Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[N:16]1([CH2:21][CH2:22][CH2:23]N)[CH:20]=[CH:19][N:18]=[CH:17]1.[Cl-].[NH4+]>>[CH3:15][C:5]1[C:6]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8][C:7]=2[CH2:2][N:3]([CH2:23][CH2:22][CH2:21][N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[N:4]=1
Reactant: NCCCn1ccnc1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Agent: [Cl-]
Agent: [NH4+]
Product: CC1=NN(CCCn2ccnc2)Cc2cc3ccccn3c21
Temperature: 25 °C

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine, eight equivalents of 3-(1H-imidazol-1-yl)propylamine and one equivalent of ammonium chloride under reflux in a nitrogen atmosphere for 1 hour and at room temperature for 48 hours gave the title compound as the free base after removal of excess amine in vacuo and purification by flash chromatography (silica gel, 10 to 40% methanol in ethyl acetate). The free base was converted to the dihydrochloride salt (methanol/ethereal HCl/diethyl ether), mp 162°-163° C.
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20]([OH:22])=O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:22])[NH:42][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[C:38]([Cl:37])[CH:39]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NCc1cccc(Cl)c1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 48 %

Procedure:
The title compound (29 mg, 48%) was obtained from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and 3-chlorobenzylamine as in Example 1, Part C. HPLC: RT=10.95 min. MS (ESI−): mass calcd. for C29H21Cl4N5O4S2, 709.45; m/z found, 706/708 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.55 (s, 1H), 8.39 (dd, J=7.0, 0.9, 1H), 8.22 (dd, J=8.8, 0.8, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.70 (d, J=2.0, 1H), 7.38-7.30 (m, 3H), 7.16 (d, J=0.5, 1H), 7.05-6.99 (m, 2H), 6.96 (dd, J=8.5, 2.0, 1H), 6.88-6.81 (m, 1H), 5.87-5.80 (m, 1H), 4.70-4.61 (m, 1H), 4.49-4.41 (m, 1H), 4.34-4.26 (m, 1H), 3.17-3.09 (m, 1H), 3.06-2.96 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]=1[O:13][CH3:14])[C:7]([OH:9])=O)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[CH:39]=2)=[CH:32][CH:31]=1>CN(C)C=O.C(Cl)Cl>[Br:29][C:30]1[CH:43]=[CH:42][C:33]([CH2:34][C:35]2[O:36][C:37]([CH3:41])=[C:38]([CH3:40])[C:39]=2[C:7]([C:6]2[CH:10]=[C:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:13][CH3:14])=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=2)=[O:9])=[CH:32][CH:31]=1
Reactant: Cc1cc(Cc2ccc(Br)cc2)oc1C
Reactant: COc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)C)cc(C(=O)c2c(Cc3ccc(Br)cc3)oc(C)c2C)cc1C(C)C
Yield: 77.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2 using 3,5-diisopropyl-p-anisic acid (1.03 g, 4.35 mmol, RN-1 17439-59-5), oxalyl chloride (0.417 mL, 4.79 mmol), N,N-dimethylformamide (2 drops), tin (IV) chloride (0.560 mL, 4.79 mmol) and 2-(4-bromo-benzyl)-4,5-dimethyl-furan (1.15 g, 4.35 mmol) in CH2Cl2. Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 1.63 g (77%) of the title compound as a yellow clear oil. 1H NMR (DMSO-d6) δ 1.16 (d, 12H), 1.80 (s, 3H), 2.19 (s, 3H), 3.28 (septet, 2H), 3.74 (s, 3H), 3.83 (s, 2H), 6.98 (d, 2H), 7.41 (dd, 2H), 7.44 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=[N:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.ClC1C=CC=C(C(OO)=[O:28])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[N:16][C:5]2=[N:6][C:7]=1[S:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nc2cccnc2nc1SCc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccnc2nc1S(=O)Cc1ccccn1
Yield: 28.3 %

