Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[OH:27])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:35](I)[CH3:36]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[O:27][CH2:35][CH3:36])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: CCI
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
In a 4 mL screw cap vial fitted with a small egg-shaped stir bar, were combined 5-fluoro-2-(4-fluoro-2-hydroxybenzoylamino)-N-(5-chloropyridin-2-yl)benzamide (200 mg, 0.49 mmol) and powdered anhydrous K2CO3 (103 mg, 0.74 mmol, 1.5 eq) in 0.5 mL of dry dimethylformamide (DMF). Ethyl iodide (115 mg, 0.74 mmol) was then added, the vial was capped, and the slurry heated to 50° C. with vigorous stirring overnight. The slurry was diluted with 20 mL water and extracted into 15 mL of dichloromethane. The organic layer was then washed with 20 mL portions of saturated NaHCO3, water, and brine; then dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a few mL of dichloromethane and purified by radial chromatography, eluting using hexanes, then 4:1 hexanes:EtOAc, to provide 135 mg (63%) of the title compound as pinkish-white crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:32]=[CH:31][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH3:33][C:34]1([CH3:37])[CH2:36][O:35]1>>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:3][N:2]([CH2:33][C:34]([CH3:37])([OH:35])[CH3:36])[CH2:5]5)[CH:32]=[CH:31][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1
Reactant: CC1(C)CO1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Agent: Cl
Product: CC(C)(O)CN1CC(c2ccc3c(c2)OCCc2cn(-c4ncnn4-c4ccc(F)cc4F)nc2-3)C1

Procedure:
Following the procedure for 177, 8-azetidin-3-yl-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with 2,2-dimethyl-oxirane to give 183 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.45 (s, 1H); 8.31 (s, 1H); 8.17 (s, 1H); 7.84 (td, J=8.75, 5.92 Hz, 1H); 7.66 (ddd, J=10.33, 9.02, 2.79 Hz, 1H); 7.40-7.34 (m, 1H); 7.31 (d, J=8.17 Hz, 1H); 7.00 (d, J=1.69 Hz, 1H); 6.93 (dd, J=8.25, 1.78 Hz, 1H); 4.26 (t, J=5.06 Hz, 2H); 3.79 (t, J=7.52 Hz, 2H); 3.64 (t, J=7.75 Hz, 1H); 3.35 (t, 2H); 3.08 (t, J=5.05 Hz, 2H); 2.35 (t, 2H); 1.10 (s, 6H). LCMS: RT=7.45 min, M+H+=493
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH:9]([CH3:22])[C:10](=[O:21])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])=O.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:11][C:10](=[O:21])[C:9]=1[CH3:22]
Reactant: Nc1ccccc1
Reactant: CC(C(=O)CC(=O)c1ccccc1F)C(=O)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2Cl)n(-c2ccccc2)c(-c2ccccc2F)cc1=O
Yield: 25.1 %

Procedure:
In 450 ml of xylene were suspended 15.3 g of 1-(2-chlorophenyl)-2-methyl-5-(2-fluoro-phenyl)-1,3,5-pentanetrione, 6.4 g of aniline, 6.6 g of para-toluenesulfonic acid and 85 g of Molecular Sieves 5A, followed by refluxing the resultant mixture for 8 hours. Xylene was distilled off from the reaction mixture and 300 ml of chloroform was added to the residue. The mixture obtained was filtered and the filtrate was washed first with 10% hydrochloric acid and then with a 10% aqueous solution of sodium hydroxide. After washing the chloroform phase further with water, the solution in chloroform was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate-n-hexane, 1:3) to afford crude crystals. The crystals were recrystallized from ethyl acetate, yielding 4.5 g of 2-(2-chlorophenyl)-6-(2-fluorophenyl)-3-methyl-1-phenyl-4(1H)-pyridinone having a melting point of 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=O)[NH:8][C:5]2=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:14]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([Cl:14])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Br)cnc2[nH]1
Product: Clc1nc2cc(Br)cnc2[nH]1

Procedure:
The pyridin-2-one from step (a) above (1 g, 4.7 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 232 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12](C)=[N:13][N:14]=[C:7]1[CH:6]=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](=O)=O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5](=[O:24])[C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=1[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[CH3:6]
Reactant: Cc1nnc2cc(-c3ccccc3F)c3cc(Cl)ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc(Cl)cc1C(=O)c1ccccc1F

