Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]([NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:9][CH2:10][N:11]([CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.[Br:52][C:53]1[CH:58]=[CH:57][C:56]([N:59]=[C:60]=[O:61])=[CH:55][CH:54]=1.CO.C(Cl)(Cl)Cl>CN(C=O)C>[Br:52][C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:61])[NH:28][C@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10][N:11]([CH:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:55][CH:54]=1
Reactant: CC(C)(C)OC(=O)[C@H](CCN(CCCC(=O)O)C1CCCc2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)[C@H](CCN(CCCC(=O)O)C1CCCc2ccccc21)NC(=O)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-[[(3S)-3-(tert-butoxycarbonyl)-3-[[(9H-9-fluorenylmethoxy)carbonyl]amino]propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (18 mg, 0.029 mmol) in DMF (0.4 ml) was added piperidine (0.1 ml), and the mixture was stirred at RT for 1.5 h. The reaction mixture was concentrated under vacuum to dryness, and the residue was dissolved in CH2Cl2 (0.5 ml). To the solution was added 4-bromophenyl isocyanate (8.7 mg, 0.044 mmol), and the mixture was stirred at RT for 2h. The reaction mixture was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford 2 diastereoisomers of 4-[[(3S)-3-(4-bromophenylureido)-3-(tert-butoxycarbonyl)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (6.8 mg, 39%, less polar isomer, Compound 165): MS(ES+) m/e 588 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 9.86 (br, 1H), 8.38 (br, 1H), 7.99 (br, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.42 (d, 1=8.3 Hz, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.08 (m, 3H), 4.81 (t, J=7.3 Hz, 1H), 4.41 (m, 1H), 3.42 (m, 1H), 2.97 (m, 1H), 2.71 (m, 1H), 2.59 (m, 1H), 2.46 (dd, J=16.3, 7.1 Hz, 1H), 2.18 (m, 2H), 1.95-1.74 (m, 4H), 1.62 (m, 1H), 1.48 (m, 1H), 1.32 (s, 9H). (7.4 mg, 43%, more polar isomer, Compound 166): MS(ES+) m/e 588 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 9.16 (br, 1H), 8.57 (br, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.42 (br, 1H), 7.33 (d, 1=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 7.15 (m, 2H), 7.07 (m, 1H), 4.57 (t, J=7.3 Hz, 1H), 4.26 (m, 1H), 3.25 (m, 1H), 2.92 (m, 1H), 2.69 (m, 5H), 2.40 (m, 1H), 2.11 (m, 4H), 1.90 (m, 2H), 1.65 (m, 2H), 1.33 (s, 9H).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23]2)#[N:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([O:30][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:24]=[CH:23]2)#[N:19]
Reactant: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: N#Cc1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc2cc(C#N)ccc2c1
Temperature: 25 °C

Procedure:
The compound (t-butyl 2-fluoro-5-nitrobenzoate) (1.74 g) obtained in a previous production example, 6-cyano-2-naphthol (1.86 g) and potassium carbonate (8.2 g) were heated to 50° C. in N,N-dimethylformamide and reacted for 2 hours. After cooling to room temperature, water was added and extraction was performed with ethyl acetate. The ethyl acetate layer was washed with saturated saline and dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (300 g, hexane:ethyl acetate=5:1) to obtain 3.23 g of t-butyl 2-(6-cyano-2-naphthyloxy)-5-nitrobenzoate.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:11][O:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]1[O:17][C:16]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[NH:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:15][CH:14]=1>CO>[CH3:12][C:13]1[O:17][C:16]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]2[NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH2:11][CH:9]([CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[OH:10])[CH2:31][CH2:30]2)=[CH:15][CH:14]=1
