Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C@@H:9]2[NH:12][C:11](=[O:13])[C@H:10]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Si:49](Cl)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]>CN(C=O)C>[C:1]1([CH:7]=[CH:8][C@@H:9]2[N:12]([Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[C:11](=[O:13])[C@H:10]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH:31][C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=[N:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N=C(NCCCC[C@@H]1C(=O)N[C@H]1C=Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. DMF (25 mL) solution of compound 33 (6.8 g, 12.3 mmol) was added triethylamine (2.05 g, 20 mmol) and tert-butyldimethylsilyl chloride (3.05 g, 20 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The suspension was partitioned between Et2O and pH 7.0 aqueous buffer. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography to afford 8.4 g (quantitative) of the title product.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7](OC)=[N:6]1)[CH2:2][CH2:3][CH3:4].[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH2:1]([CH:5]1[NH:6][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH2:2][CH2:3][CH3:4]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: CCCCC1CCCCC(OC)=N1
Solvent: CO
Product: CCCCC1CCCCC(=N)N1
Product: Cl
Yield: 90.3 %

Procedure:
The product of EXAMPLE 186 (500 mg, 2.7 mmol) in 20 mL of MeOH was reacted with ammonium chloride (124 mg, 2.3 mmol) by the method of EXAMPLE 27 to yield 425 mg (74%) of the title material.
Reaction SMILES: Cl[C:2]1[N:12]2[C:13]3[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=1.[NH:14]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:16]=[CH:15]1>C(O)CC(C)C>[NH:14]1[CH:18]=[C:17]([CH:19]2[CH2:24][CH2:23][N:22]([C:2]3[N:12]4[C:13]5[C:8]([CH2:9][CH2:10][CH2:11]4)=[CH:7][CH:6]=[CH:5][C:4]=5[N:3]=3)[CH2:21][CH2:20]2)[N:16]=[CH:15]1
Reactant: Clc1nc2cccc3c2n1CCC3
Reactant: c1nc(C2CCNCC2)c[nH]1
Solvent: CC(C)CCO
Product: c1cc2c3c(c1)nc(N1CCC(c4c[nH]cn4)CC1)n3CCC2
Yield: 62.6 %

Procedure:
1 g (0.0052 mol) of 2-chloro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline, 1.57 g (0.0104 mol) of 4-(1H-imidazol-4-yl)piperidine and 5 ml of isoamyl alcohol are heated at 120° C. for 1 day. The alcohol is then evaporated to dryness, the residue is taken up in a water/ether (50/50) mixture and the product sucked dry. The product is purified by chromatography on a column of silica gel, the eluent being a dichloromethane/methanol/aqueous ammonia (95/5/0.5) mixture, is then triturated in ether and dried under vacuum at 60° C. 1 g of product is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:17])[CH3:16])[C:10](=[O:14])[N:11]([CH3:13])[N:12]=2)=[C:4]([Cl:21])[CH:3]=1.N([O-])=O.[Na+].[C:26]([CH2:28][C:29]([NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:30])#[N:27].[N:37]1C=CC=CC=1>O.Cl>[CH2:35]([O:34][C:32](=[O:33])[NH:31][C:29](=[O:30])[C:28]([C:26]#[N:27])=[N:37][NH:1][C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:17])[CH3:16])[C:10](=[O:14])[N:11]([CH3:13])[N:12]=2)=[C:18]([Cl:20])[CH:19]=1)[CH3:36]
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N)cc2Cl)nn(C)c1=O
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: c1ccncc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Cc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A mixture of 6-(4-amino-2,6-dichloro-benzyl)-4-isopropyl-2-methyl-2H-pyridazin-3-one (94) (148 mg, 0.45 mmol) in water (6 mL) and concentrated hydrochloric acid (3 mL) cooled to 0° C. was treated with a solution of sodium nitrite (37.3 mg, 0.54 mmol) in water (0.5 mL) via Pasteur pipette under the surface of the reaction mixture. This was followed by a water rinse (0.5 mL) of the Pasteur pipette. The resulting pale yellow solution was stirred at 0° C. for 45 min. At this time, the reaction was filtered through a pad of cotton and was drained directly into a solution of cyanoacetylurethane (77.3 mg, 0.49 mmol), pyridine (3 mL) and water (9 mL) cooled to 0° C. Upon mixing, orange-red solids immediately formed. This mixture was stirred at 0° C. for 30 min. At this time, the solids were collected by filtration through filter paper. The solids were washed with water and petroleum ether, air-dried under house vacuum, and then dried under vacuum to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (95) (192 mg, 86%) as an orange solid; ES-HRMS m/e calcd for C21H22Cl2N6O4 (M+H)+ 493.1153, found 493.1155. Exact Mass=492.1080; Molecular weight=493.3533.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>C1COCC1.CO.O.[Fe]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[CH:15][CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1ccc(N)cc1
Temperature: 50 °C
Yield: 99.8 %