Procedure:
In the manner given in Example 3, 7-chloro-1-methyl-5-(o-fluorophenyl)-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 2'-fluoro-5-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=2[O:20][CH2:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:8]=1)C.[Li+].[OH-].O.[CH2:31]1COCC1>CO>[Br:19][C:17]1[CH:16]=[CH:15][C:14]([O:20][CH2:21][CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[C:13]([CH:18]=1)[CH2:12][N:9]1[C:10]([CH3:31])=[CH:11][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:27])=[N:8]1
Reactant: C1CCOC1
Reactant: CCOC(=O)COc1ccn(Cc2cc(Br)ccc2OCC(CC)CC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(CC)COc1ccc(Br)cc1Cn1nc(OCC(=O)O)cc1C
Temperature: 100 °C

Procedure:
To a solution of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-1H-pyrazol-3-yloxy}-acetic acid ethyl ester, 4, (0.017 g, 0.038 mmol) in a mixture of THF (1 mL) and methanol (0.5 ml) was added a solution of LiOH (0.05 g in 1 ml H2O). The resulting mixture was heated at 100° C. in an Emrys microwave reactor for 15 minutes. The mixture was poured into water (20 mL) and extracted with EtOAc (3×15 mL). The organic layers were combined, washed with brine (30 mL), dried (MgSO4) and the volatiles were removed in vacuo. The crude product was purified on silica to yield 0.016 g of {1-[5-bromo-2-(2-ethyl-butoxy)-benzyl]-5-methyl-1H-pyrazol-3-yloxy}-acetic acid, 5 as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([OH:8])=O)[CH3:2].O1CCCC1.[F:17][C:18]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:19][NH2:20].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[CH2:1]([O:3][C:4](=[O:11])[C:5]([OH:10])([CH3:9])[C:6]([NH:20][CH2:19][C:18]([F:25])([F:17])[C:21]([F:24])([F:23])[F:22])=[O:8])[CH3:2]
Reactant: CCOC(=O)C(C)(O)C(=O)O
Reactant: NCC(F)(F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(O)C(=O)NCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
To a solution of 2.08 g (12.8 mmol) 2-hydroxy-2-methyl-malonic acid monoethyl ester in 50 ml of tetrahydrofuran 1.39 g (12.8 mmol) of 2,2,3,3,3-pentafluoropropylamine, 2.51 g (12.8 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1.77 g (12.8 mmol) of 1-hydroxybenzotrizole hydrate and 4.48 ml (25.7 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. Silicagel was added and the solvent was removed by distillation. The residue was purified by chromatography on silicagel (ethyl acetate/heptane=0:100 to 50:50) to yield 3.01 g (80%) of the title compound as white solid, MS m/e (%): 292.1 (M−H+, 100).
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:35]2[C:36]([C:41]3C=CC=CN=3)=[N:37]OC=2C)C=1)=O.C(N)(C)C>>[CH:36]([NH:37][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:41])[CH3:35]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)ns1
Solvent: CC(C)N
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NC(C)C)sn1
Yield: 83 %

Procedure:
As described for example 14e, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (22 mg, 0.37 mmol), to the title compound (95 mg, 83%) which was obtained as an off white solid after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 1:4). MS: m/e=343.2 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][C:6](=O)[C:5]=2[C:4]([CH3:18])=[CH:3]1.[C:19]([NH:22][NH2:23])([NH2:21])=[NH:20].[ClH:24].Cl.O>C(O)C>[ClH:24].[NH:22]([N:23]=[C:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][C:10]2[N:2]([CH3:1])[CH:3]=[C:4]([CH3:18])[C:5]1=2)[C:19]([NH2:21])=[NH:20]
Reactant: Cc1cn(C)c2c1C(=O)CC(c1ccccc1)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cn(C)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 23.3 %