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CO
Product: Cc1ccc(Cn2c(NC3CCN(CC(O)COc4ccccc4)CC3)nc3ccccc32)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of 4.5 parts of 2-(phenoxymethyl)oxirane, 4.65 parts of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 120 parts of methanol was stirred overnight at room temperature. The precipitated product was filtered off and dried, yielding 3.1 parts (44.8%) of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-α-(phenoxymethyl)-1-piperidineethanol; mp. 164.8° C. (compound 25).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18](OB(O)O)[CH:19]=[CH:20][CH:21]=1>>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:15][CH3:14])[CH:21]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2)c1
Reaction time: 22 h
Yield: 81 %

Procedure:
The compound is prepared by the reaction of 2-bromo-6-methoxynaphthalene (500 mg, 2.11 mmol, 1 eq) with 3-methoxyphenylboric acid (321 mg, 2.11 mmol, 1 eq) according to method A within 22 h. Purification by column chromatography with a mixture of hexane/ethyl acetate 9/1 yields the desired product in a yield of 81% (451 mg).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH3:14])[N:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH3:13].C(N(CC)CC)C>C(O)C.[Pd]>[CH3:14][N:4]1[C:3](=[O:15])[CH:2]=[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])[CH:6]=[N:5]1
Reactant: Cc1nccn1-c1cnn(C)c(=O)c1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nccn1-c1cnn(C)c(=O)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 82.2 %

Procedure:
To a solution of 3.30 g (14.7 mmol) of 4-chloro-2-methyl-5-(2-methyl-imidazol-1-yl)-2H-pyridazin-3-one in 60 ml of ethanol at 50° C. were added 2.44 ml (1.78 g, 17.6 mmol) of triethylamine and 0.312 g of Pd 10%/C. The suspension was stirred under hydrogen atmosphere for 15 h at 50° C. The catalyst was filtered off and washed twice with 10 ml of ethanol. The filtrate was concentrated in vaccuo, and taken up in 50 ml of methylene chloride. The organic phase was washed four times with water, dried and concentrated to yield the title compound (2.30 g, 12.09 mmol, 82%) as a white crystalline solid, MS: m/e=191.2 (M+H+).
Reaction SMILES: CC([N:5]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([C:16]#[C:17]C(O)(C)C)[C:10]=1[CH3:22])[C:6](=[O:8])[O-:7])(C)C.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[C:47]1([CH3:53])[CH:52]=CC=C[CH:48]=1>>[Cl:15][C:13]1[CH:12]=[C:11]([C:16]#[CH:17])[C:10]([CH3:22])=[C:9]([NH:5][C:6](=[O:8])[O:7][C:47]([CH3:53])([CH3:52])[CH3:48])[CH:14]=1
Reactant: Cc1c(C#CC(C)(C)O)cc(Cl)cc1N(C(=O)[O-])C(C)(C)C
Reactant: Cc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C#Cc1cc(Cl)cc(NC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1,1-dimethylethyl[5-chloro-3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-methylphenyl]carbamate (504 mg 1.56 mmol) in toluene (3 mL) was added potassium carbonate (215 mg, 1.56 mmol) and 18-crown-6 (82 mg, 0.31 mmol). The mixture was stirred at reflux for 5 hours, then was cooled to room temperature and partitioned between water and ethyl acetate. The aqueous portion was extracted twice with ethyl acetate. The combined organic portions were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo to afford a brown residue which was purified by column chromatography (silica gel, 5% ethyl acetate in hexane). The product was collected to afford 242 mg, 0.91 mmol (58%) of 1,1-dimethylethyl (5-chloro-3-ethynyl-2-methylphenyl)carbamate as a tan solid. 1H NMR (400 MHz, CDCl3): 7.40 (d, 1H), 7.07 (d, 1H), 3.32 (s, 1H), 2.25 (s, 3H), 1.39 (s, 9H); MS (EI) for C14H16ClNO2: 266 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[BH4-].[Na+].Cl>CO>[CH3:1][C:2]([CH2:9][CH2:10][CH:11]=[C:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:3][CH2:4][CH2:5][CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