Procedure:
To a solution of N-methyl-4-nitroaniline (5.0 g, 32.9 mmol) in THF (50 mL) were added di-tert-butyl dicarbonate (10.76 g, 49.4 mmol) and DMAP (201 mg, 1.6 mmol). The reaction mixture was refluxed under N2 for 2 h before cooled to rt. After removal of the solvent, the residue was dissolved with EtOAc (200 mL). The resulting solution was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to give tert-butyl methyl(4-nitrophenyl)carbamate (8.3 g, 100%) as a brown oil. To a solution of tert-butyl methyl(4-nitrophenyl)carbamate (8.3 g, 32.9 mmol) in THF/MeOH/H2O (150 mL/40 mL/80 mL) was added Fe powder (9.4 g, 168 mmol) and NH4C1 (18 g, 337 mmol). The reaction mixture was heated at 50° C. for 4 h under N2. After cooling to rt, the reaction mixture was filtered through a pad of Celite. The filtrate was extracted with EtOAc (100 mL×3), washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford tert-butyl 4-aminophenyl(methyl)carbamate (36) (7.3 g, yield 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 223.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=3)[C:17](=[O:30])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[ClH:31].[NH2:32][OH:33].C(=O)([O-])O.[Na+]>C(O)C>[Cl:31][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28](=[NH:29])[NH:32][OH:33])=[CH:26][CH:27]=3)[C:17](=[O:30])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: N#Cc1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Reactant: NO
Reactant: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)cc1
Yield: 74.6 %

Procedure:
A mixture of 4-(6-chloronaphthalene-2-sulfonyl)-1-(4-cyanobenzyl)-2-piperazinone (440 mg), hydroxylamine hydrochloride (347 mg), sodium hydrogen carbonate (420 mg) and 80% ethanol (30 ml) was refluxed for 2 hours, and ethanol was evaporated. Precipitated crystals were washed with water, ethanol and ethyl acetate, and dried to give colorless crystals of the title compound (353 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[NH3:11].C[Si]([C:16]#[N:17])(C)C.O>CO.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[NH2:11][CH:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[C:3]([F:10])[CH:4]=1)[C:16]#[N:17]
Reactant: C[Si](C)(C)C#N
Reactant: N
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: CO
Product: N#CC(N)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 25.0 g (158 mmol) 4-chloro-3-fluorobenzaldehyde in 130 ml methanol and 175 ml methanol saturated with ammonia were added 54.9 ml (52.7 g, 185 mmol) tetraisopropyl orthotitanate and the mixture stirred at ambient temperature for 1.5 hours. Then 20.35 ml (16.14 g, 163 mmol) trimethylsilyl cyanide were added drop-wise and the resulting mixture stirred at ambient temperature for further 2 hours. The reaction mixture was poured onto 1500 ml iced water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by flash-chromatography on silica gel with a gradient of heptane and 0 to 50% ethyl acetate. rac-Amino-(4-chloro-3-fluoro-phenyl)-acetonitrile was obtained as orange oil: MS (ISN): 183.2 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.ClCCl.Cl.[CH:16]12[O:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:17][CH:16]3[O:23][CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1nc(N2CC3CCC(C2)O3)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
432 mg (2.57 mmol) of thieno[3,2-d]pyrimidine-2,4-diol was chlorinated as above (heat 100° C. overnight in 6.25 mL POCl3) to give 2,4-dichloro-thieno[3,2-d]pyrimidine after the usual workup (removal of toluene, quenching with ice and extraction with dichloromethane followed by drying over MgSO4 and concentration). Thus obtained 2,4-dichloro-thieno[3,2-d]pyrimidine was reacted without any further purification. 2,4-Dichloro-thieno[3,2-d]pyrimidine was dissolved in 25 mL ethanol and 5 mL dichloromethane and 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (384 mg, 2.57 mmol) and 2.1 mL triethylamine (15 mmol, 6 equivalents) were added. After stirring at room temperature for 45 minutes, the mixture was concentrated, dissolved in dichloromethane and washed with sat. NH4Cl, water and sat. NaHCO3. The organic phase was dried over MgSO4 and concentrated to give 626 mg (2.22 mmol, 86% over 2 steps) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[NH:25][C:26]([C:28]2[S:29][CH:30]=[C:31]([CH2:34]Cl)[C:32]=2[Cl:33])=[O:27])=[N:12][CH:13]=1.CS(C)=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:36])[C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[NH:25][C:26]([C:28]2[S:29][CH:30]=[C:31]([CH2:34][O:4][N:3]([CH2:5][CH3:6])[CH2:1][CH3:2])[C:32]=2[Cl:33])=[O:27])=[N:12][CH:13]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: CCN(O)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)OCc1csc(C(=O)Nc2c(OC)cc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)c1Cl
Temperature: 40 °C
Reaction time: 48 h

