Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=1.CC[Mg+].[Br-].[CH:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CO>C1COCC1>[NH:3]1[CH:2]=[C:6]([CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[OH:37])[N:5]=[CH:4]1
Reactant: O=Cc1ccccc1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CO
Product: OC(c1ccccc1)c1c[nH]cn1
Temperature: 25 °C
Yield: 57 %

Procedure:
To the stirred solution of 4-iodo-1-trityl-1H-imidazole (0.5 mmol) in THF under anhydrous condition, EtMgBr (0.33 mL, 3M in diethyl ether) was added. The reaction was allowed to stir at room temperature. After 1.5 h benzaldehyde was added and the reaction was allowed to stir overnight. After the completion of reaction few drops of methanol was carefully added at 0° C. The crude residue was used in next step without further purification. To a solution of the crude imidazole from the previous step was added acetic acid (1.0 mL) and MeOH (4.0 mL). The solution was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to ˜10 with 10% NaOH (aq). The aqueous phase was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water, brine, and dried. The solvent was removed in vacuum to afford the crude residue, which was purified by flash column chromatography on silica gel to afford the desired product in 57% yield. 1H NMR: 1.27 (s, 1H), 5.78 (s, 1H), 6.80 (s, 1H), 7.07 (s, 1H), 7.25 (d, 1H, J=7.2 Hz), 7.32 (t, 1H, J=7.2 Hz), 7.40 (d, 1H, J=7.2 Hz), 7.64 (s, 1H), 7.74 (s, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23]3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:26]([C:22]2[CH:23]=[C:24]3[C:19]([CH:18]=[CH:17][C:16]([O:15][C:13]4[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=4)=[CH:25]3)=[CH:20][CH:21]=2)=[O:27])=[CH:32][C:31]=1[C:37]([F:38])([F:39])[F:40]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)O)cc3c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3c2)ccn1
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of 7-({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}oxy)-2-naphthoic acid (350 mg, 0.92 mmol) in DCM (9.0 mL), was added 4-chloro-3-(trifluoromethyl)aniline (198.0 mg, 1.0 mmol); EDCl (194 mg, 1.0 mmol) and DMAP (124 mg, 1.0 mmol). The mixture was allowed to stir for 18 h then diluted with EtOAc and washed with water and then brine. The organic phase was dried (Na2SO4) and evaporated, and the residue was triturated with DCM/EtOAc/MeOH to yield the title compound as a white solid (420 mg, 81.8%). LCMS: (FA) ES+ 558.1, ES− 556.1.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:13][CH2:12][CH:11]([O:26][C:27](=[O:29])[CH3:28])[CH2:10]1)=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH2:24][CH3:25])[CH:16]=2)[CH2:13][CH2:12][CH:11]([O:26][C:27](=[O:29])[CH3:28])[CH2:10]1
Reactant: CCOc1cc(C2CCC(OC(C)=O)CC2NC(=O)OC(C)(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: CCOc1cc(C2CCC(OC(C)=O)CC2N)ccc1OC
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
3.0 g (7.36 mmol) of acetic acid (1SR,3RS,4RS)-3-tert-butoxycarbonylamino-4-(3-ethoxy-4-methoxyphenyl)-cyclohexyl ester (compound F6) are dissolved in 6 ml of 4 M HCl in dioxane and stirred for 30 min. After removal of the solvent the residue is dissolved in dichloromethane and 25 ml of sat. NaHCO3 solution are added carefully. After phase separation, reextraction of the water layer and drying of the combined organic layers (Na2SO4) the solvent is removed to give 2.25 g of the title compound.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])=[CH:16][CH:15]=1
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 35.1 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid methyl ester (648 mg, 2.43 mmol) and 2-aminothiazole (487 mg, 4.86 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 14.0 mL, 9.72 mmol) was refluxed at 100° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (286 mg, 35%) as a white solid: mp 156.6-159.8° C.; EI-HRMS m/e calcd for C17H19ClN2OS (M+) 334.0906, found 334.0910.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:25][C:26]1([C:29]([OH:31])=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:29]([C:26]1([NH:25][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]4[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([Cl:24])[CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:28][CH2:27]1)([OH:31])=[O:30]