Procedure:
In 14 ml of chloroform was dissolved 1.4 g of 2-methyl-3-(2-pyridylmethylthio)pyrido[2,3-b]pyrazine. To the solution under chilling with ice was added portionwise 1.1 g of m-chloroperbenzoic acid (purity: 80%). The reaction mixture was then left to have room temperature, and poured into saturated aqueous NaHCO3 solution. The aqueous mixture was extracted with chloroform. T he chloroform layer was washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (chloroform/methanol), to give 420 mg of 2-methyl-3-(2-pyridylmethylsulfinyl)pyrido[2,3-b]pyrazine as a brown crystalline powder, m.p. 120°-125° C. (decompn.).
Reaction SMILES: N1[C:8]([Cl:9])=NC(Cl)=NC=1Cl.C(Cl)Cl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([CH2:20]CO)=[CH:18][CH:17]=1)([O-:15])=[O:14]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[Cl:9][CH2:8][CH2:20][C:19]1[CH:23]=[CH:24][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][CH:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of cyanuric chloride (1.83 g) in DMF (2 mL) was stirred at RT for 1 h. To the resulting white suspension was added DCM (25 mL) followed by 4-nitrophenethyl alcohol (1.59 g). The reaction mixture was stirred at RT for 4 h and diluted with 1M Na2CO3. The phases were separated, the org. layer was washed with 1M HCl and brine and evaporated in vacuo to afford 1.4 g of orange slurry. 1H-NMR (CDCl3): 8.22 (m, 2H); 7.43 (m, 2H); 3.79 (t, 2H, 7.0 Hz); 3.20 (t, 2H, 6.8 Hz).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][CH:21]=2)=[CH:16][C:15]=1[O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:13])(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1>[OH:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:39](=[O:40])[O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[CH:24][CH:25]=2)=[CH:16][C:15]=1[O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:13])(=[O:10])=[O:9]
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)COc1cc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
To a solution of 3-[[[[4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (108 mg) in methanol (1.08 ml) and tetrahydrofuran (0.324 ml) was added 1N aqueous sodium hydroxide solution (0.455 ml) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure and the pH value was adjusted to 6.0 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice) and the extracts were washed with water and brine, and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave tert-butyl [3-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-isobutoxy-4-biphenylyl]-propyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (91.1 mg) as a white solid (foam).
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[C:16]([CH3:24])[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[C:16]([CH3:24])[CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(C(=O)O)cc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NS(=O)(=O)C2CC2)cc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a suspension of 60% sodium hydride (664 mg, 16.6 mmol) in N,N-dimethylformamide (5 mL) was added cyclopropanesulfonic acid amide (2.01 g, 16.6 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A66. A solution of 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.9 g, 2.37 mmol) and 1,1′-carbonyldiimidazole (768 mg, 4.74 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B66. Solution B66 was added to Solution A66 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (107 mg, 9%) as a brown solid: MS (ESI) M+1=484.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:20][C:14]1[CH:15]=[C:16]([C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[NH2:8])[C:11]([F:10])=[N:12][CH:13]=1
Reactant: Nc1cnc(Cl)cc1I
Reactant: OB(O)c1cc(Br)cnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(Cl)cc1-c1cc(Br)cnc1F
Temperature: 80 °C
Yield: 48.6 %

Procedure:
A mixture of 6-chloro-4-iodo-pyridin-3-ylamine (2.37 g, 9.31 mmol), 2-fluoro-5-bromopyridine-3-boronic acid (2.64 g, 12.0 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.76 g, 0.93 mmol) in acetonitrile (35 mL) and 1N aqueous potassium fluoride solution (35 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 80° C. for 3 h, allowed to cool to ambient temperature then partitioned between ethyl acetate (100 mL) and water (75 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant solid residue was triturated using 1:1 DCM/methanol, collected by filtration, washed with diethyl ether and ethyl acetate to afford the title compound as a tan solid (1.37 g, 49%). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-40% ethyl acetate in pentane) to afford further title compound as a brown solid (0.73 g, 26%). 1H NMR (DMSO-D6, 300 MHz): 8.46 (dd, J=2.5, 1.3 Hz, 1H), 8.24 (dd, J=8.3, 2.5 Hz, 1H), 7.88 (s, 1H), 7.19 (s, 1H), 5.57 (s, 2H). LCMS (Method B): RT=3.21 min, M+H+=304.
Reaction SMILES: [H-].[Na+].[CH2:3]([S:5]([NH2:8])(=[O:7])=[O:6])[CH3:4].[CH3:9][C:10]1([CH3:35])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20](O)=[O:21])[CH:17]=2)[NH:12][CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:24]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:9][C:10]1([CH3:35])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]([NH:8][S:5]([CH2:3][CH3:4])(=[O:7])=[O:6])=[O:21])[CH:17]=2)[NH:12][CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:24]=1
Reactant: CCS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)NC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.9 %