Procedure:
In a manner similar to that described in Paragraph J above, to a solution of N,N-diethylhydroxylamine (0.45 g, 5.0 mmol), N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide (0.51 g, 1.0 mmol), and DMSO (10 mL) was added K2CO3 (0.68 g, 4.9 mmol). The mixture was stirred at 40° C. for 2 days, then it was poured into water. The resulting mixture was extracted with CH2Cl2 (2×50 mL). The organic layer was washed with 1% K2CO3, brine, treated with charcoal and concentrated. Purification by silica gel chromatography using 10:1 CH2Cl2:CH3OH with 1% NH4OH followed by precipitation from CH2Cl2 and hexane afforded N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide, as a white solid; NMR (DMSO-d6) 8.35 (s, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.90 (dd, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 4.20 (s, 2H), 3.85 (s, 3H), 3.20-2.80 (m, 4H), 1.20 (t, 6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.[CH:21]([N:24]=[C:25]=[O:26])([CH3:23])[CH3:22].N>C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH:20][C:25]([NH:24][CH:21]([CH3:23])[CH3:22])=[O:26])=[N:8][C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: CC(C)N=C=O
Agent: C
Agent: N
Product: CC(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)cccc1Cl

Procedure:
The title compound was prepared from 0.5 g of 6-(2,6-dichlorophenyl)-pyrido{2,3-d]pyrimidine-2,7-diamine from Example 1 and 0.172 mL of isopropyl isocyanate according to Example 2. The product was purified by MPLC eluting with a gradient of CHCl3 :EtOAc (1:1) to afford the pure product; mp 184°-188° C., CIMS (1% ammonia in methane): m/z (relative intensity) 391 (MH+, 16), 393 (MH+ +2, 11), 306 (100).
Reaction SMILES: [Li]CCCC.C([Mg]Cl)CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.CN([CH:23]=[O:24])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Br:19][C:15]1[N:14]=[C:13]([CH:23]=[O:24])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: CCCC[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cccc(Br)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a −10° C. solution of n-BuLi (2.5 M in hexane, 5.6 mL, 14 mmol) in anhydrous toluene (20 mL) was added a solution of n-BuMgCl (2 M in THF, 3.5 mL) over 20 min, maintaining the temperature between −10° C. and 0° C. The mixture was stirred at −10° C. for 30 min. A solution of 2,6-dibromo-pyridine (4.74 g, 20 mmol) in toluene (20 mL) was added drop-wise over a period of 30 min while keeping the temperature below −5° C. The resulting suspension was stirred at −10° C. for 2.5 h. The mixture was transferred via cannula to a −10° C. solution of DMF (1.9 g, 26 mmol) in toluene (10 mL). The solution was allowed to stand between −5° C. and −10° C. for 30 min and then was transferred into a solution of citric acid (8.00 g) in H2O (15 mL), maintaining the temperature below 20° C. The resulting solution was stirred for 10 min and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified (SiO2: 10% ethyl acetate/hexanes) to afford the title compound (1.94 g, 52%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:28]([N:30]=[C:31]=[O:32])[CH3:29]>>[CH2:28]([NH:30][C:31]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)=[O:32])[CH3:29]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)NCC)C3)cc1