Reactant: NC1(C(=O)O)CC1
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Yield: 31.4 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (408.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. 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 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (130.4 mg, 31.5%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 415.1.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][C:19](=[O:21])[N:18]([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:17]2(=[O:29])=[O:28])=[C:12]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:11]=1)(C)(C)C.C(OC(=O)N[C@@H](CC1C=CC=CC=1)CC1C=CC(N2CC(=O)NS2(=O)=O)=C(O)C=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[S:17](=[O:29])(=[O:28])[N:18]([CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:19](=[O:21])[CH2:20]2)=[C:12]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H](N)Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ((S)-1-benzyl-2-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester (intermediate from Example 60) (510 mg, 0.78 mmol) in methylene chloride (5 mL) is added TFA (2 mL) and the mixture is stirred at RT for 5 h. The solvent is removed under reduced pressure to give the title compound. This material is used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=1.[H-].[Na+].[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@@:25]1([O:56][CH3:57])[CH2:43][CH2:44]OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:22])[CH3:21].[O-]C1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[C:20]([O:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@:25]1([CH2:43][CH2:44][O:17][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)=[C:2]([Cl:1])[CH:3]=1)[O:56][CH3:57])(=[O:22])[CH3:21]
Reactant: CCc1ccc(Cc2ccc(O)cc2Cl)cc1
Reactant: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2ccc(OCC[C@]3(OC)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 16.6 %

Procedure:
3-Chloro-4-(4-ethylbenzyl)phenol (15) (55 mg, 0.22 mmol) was dissolved in DMF (0.30 mL) and NaH (9 mg, 0.22 mmol) was added to the solution. After stirring for 5 min, a solution of (2S,3R,4S,5R,6R)-6-(acetoxymethyl)-2-methoxy-2-(2-(tosyloxy)ethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (17) (102 mg, 0.18 mmol in 200 μL DMF) was added to the phenoxide solution. After 2 h, the reaction was heated to 70° C. and stirred for 18 h. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 (1×). The aqueous layer was back-extracted with EtOAc (2×). The organic layers were combined, dried (Na2SO4), concentrated onto celite and chromatographed over SiO2 (ISCO system, 0-60% EtOAc/hexanes) to provide an oil (19 mg, 17%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.07 (m, 5H), 6.88 (d, J=2.4 Hz, 1H), 6.69 (dd, J=8.9, 2.6 Hz, 1H), 5.47 (t, J=9.6 Hz, 1H), 5.00-5.15 (m, 3H), 3.85-4.17 9 m, 6H), 3.32 (s, 3H), 2.61 (q, J=15, 7.5 Hz, 2H), 2.06 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.21 (t, J=7.5 Hz, 3H). LC/MS: tR=3.07 min, calcd for C32H39ClO11: 634.22, found 657.4 (M+Na)+.
Reaction SMILES: Cl.C(OC1C=C(C=CC=1C)N[C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.Cl[CH2:28][C:29]1[C:30]([CH3:35])=[N:31][O:32][C:33]=1[CH3:34]>[I-].[K+]>[CH3:35][C:30]1[C:29]([CH2:28][O:22][C:16]2[CH:15]=[C:14]3[C:19]([CH:10]=[N:11][CH:12]=[N:13]3)=[CH:18][C:17]=2[O:20][CH3:21])=[C:33]([CH3:34])[O:32][N:31]=1
Reactant: Cc1noc(C)c1CCl
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Product: COc1cc2cncnc2cc1OCc1c(C)noc1C
Yield: 112.6 %

Procedure:
Using an analogouls procedure to that described for the starting material in Example 1, 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg) was reacted in the presence of potassium iodide (16 mg) with 4-chloromethyl-3,5-dimethylisoxazole (177 mg) to give 4-(3-acetoxy)-4-methylanilino)-7-(3,5-dimethylisoxazol-4-ylmethoxy)-6-methoxyquinazoline (342 mg, 72%).