1 g of 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2-on was dissolved in 20 ml. of methanol. 60 mg of sodium borohydride was added to the solution and the whole was stirred for 30 minutes. The reaction liquid was poured in ice-water. Dilute hydrochloric acid solution was added thereto to make the same acidic. The liquid was then subjected to the extraction with 50 ml. of n-hexane. The extract was washed with water and dried with magnesium sulfate. The solvent was distilled out to obtain 1 g of an oily product. The product was purified according to silica gel column chromatography to obtain 0.95 g of the intended product in the form of a colorless oil from 10% ether/n-hexane effluent.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13].[H-].[Na+].[Br:16][CH2:17][CH2:18]Br>CN(C)C=O>[Br:16][CH2:17][CH2:18][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][CH:3]([C:4]=23)[C:2]1=[O:13]
Reactant: O=C1Nc2cccc3c2C1CCC3
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CCCc3cccc(c32)N1CCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
2a,3,4,5-Tetrahydrobenz[cd]indole-2(1H) -one (3.46 g, 20mmol) was dissolved in anhydrous N,N-dimethylformamide (20 ml). Thereto was added sodium hydride (0.8 g, 20 mmol), and the resulting solution was stirred at room temperature for 1 hour. The reaction solution was mixed with 1,2-dibromoethane (10 ml, 115 mmol) and again stirred for 1 hour. The reaction solution was extracted by adding 100 ml of ethyl acetate and 100 ml of water, and the resulting ethyl acetate layer was separated, washed with water and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was crystallized from a dimethylformamide-water mixture to obtain 1.9 g of the title compound (34% in yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[CH2:17]>C(O)C>[N:21]1[CH:22]=[CH:23][C:18]([CH2:16][CH2:17][N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH2:9][CH2:8]3)[CH2:3][CH2:2]2)=[CH:19][CH:20]=1
Reactant: C=Cc1ccncc1
Reactant: c1ccc2c(c1)CCN2C1CCNCC1
Solvent: CCO
Product: c1ccc2c(c1)CCN2C1CCN(CCc2ccncc2)CC1
Yield: 42.5 %

Procedure:
1-(4-Piperidyl)indoline (0.1 g) was dissolved in ethanol (5 ml). After adding 4-vinylpyridine (0.16 ml), the resultant mixture was heated under reflux in a nitrogen atmosphere for 12 hr. Then the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (toluene/acetone system) to give the title compound (0.064 g) as a colorless oil (yield: 42.5%).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[S:8][C:9]3[C:10](=[O:17])[N:11]([CH3:16])[C:12](=[O:15])[C:13]=3[S:14][C:4]=2[C:3]1=[O:18].[N+]([O-])(O)=[O:20]>>[CH3:1][N:2]1[C:3](=[O:18])[C:4]2[S:14][C:13]3[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[C:9]=3[S:8](=[O:20])[C:5]=2[C:6]1=[O:7]
Reactant: Cn1c(=O)c2sc3c(=O)n(C)c(=O)c3sc2c1=O
Reactant: O=[N+]([O-])O
Product: CN1C(=O)C2=C(C1=O)S(=O)C1=C(S2)C(=O)N(C)C1=O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
With stirring, 3 g (10.63 mmol) of 2,6-dimethyl-1H,5H-[1,4]dithiino[2,3-c:5,6-c′]dipyrrole-1,3,5,7(2H,6H)-tetrone [compound No. (1)] were added to 20 ml of ice-cooled (5° C.) fuming nitric acid. After dissolution was complete, stirring was continued for 5 min, the mixture was subsequently poured into ice-water and the yellow crystals were filtered off with suction. This gave 2.56 g (80.8% of theory) of the desired compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:40]1(NCC(F)(C)C(OCC)=O)CCCCC1.CC1(C(OC)=O)CO1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:24][C:23]=4[O:38][CH3:39])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:40][CH2:5]1