Procedure:
Method as described for example 33 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and ethyl isocyanate as starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[N:13]=[C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]3[CH:21]=2)[CH:9]=[CH:10][CH:11]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:20][C:18]1[CH:17]=[CH:16][N:15]2[CH:21]=[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=3)[N:13]=[C:14]2[CH:19]=1
Reactant: Cc1ccn2cc(-c3cccc(OCCCCl)c3)nc2c1
Reactant: C1CCNCC1
Product: Cc1ccn2cc(-c3cccc(OCCCN4CCCCC4)c3)nc2c1
Temperature: 25 °C

Procedure:
The product of Step C (271 mg) and piperidine (2.0 mL) were heated at 100° C. for 2 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (10 mL) and the organic portions combined and washed with brine (10 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (193 mg). 1H-NMR (CD3OD) δ 8.27 (d, J=7.0 Hz, 1H), 8.08 (s, 1H), 7.46 (m, 2H), 7.31 (m, 2H), 6.88 (m, 1H), 6.76 (m, 1H), 4.09 (t, J=6.0 Hz, 2H), 2.58 (m, 6H), 2.42 (s, 3H), 2.04 (m, 2H), 1.65 (m, 4H), 1.51 (m, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:16][CH2:15]1>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:23]2[CH2:22][CH2:21][CH:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)[CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCN(C2CCNCC2)CC1
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]