Procedure:
To a suspension of 60% sodium hydride (745 mg, 18.6 mmol) in N,N-dimethylformamide (2.5 mL) was added ethanesulfonamide (2.3 g, 19 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (690 mg, 1.9 mmol) and 1,1′-carbonyldiimidazole (650 mg, 3.8 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of ethanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded ethanesulfonic acid [3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (347 mg, 40%) as a white solid: LC/MS m/e calcd for C24H31N3O4S (M+H)+: 458.61, observed: 458.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2.[S:17]1[CH:21]=[C:20]([CH2:22][C:23](O)=O)[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2>>[S:17]1[CH:21]=[C:20]([CH2:22][CH2:23][N:13]([CH:10]2[CH2:9][CH2:8][C:7]3[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[CH2:11]2)[CH2:14][CH2:15][CH3:16])[C:19]2[CH:26]=[CH:27][CH:28]=[CH:29][C:18]1=2
Reactant: O=C(O)Cc1csc2ccccc12
Reactant: CCCNC1CCc2cccc(OC)c2C1
Product: CCCN(CCc1csc2ccccc12)C1CCc2cccc(OC)c2C1

Procedure:
Synthesis works according to the preparation of A4-1 or A4-4 when using N-(8-methoxytetralin-2-yl)-N-propylamine (A2-1: R═OMe) and 3-benzo[b]thienyl acetic acid (A3-11: R═OMe, Cy=3-benzo[b]thienyl) (purchasable from Alfa Aesar, Karlsruhe (Germany); order number: LO 5855 or Maybridge, Tintagel, Cornwall (UK); order number: S11080) and subsequent reaction according to the synthesis of A5-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][S:21]([CH3:20])(=[O:23])=[O:22])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(F)cc1-c1ccc2cc(NS(C)(=O)=O)ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (5 mL) was added methanesulfonyl chloride (137 mg, 1.20 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature overnight. A small amount of water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic phase was pooled and concentrated. It was purified by prep-HPLC to give the desired product (80.5 mg, 41.0%). LCMS (ESI): RT (min)=1.181, M+H+=330.9, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.17 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.44 (s, 1H), 7.38-7.34 (m, 1H), 7.15 (d, J=9.2 Hz, 2H), 3.30 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[CH2:6]([C:13]#[N:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[O-].[Na+]>>[CH3:1][C:2]([CH2:3][CH3:4])=[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]#[N:14]
Reactant: CCC(C)=O
Reactant: N#CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCC(C)=C(C#N)c1ccccc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 22.2 %

Procedure:
Butanone (45.0 g, 0.63 mol) is added to the mixture of benzyl cyanide (58.5 g, 0.50 mol) and sodium methoxide (30% in MeOH, 34.3 ml, 0.185 mol) and the resulting suspension is heated to 60° C. (oilbath) and stirred for 6 h at this temperature. The product is extracted with cyclohexane, washed with dilute NaHCO3-solution and brine. The organic layer is dried over MgSO4, the solvent removed under reduced pressure and the residue distilled over a short-path apparatus at 0.05 mbar. The fraction distilling at 90° C. is collected (45 g) and subjected to a fine distillation over a Widmer-column to yield olfactorily pure 3-methyl-2-phenyl-pent-2-ene nitrile (19 g, 22%) as a colourless oil (b.p. 102° C./0.05 mbar). (E/Z) ratio about 55:45.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].[CH2:17]([Li])CCC>C1COCC1.CCOCC>[CH3:17][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16]
Reactant: [Li]CCCC
Reactant: Nc1ccccc1-c1nc2ccccc2[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2N)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2-(1H-benzo[d]imidazol-2-yl)benzenamine (525 mg, 2.5 mmol) in 5 mL dry THF was cooled to −78 degrees before 1 mL n-Bu-Li (2.5 mmol, 2.5 N in hexanes) was added via a syringe. The reaction was stirred at −78 degrees for 20 min and Mel (360 mg, 2.6 mmol) was added. The reaction was warmed to r.t. gradually and kept at room temperature for another hour. The reaction crude was diluted with 25 mL ether and the resulted suspension was filtered off the solid. The crude product was isolated after the solvent was removed from the collected filtrate to product 510 mg of 2-(1-methyl-1H-benzo[d]imidazol-2-yl)benzenamine in greater than 95% purity (MS, M++H=224.1).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16](=O)[CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.O.[NH2:24][NH2:25]>C(O)C>[N:1]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:21])[NH:24][N:25]=3)=[CH:12][CH:11]=2)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)CCC(=O)c1ccc(-n2cnc3c2CCCC3)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(-n3cnc4c3CCCC4)cc2)=NN1
Yield: 50.7 %

