added until the pH remained constant at 11 for 5 minutes, after which 200 ml. of water was added and the organic layer was removed, washed twice with aqueous hydrochloric acid solution and filtered. Upon vacuum stripping, the desired bis(pentamethylene)urea was obtained in 96% yield. Its structure was confirmed by proton nuclear magnetic resonance spectroscopy.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCNCC2)cc1
Yield: 89.1 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(4-methoxyphenyl)piperidine (0.42 g) in ethanol (5 mL) was treated with 10% palladium on carbon (0.04 g) and hydrogenated for 16 hours at atmospheric pressure. The reaction mixture was filtered through diatomaceous earth and evaporated to afford 4-(4-methoxyphenyl)piperidine as a colorless oil (0.22 g); NMR (CDCl3): 1.59-1.71 (m, 2), 1.85 (d, 2, J=12), 2.71-2.81 (d of t,2, J=12), 3.19-3.23 (broad, 2), 3.79 (s, 3), 6.83-6.87 (m, 2), 7.12-7.26 (m, 2); MS: m/z=192(M+1). This material was used in the next step without further purification.
Reaction SMILES: [Na].[N+:2]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)([O-:4])=[O:3].Br[CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]>C(#N)C>[CH3:14][C:13]([CH3:15])=[CH:12][CH2:11][N:6]1[CH:7]=[CH:8][N:9]=[C:5]1[N+:2]([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC(C)=CCBr
Agent: [Na]
Solvent: CC#N
Product: CC(C)=CCn1ccnc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80 %

Procedure:
To the sodium salt of 2-nitroimidazole prepared above was added acetonitrile (50 ml), 15-crown-5-ether (3.5 ml, 14.3 mmol) and 4-bromo-2-methyl-2-butene (2 ml; 17.4 mmol). The mixture was stirred at RT for ca 16 h. and then the solvent was removed to leave a crude semi-solid which was purified by column chromatography on silica. The intermediate product, 1-(3-methyl-2-butenyl)-2-nitroimidazole (80% yield) was eluted using a mixture of petroleum ether (40-60)/ethyl acetate (ratio 4:1 respectively).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].F[C:25]1[C:26]([N+:31]([O-:33])=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>C1COCC1>[N+:31]([C:26]1[C:25]([O:13][C:9]2[CH:8]=[C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[CH:12]=[CH:11][CH:10]=2)=[CH:30][CH:29]=[CH:28][N:27]=1)([O-:33])=[O:32]
Reactant: O=[N+]([O-])c1ncccc1F
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ncccc1Oc1cccc(N2CCOCC2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
In a 125 mL round-bottom flask, 3-morpholinophenol (0.91 g, 5.07 mmol) was dissolved in THF (40 mL). Solution was cooled to 0° C. and NaHMDS (5.07 mL, 5.07 mmol) (1M in THF) was added slowly. The mixture was agitated for 15 minutes and solution of 3-fluoro-2-nitropyridine (0.60 g, 4.22 mmol) in THF (5 mL) was added slowly. After agitating for 2 hours the solvent was evaporated and the residue dissolved in 100 mL of CH2Cl2 and washed with diluted sodium bicarbonate solution twice, dried over magnesium sulfate, filtered and evaporated. Crude material was purified by chromatography on silica gel, eluted with 25% ethyl acetate/Hexane to give the title compound (0.93 g, 72%) was obtained as thick red oil.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([CH3:34])([CH3:33])[CH2:19][S:20](=[O:32])(=[O:31])[NH:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)C3C(=CC=CC=3)C=2C=CC=1.N1CCOCC1>CN(C=O)C>[CH:28]([N:25]1[CH2:26][CH2:27][CH:22]([NH:21][S:20]([CH2:19][C:18]([NH2:17])([CH3:33])[CH3:34])(=[O:32])=[O:31])[CH2:23][CH2:24]1)([CH3:30])[CH3:29]
Reactant: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NS(=O)(=O)CC(C)(C)N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
607 mg (1.2 mmol) of crude [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-1,1-dimethyl-ethyl]-carbamic acid 9H-fluoren-9-ylmethyl ester were dissolved in 6 ml DMF. 1.5 ml morpholine were added and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure and co-distilled three times with 20 ml DMF to give crude 2-amino-2-methyl-propane-1-sulfonicacid (1-isopropyl-piperidin-4-yl)-amide as yellow oil. Yield: 360 mg MS (ES+): m/e=278.