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Reactant: CCOC(=O)C(C)(F)CNC1CCCCC1
Agent: COC(=O)C1(C)CO1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with Compound 87 except that ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate, made from commercially available starting material methyl 2-methyloxirane-2-carboxylate, was used and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.36 (m, 2H) 1.28-2.08 (m, 17H) 2.19 (s, 3H) 2.81 (d, J=10.6 Hz, 2H) 3.26 (s, 3H) 3.60-3.85 (m, 3H) 3.95 (s, 3H) 4.45 (m, 1H) 7.47 (d, J=8.3 Hz, 1H) 7.50 (s, 1H) 7.75 (s, 1H) 7.97-8.20 (m, 2H) 8.32 (d, J=8.3 Hz, 1H). [M+H] calc'd for C29H40FN7O3, 554. found 554.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[SH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([CH2:2][S:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[O:4]
Reactant: O=C(O)CCCCS
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)CCCCSCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of bromomethyl-2-naphthyl ketone (2 g, 8.00 mmol) in anhydrous THF (50 mL) was added 5-mercaptovaleric acid (1.07 g, 8.00 mmol), followed by potassium carbonate (5.71 g, 41 mmol). The suspension was refluxed for 1 hour, cooled to the room temperature and filtered. The solid was collected, dissolved in a 1:1 mixture water-THF and acidified with HCl (pH 1-2). The acidic solution was extracted with ether, dried (MgSO4), filtered and evaporated to produce the title compound 225a (1.21 g, 50% yield). 1H NMR: (300 MHz, DMSO-d6) δ 11.98 (br s, 1H), 8.69 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 8.00-7.98 (m, 3H), 7.67-7.61 (m, 2H), 4.09 (s, 2H), 2.52 (t, J=6.6 Hz, 2H), 2.19 (t, J=6.6 Hz, 2H), 1.56-1.53 (m, 4H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:18]SC1C(C2C=NC=CC=2)=NNC=1>>[CH2:1]([O:6][C:7]1[C:8]([C:12]2[CH2:13][N:14]([CH3:18])[CH2:15][CH2:16][CH:17]=2)=[N:9][NH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCCOc1c[nH]nc1-c1cccnc1
Product: CCCCCOc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 32G was converted to the title compound (33G), using the methodology described for the conversion of 21A to 22A (see Scheme 3).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)CN)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:36]4[CH:35]=[CH:32][CH:31]=[C:30]([O:29][CH:26]5[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]5)[CH:37]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CN1CCC(Oc2cccc(CN)c2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: Oc1ccccc1
Product: CN1CCC(Oc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.100 g, 0.310 mmol), 3-(1-methyl-piperidin-4-yloxy)-benzylamine (0.109 g, 0.370 mmol) and phenol (1.0 g) were stirred at 130° C. for 2 hours. The reaction mixture was allowed to cool to r.t. and the product was partially purified by flash chromatography using a gradient elution with n-heptane against MeOH/TEA. The fractions containing the title product were concentrated in vacuo and purified further by washing with MeOH to give the title compound. Yield: 0.052 g (36%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.61 (d, 2H, J=8.52 Hz), 7.45 (s, 1H), 7.41 (d, 2H, J=8.52 Hz), 7.24 (m, 1H), 6.89 (m, 2H), 6.83 (d, 1H, J=9.02 Hz), 5.16 (s, 2H), 4.29 (bs, 1H), 2.65 (bs, 2H), 2.21-2.31 (m, 5H), 1.95 (m, 2H), 1.79 (m, 2H). MS (ESI+) 465.93 (M+1H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH2:10])=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>C(OCC)(=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH:10][C:23](=[O:25])[CH3:24])=[CH:5][C:4]=1[C:11]1[NH:12][C:13]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:14]([CH3:16])[N:15]=1