Procedure:
A mixture of 9 g of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)-γ-oxobenzenebutanoic acid and 3.5 g of hydrazine hydrate in 80 ml of ethanol is heated under reflux for six hours. The reaction mixture is allowed to cool and filtered. The crude product is finally crystallized from 2-methoxyethanol to yield 4.5 g of the product 4,5-dihydro-6-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)phenyl]-3(2H)-pyridazinone, mp 296°-297° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([F:19])=[CH:7][C:8]([Cl:18])=[C:9]([NH:11][C:12]([NH:14][CH2:15][C:16]#[CH:17])=[O:13])[CH:10]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:26](=[O:31])=[N:27][C:28](Cl)=[O:29]>C(Cl)Cl>[Cl:18][C:8]1[C:9]([N:11]2[C:28](=[O:29])[NH:27][C:26](=[O:31])[N:14]([CH2:15][C:16]#[CH:17])[C:12]2=[O:13])=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[C:6]([F:19])[CH:7]=1
Reactant: O=C=NC(=O)Cl
Reactant: C#CCNC(=O)Nc1cc(NC(C)=O)c(F)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C#CCn1c(=O)[nH]c(=O)n(-c2cc(NC(C)=O)c(F)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(5-acetamido-2-chloro-4-fluorophenyl)-3-(2-propynyl)urea (4.50 g, 15.9 mmol), and pyridine (2.56 mL, 31.8 mmol) in methylene chloride is treated with N-(chlorocarbonyl) isocyanate (1.92 mL, 23.9 mmol), stirred at room temperature overnight, refluxed for 90 minutes, cooled to room temperature, treated with additional pyridine (1.30 mL) and N-(chlorocarbonyl) isocyanate (1.92 mL), stirred for 10 minutes, cooled to room temperature, and filtered to obtain a solid. The solid is washed sequentially with water and hexanes, and dried to give the title product as a tan solid.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:30])([CH3:3])[CH3:2].Cl.[NH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[OH:33][NH:32][C:28]([C:26]1[CH:25]=[CH:24][C:17]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:14]([CH2:13][N:6]3[C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:30])=[N:15][C:16]=2[CH:27]=1)=[NH:29]
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A mixture containing 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carbonitrile (152 mg, 0.379 mmol), hydroxylamine hydrochloride (95 mg, 1.36 mmole) and potassium carbonate (105 mg, 0.758 mmole) in ethanol (4 mL) and water (2 mL) in a sealed tube was placed in a microwave oven (Smith Creator, Personal Chemistry) and heated at 140° C. for 15 min, followed by 150° C. for 10 min while stirring. The solvents were removed in vacuo and the residue was triturated with water. The white precipitate was collected by filtration, washed with water and dried in vacuo to give N-hydroxy-2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazole-5-carboxamidine (140 mg, 85%) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[CH2:15][CH2:14]3)[N:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(C3CCNCC3)n(-c3ccccc3)n2)cc1
Reactant: BrCCc1ccccn1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1ccc(-c2cc(C3CCN(CCc4ccccn4)CC3)n(-c3ccccc3)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of INTERMEDIATE 5 (30 mg, 0.089 mmol) in dichloromethane (0.4 mL) was added 2-(2-bromoethyl)pyridine (28.4, 0.107 mmol). The mixture was stirred at 60° C. overnight, and then cooled to room temperature. The mixture was diluted with EtOAc, and washed with water. The organic layer was separated, dried and concentrated. The resulting residue was purified by preparative TLC (using 2 M NH3 in MeOH/MeOH/DCM/0.05 mL/5 mL/9.5 mL) to give the title compound. LC-MS m/z 443.17 [M+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[S:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>>[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: c1cscn1
Product: N#Cc1ccccc1-c1cccc(-n2cnc(C(=O)c3nccs3)c2)c1

Procedure:
This compound is prepared by method C using compound 12d and thiazole.