Reaction SMILES: [N:1]([CH:4]([CH3:26])[CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([O:15]CC3C=CC=CC=3)[CH:11]=[C:10]3[CH2:23][CH2:24][CH2:25][C:8]([C:9]=23)=[N:7]1)=[N+]=[N-].C([O-])=O.[NH4+].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(O)C.[Pd]>[NH2:1][CH:4]([CH3:26])[CH2:5][N:6]1[C:14]2[CH:13]=[C:12]([OH:15])[CH:11]=[C:10]3[C:9]=2[C:8]([CH2:25][CH2:24][CH2:23]3)=[N:7]1
Reactant: CC(Cn1nc2c3c(cc(OCc4ccccc4)cc31)CCC2)N=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: CC(N)Cn1nc2c3c(cc(O)cc31)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product from Step G (0.74 g, 2.2 mmol) in ethanol under a nitrogen atmosphere at room temperature was added Pd/C (10%, 0.10 g) followed by ammonium formate (0.54 g, 8.5 mmol). This suspension was stirred for 24 h at room temperature followed by filtration through a filter-aide. The filtrate was evaporated to a residue that was purified by column chromatography (silica, 5% to 20% gradient of methanol in dichloromethane) to give a solid that was converted to the dihydrochloride salt, which was crystallized from methanol/ether (0.38 g, 58%): m.p 286-288° C.; MS (ES) m/z 232 (M+); 1H NMR (DMSO-d6) δ 8.28 (3H, brs), 6.59 (1H, s), 6.43 (1H, s), 4.40-4.22 (2H, m), 3.61 (11H, m), 2.79 (4H, m), 2.27 (2H, m), 1.18 (3H, d, J=8.0 Hz).
Reaction SMILES: [C:1]([C:3](=[C:8](SC)[NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:19]1([CH2:24][C:25]([NH2:27])=[NH:26])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CN(C=O)C.O>[CH:19]1([CH2:24][C:25]2[NH:27][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[N:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N=C(N)CC1CCCC1
Reactant: COC(=O)C(C#N)=C(Nc1cccnc1)SC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1c(Nc2cccnc2)nc(CC2CCCC2)[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
0.1 g (0.40 mmol) of methyl 2-cyano-3-(methylsulfanyl)-3-(3-pyridinylamino)-2-propenoate and 0.065 g (0.40 mmol) of 2-cyclopentylethanamidine hydrochloride and 0.16 g (1.60 mmol) of triethylamine are dissolved in 0.5 ml of DMF and stirred at 100° C. overnight. After cooling, the mixture is diluted with 10 ml of water and extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated in vacuo, and the residue is purified by flash chromatography (mobile phase: dichloromethane/methanol 200:1, 100:1, 50:1). 78 mg (64% of theory) of the product are obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:30]4[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=4)([C:20]4[CH:21]=[N:22][C:23]5[C:28]([CH:29]=4)=[CH:27][CH:26]=[CH:25][CH:24]=5)[OH:19])[CH:16]=3)[N:11]=[C:10]([O:36]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([OH:19])([C:30]4[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=4)[C:20]4[CH:21]=[N:22][C:23]5[C:28]([CH:29]=4)=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:16]=3)[NH:11][C:10](=[O:36])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cnc4ccccc4c3)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1cnc2ccccc2c1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1

Procedure:
Following the same procedure as described in Example 1F, the title compound of 38A (81 mg, 0.16 mmol) was treated with HCl in aqueous THF to yield the title compound of example 38B (56.4 mg, 71% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]1=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]2[C:33](=[O:42])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:40]2=[O:41])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: O=[N+]([O-])c1ccc(CCNCCOc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCN(CCOc1ccc([N+](=O)[O-])cc1)CCc1ccc([N+](=O)[O-])cc1
Reaction time: 120 h
Yield: 85 %

Procedure:
[2-(4-Nitrophenyl)ethyl]{2-[(4-nitrophenyl)oxy]ethyl}amine (253 mg) and 2-(6-bromohexyl)-1H-isoindole-1,3(2H)-dione (1186 mg) were dissolved in DMF (4 ml) and basified by the addition of DIPEA (0.665 ml). The reaction was stirred for 120 h. The reaction mixture was evaporated to dryness and the residue dissolved in DCM, the solution was absorbed onto a pad of silica and purified on a silica cartridge (12 g) eluting with the following gradient: (A=DCM, B=methanol) t=0 min: B=10%; t=7.5 min: B=0%; t=22.5 min: B=5%. The desired product eluted at ˜15% B (isocratically) and evaporation of the solution to dryness gave the title compound (0.364 g).