Reactant: COc1cc(Cl)c(N)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(NC(C)=O)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Temperature: 0 °C

Procedure:
A solution of 2-(2-methoxy-4-chloro-5-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (1.0 g) and acetic anhydride (2 ml) in a mixture of ethyl acetate (20 ml) and tetrahydrofuran (10 ml) was refluxed for 2 hours. The reaction mixture was cooled with ice-water and the crystalline residue was collected by filtration to give 2-(2-methoxy-4-chloro-5-acetamidophenyl)-4-methyl-5-(3-pyridyl)imidazole (0.7 g).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[C:5]([CH3:16])[CH:4]=1.[C:17](O)(=O)[CH3:18].Br>C(O)C>[CH2:17]([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][C:5]=1[CH3:16])=[O:15])[CH3:18]
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)CCC(=O)O)c(C)c1
Agent: Br
Solvent: CCO
Product: CCOC(=O)CCC(=O)c1ccc(O)cc1C
Temperature: 130 °C
Yield: 75 %

Procedure:
A mixture of 4-(4-methoxy-2-methyl-phenyl)-4-oxo-butyric acid (2 g, 9 mmol), acetic acid (30 mL) and 48% aqueous HBr (10 mL) was heated at 130° C. for 5.5 h. The reaction was cooled to rt and concentrated at reduced pressure and azeotrope twice with benzene to give a crude residue. The crude residue was dissolved in ethanol (25 mL) and added amberlyst then heated at 90° C. for 18 h. The reaction was filtered over celite and evaporated ethanol at reduced pressure then quenched with water and extracted twice with methylene chloride to obtain 4-(4-hydroxy-2-methyl-phenyl)-4-oxo-butyric acid ethyl ester (1.6 g, 75%). The crude material was used for the next reaction without purification.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:36]([O-])=O)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pd]>[NH2:36][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:14]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=1)[C:13]2=[O:35]
Reactant: CCCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 66.7 %

Procedure:
0.11 g (0.21 mmol) of 2-butyl-3-[(2'-(t-butoxycarbonyl)biphen-4-yl)methyl]-6-nitroquinazolin-3(1H)-one (Example 21) was suspended in 7.5 mL of MeOH and hydrogenated over 55 mg of 10% Pd/C under an atmospheric pressure hydrogen blanket. After 1 hour the reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 50% EtOAc/hexane to give 69 mg (0.14 mmol) of a white foam, 67% yield. 1H-NMR (CDCl3): 0.94 (t, 3H, J=7. Hz), 1.23 (s, 9H), 1.41 (m, 2H), 1.79 (m, 2H), 2.74 (3 line m, 2H, J=7.7 Hz), 5.44 (bs, 2H), 7.05-7.57 (m, 10H), 7.77 (d, J=7.5 Hz).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[CH3:33][O:34][CH2:35][CH2:36]Br.C(=O)([O-])[O-].[K+].[K+].Cl>CCO.C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:36][CH2:35][O:34][CH3:33])[CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: COCCBr
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CCCCc1nnc(OC2CCN(CCOC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 0.2 mmol, 97 mg) in EtOH (2 mL) was added 2-bromoethyl methyl ether (0.6 mmol, 57 μL), and potassium carbonate (0.6 mmol, 83 mg). The mixture was stirred at 60° C. for 3 hours, then cooled to room temperature, and filtered through celite. The celite cake was washed with DCM. The organic layers were combined and condensed in vacuo, and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (2 mL), 1N HCl in ether (2 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (52 mg). LCMS: m/z 469 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.31-7.40 (3H, m), 7.06-7.10 (2H, m), 5.38-5.57 (1H, m), 4.39-4.44 (1H, m), 3.53-3.78 (4H, m), 3.43 (3H, s), 3.25-3.42 (4H, m), 2.96-3.02 (2H, m), 2.04-2.55 (4H, m), 1.97-2.02 (2H, m), 1.78-1.83 (2H, m), 1.29-1.62 (8H, m), 1.22-1.30 (2H, m), 0.80 (3H, t).