Procedure:
Starting Materials: 4-fluoro-2-methoxy-1-nitrobenzene and 1-methyl-4-(piperidin-4-yl)piperazine.
Reaction SMILES: [CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:14][CH2:13]1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].S(OC)(O[CH3:35])(=O)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>CN(C=O)C.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[CH3:1][N:2]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=2)[CH2:14][CH2:13]1)[C:3](=[N:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[S:4][CH3:35]
Reactant: Cc1ccc(OCCCCN2CCC(N(C)C(=S)Nc3ccccc3)CC2)cc1C
Reactant: COS(=O)(=O)OC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Product: CSC(=Nc1ccccc1)N(C)C1CCN(CCCCOc2ccc(C)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1 g (2.35 mmol) of the preceding thiourea (10.2) in 10 ml of DMF is treated at 25° C. with 245 μl of dimethyl sulfate, stirred overnight at 25° C. and then heated for 1 h at 60° C. The mixture is evaporated to dryness and the residue is recovered in the usual way and purified by flash chromatography to give 325 mg (Yd: 32%) of a light yellow oil. This oil is taken up in ethanol and salified with a solution of 80 mg of fumaric acid in the same solvent to give 340 mg (Yd: 26%) of compound of formula:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:31])[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1.C1COCC1>C(OCC)(=O)C>[Cl:3][CH2:6][C:7]1[C:12]2[NH:13][C:14]([CH2:16][N:17]([CH3:31])[S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])=[N:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CO)c3[nH]2)c(C)c1
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc3cccc(CCl)c3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
Thionyl chloride (3.22 mmol, 2.5 eq.) was added to a cooled (0° C.) solution of N-((7-(hydroxymethyl)-1H-benzo[d]imidazol-2-yl)methyl)-4-methoxy-N,2,6-trimethylbenzenesulfonamide (1.29 mmol, 1.0 eq.) in abs. THF (10 ml). The reaction mixture was stirred at room temperature for 24 h. The mixture was then diluted with ethyl acetate and washed successively with NaHCO3 solution and NaCl solution. The organic phase was dried over Na2SO4 and the solvent was distilled off in vacuo to obtain the crude product, which led to the desired product by purification by column chromatography over silica gel. Yield: 76%
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[O:16][CH3:17].C([Li])CCC.[CH2:23]([Si:26](OC)([O:29][CH3:30])[O:27][CH3:28])[CH2:24][CH3:25]>C(O)C>[CH3:17][O:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[Si:26]([CH2:23][CH2:24][CH3:25])([O:29][CH3:30])[O:27][CH3:28]
Reactant: CCC[Si](OC)(OC)OC
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Li]CCCC
Solvent: CCO
Solvent: CCCCCC
Product: CCC[Si](OC)(OC)c1ccc(OC)cc1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A 500 mL round bottomed flask was charged with hexane (200 mL, Aldrich) and bromo-2,4-dimethoxybenzene (12.2 g, 56.0 mmol, Aldrich). The contents were cooled to 0° C. and n-butyl lithium (34.7 mL of a 1.6M solution in hexanes, 55.5 mmol, Aldrich) was added over 15 minutes (white precipitate). The contents were stirred at room temperature for ninety (90) minutes. The solution was added, via cannula, into a 1000 mL round bottomed flask containing hexane (300 mL, Aldrich) and propyl-trimethoxysilane (9.8 mL, 56 mmol). The reaction was stirred at room temperature overnight (18 hours). Ethanol (10 mL, Aldrich) was added to quench residual base. The contents were poured into 0.2N HCl (250 mL). The layers were separated and the product extracted into ether (2×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (16.2 g crude). Distillation under reduced pressure (b.p. 115° C., 0.04 mm Hg) provided 2,4-dimethoxyphenyl-propyl-dimethoxysilane (9.13 g, 33.8 mmol, 61% yield); C13H22O4Si (Mw=270.40); 1H NMR (CDCl3) δ 7.5 (d, 1H), 6.5 (m, 1H), 6.4 (d, 1H), 3.8 (s, 3H), 3.8 (s, 3H), 3.5 (s, 6H), 1.4 (m, 2H), 0.9 (t, 3H), 0.8 (t, 2H); 13C NMR (CDCl3) δ 165.8, 163.2, 137.6, 112.7, 104.6, 97.5, 55.0, 54.9, 50.4, 17.7, 16.2, 15.4; IR (capillary film) ν 2950, 2836, 1596, 1571, 1460, 1299, 1206, 1154, 1089, 1036; MS m/z (relative abundance) 270 (11.1), 227 (45.6), 197 (100), 167 (24.4), 137 (10.9), 121 (22.6), 91 (9.9), 59 (18.4).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O:21][C:22]([N:24]1CC[N:27]([CH2:30][C:31]2[CH:39]=CC3OCOC=3C=2)[CH2:26][CH2:25]1)=O)(C)(C)C>>[N:27]1[CH:30]=[CH:31][CH:39]=[C:25]([NH:24][C:22]([N:14]2[CH2:13][CH2:12][N:11]([CH2:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:16][CH2:15]2)=[O:21])[CH:26]=1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Product: O=C(Nc1cccnc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
1-Benzo[1,3]dioxol-5-ylmethyl-piperazine. The title compound was prepared from 4-benzo[1,3]dioxol-5-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester in analogy with Example 6.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:11])[CH:7]=[N:8]2)=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[CH:13]1([NH:12][C:4]2[N:3]=[C:2]([N:21]3[C:20]([CH3:19])=[CH:24][C:23]([CH3:25])=[N:22]3)[N:10]=[C:9]3[C:5]=2[N:6]([CH3:11])[CH:7]=[N:8]3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Cn1cnc2nc(Cl)nc(NC3CCCCC3)c21
Reactant: Cc1cc(C)[nH]n1
Product: Cc1cc(C)n(-c2nc(NC3CCCCC3)c3c(ncn3C)n2)n1

Procedure:
Was prepared according to Example 6 from (2-chloro-7-methyl-7H-purin-6-yl)-cyclohexyl-amine and 3,5-dimethylpyrazole.