Reaction SMILES: [OH:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[CH:3]=1)[NH:11][CH:10]=[C:9]([C:14]#[N:15])[C:8]3=O.P(Cl)(Cl)([Cl:23])=O>C1(C)C=CC=CC=1>[Cl:23][C:8]1[C:7]2[C:12](=[CH:13][C:4]3[CH:3]=[C:2]([OH:1])[C:18]([O:19][CH3:20])=[CH:17][C:5]=3[CH:6]=2)[N:11]=[CH:10][C:9]=1[C:14]#[N:15]
Reactant: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1O
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (11.3 mmol) of 8-hydroxy-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 20.0 mL of phosphorus oxychloride is heated under reflux for 0.5 hour, then is cooled to room temperature. Excess phosphorus oxychloride is evaporated to yield a residue, to which toluene is added and the resulting solution is reduced in vacuo. Toluene is added and evaporated twice more. The resulting residue is cooled with ice bath, neutralized with cold saturated solution of sodium bicarbonate and stirred. The solid was collected by filtration, is washed with cold water and is dried to yield 2.83 g of 4-chloro-8-hydroxy-7-methoxybenzo[g]quinoline-3-carbonitrile as a yellow solid. A sample of the material is purified by silica gel chromatography, eluting with 97:3 methylene chloride/methanol to yield a yellow solid, mp.>300° C.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH2:12][C@@H:11]3[CH2:13][C@H:8]2[CH2:9][N:10]3C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[ClH:23]>C(Cl)Cl>[ClH:23].[ClH:23].[C@H:8]12[CH2:13][C@H:11]([NH:10][CH2:9]1)[CH2:12][N:7]2[CH2:6][C:5]1[CH:21]=[CH:22][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Product: Oc1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of tert-butyl (1S,4S)-5-(4-hydroxybenzyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (3.47 g, 0.0114 mol, 1 equiv.) in CH2Cl2 (42 mL) was added HCl (4 M in dioxane, 22.5 mL, 0.114 mol, 10 equiv.). The solution was stirred at rt for 12 h. The mixture was then concentrated, affording a white solid (100%). 1H NMR (500 MHz, DMSO-d6): 11.60-11.28 (m, 1H), 10.38-9.95 (m, 1H), 9.93-9.56 (m, 2H), 7.49 (s, 2H), 6.81 (s, 2H), 4.39 (m, 4H), 3.88 (s, 1H), 3.67 (s, 1H), 2.72-2.52 (m, 0.5H), 2.45-2.30 (m, 0.5H), 2.08 (s, 1H). MS (ESI): mass calcd. for C12H16N2O, 204.27; m/z found, 205.1 [M+H]+.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:36])(=[O:6])=[O:5])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([C:27]4[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:36])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4ccc([N+](=O)[O-])cc4)[nH]c3-c3ccccc3)cc21
Agent: [Pd]
Solvent: CO
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4ccc(N)cc4)[nH]c3-c3ccccc3)cc21
Reaction time: 6 h
Yield: 28 %

Procedure:
Purge a suspension of 1-isopropylsulfonyl-2-amino-6-(2-(4-nitrophenyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.149 g, 0.3 mmol) and 10% palladium on carbon (0.03 mmol) in methanol with hydrogen for 10 minutes and then stir under a hydrogen atmosphere for 6 hours. Filter through a bed of Celite® and concentrate the residue under reduced pressure. Subject the residue to silica gel chromatography, eluting with 4% methanol in dichloromethane to provide the title compound in 28% yield. MS(ES+): m/z=473.0 (M+H)+
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>ClCCl.C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([NH:30][S:45]([C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH2:28][CH2:29]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(NS(=O)(=O)c3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To the mixture of the compound obtained in Example 194 (528 mg, 1.00 mmol), triethylamine (0.502 mL, 3.60 mmol), THF (10 mL) and dichloromethane (10 mL) was added 4-fluorobenzenesulfonyl chloride (234 mg, 1.20 mmol), and the mixture was stirred at room temperature for 16 hours. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (15 ml), and the organic solvent was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate (15 mL×3). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel log, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were filtered off. The filtrate was concentrated under reduced pressure to give the titled compound (516 mg, 0.84 mmol, Yield 84%) as colorless foam like substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:10]([O:14][CH3:15])(=[O:13])[C:11]#[CH:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C(#N)C.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[O:9][CH:12]=[CH:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: C#CC(=O)OC
Reactant: Oc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COC(=O)C=COc1cc(F)cc(F)c1
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A solution of 3,5-difluorophenol (35.5 g, 273 mmol) and methyl propiolate (25.0 mL, 300 mmol) in acetonitrile (109 mL) was added to a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M commercial solution, 109 mL, 109 mmol) at room temperature over a period of 2 hours. After complete addition of the solution, the mixture was stirred for 1 hour. The reaction mixture was diluted with toluene (350 mL) and the organic mixture was washed twice with water (250 mL×2), dried over magnesium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on amino gel (hexane:ethyl acetate=3:2 as an eluent) to afford the title compound as a yellow solid (60.0 g, quant, 1:1 mixture of cis- and trans-isomers).