Procedure:
A mixture of 1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.31 g), aminoguanidine hydrochloride (0.15 g), concentrated hydrochloric acid (0.065 ml), water (0.065 ml) and ethanol (50 ml) was refluxed for 5 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the mixture was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethanol. To the solution was added 1N hydrochloric acid. The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-1,3-dimethyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 8) (0.1 g) as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[CH:12]([C:10]1[N:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]([CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([O:24][CH3:25])=[O:23])[CH:9]=1)=[O:13]
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccccc1)n1cc(C=O)nc1-c1ccccc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.73 g) in N,N-dimethylformamide (35 mL) were added potassium carbonate (2.78 g) and methyl bromo(phenyl)acetate (2.53) and the mixture was stirred at 85° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→3:7) and crystallized from diisopropyl ether to give the title compound as colorless crystals (yield 814 mg, yield 25%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29](O)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH3:40][O:41][C@@H:42]([C@@H:60]1[CH2:64][CH2:63][CH2:62][NH:61]1)[C@@H:43]([CH3:59])[C:44]([NH:46][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[S:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:38])[C@@H:26]([C@@H:34]([CH3:37])[CH2:35][CH3:36])[C@H:27]([O:32][CH3:33])[CH2:28][C:29]([N:61]3[CH2:62][CH2:63][CH2:64][C@H:60]3[C@H:42]([O:41][CH3:40])[C@@H:43]([CH3:59])[C:44]([NH:46][C@H:47]([C:55]([O:57][CH3:58])=[O:56])[CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)=[S:45])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=S)[C@H](C)[C@@H](OC)[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #@5 (260 mg, 0.648 mmol, 1 eq.), #39 (340 mg, ≦0.629 mmol, 1 eq.), dichloromethane (10 mL, 0.065 M), HATU (296 mg, 0.778 mmol, 1.2 eq.) and diisopropylethylamine (339 μL, 1.94 mmol, 3 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 40% acetone in heptane) to give #76 (466 mg, 83% over two steps) as a solid. LC-MS: m/z 871.5 [M+H+], 893.5 [M+Na+], retention time=1.10 minutes; HPLC (Protocol C): retention time=9.249 minutes (purity >99%); 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (br d, J=7.4 Hz) and 10.49 (br d, J=7.8 Hz), total 1H], 7.89 (br d, J=7.4 Hz, 2H), 7.68-7.75 (m, 2H), 7.54-7.60 (m, 1H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.28-7.36 (m, 2H), 7.15-7.28 (m, 5H), [5.20 (ddd, J=10.9, 7.3, 4.4 Hz) and 5.34-5.43 (m), total 1H], 3.65 and 3.69 (2 s, total 3H), 3.24 and 3.25 (2 s, total 3H), 3.17 (br s, 3H), 2.93 and 2.98 (2 br s, total 3H), [1.15 (d, J=6.6 Hz) and 1.18 (d, J=6.6 Hz), total 3H].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[C:3]=1[C:4]([O-:6])=O.[Li+].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:55]1([N:58]2[C:67]3[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=3)[NH:61][CH2:60][CH2:59]2)[CH2:57][CH2:56]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:4]([N:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=3)[N:58]([CH:55]3[CH2:57][CH2:56]3)[CH2:59][CH2:60]2)=[O:6])=[C:7]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[Cl:20])[CH:8]=[C:9]([CH3:11])[N:10]=1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)[O-])c(Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Oc2cc(Cl)ccc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)c(Cl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.9 %

Procedure:
To a solution of 120 mg (0.355 mmol) lithium 2-chloro-4-(2,5-dichloro-phenoxy)-6-methyl-nicotinate in 3 mL dry N,N-dimethylformamide was added 0.30 mL (1.773 mmol) N-ethyldiisopropylamine and 163 mg (0.425 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N;N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 74 mg (0.425 mmol) 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (Example 8, intermediate a). The reaction mixture was stirred for 18 hours at room temperature and evaporated. The residue was purified on a preparative HPLC system (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 100:0) to provide 45 mg (26%) of the title compound as a light yellow foam (30%). MS (ESI): m/z=488.07 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[C:18]([Br:26])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[C:18]([Br:26])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(Br)cc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1cc(Br)cc(C(=O)O)c1
Reaction time: 5 h

Procedure:
To a solution of (2S,4R)-2-(3-bromo-5-methoxycarbonyl-phenylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (480 mg, 1.08 mmol) in MeOH (10 mL), cooled to 0° C. was added LiOH.H2O (271 mg, 6.47 mmol) and the resulting solution was allowed to reach RT and stirred for 5 h. MeOH was concentrated and the residue was diluted in CH2Cl2, HCl 1 M was added (pH=1) and the layers were separated. The aqueous layer was back extracted twice with CH2Cl2 and the combined organic layers were dried over Na2SO4, filtered and concentrated to give the desired material which was used without further purification in the next step. MS (LC-MS): 453.0/455.0 [M+Na]+, 375.1/377.1 [MH−tBu]+, 331.1/333.1 [MH−Boc]+, 429.0/431.0 [M−H]−; tR (HPLC conditions a): 3.27 min.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:12](C)C)CN)=[CH:5][CH:4]=1.C([O:19]C1C(OC)=CC(C(O)=O)=CC=1OC)CCC.C(N(C(C)C)CC)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:9]([NH2:12])(=[O:19])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Reactant: COc1ccc(C(CN)N(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-(4-methoxyphenyl)-N,N-dimethylethane-1,2-diamine represented by Formula 115 (134.6 mg, 0.69 mmol, purchased from Enamine Co.) was slowly added to 4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (193.8 mg, 0.76 mmol) prepared in Preparative Example 2 and diisopropylethylamine (0.48 mL, 2.77 mmol) in DMF (6 mL) at room temperature. After cooling the reaction mixture to 0° C. and adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 289.76 mg, 0.76 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (15 mL) was added to the remaining concentrate to prepare a solution. The solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. After drying the organic layer with sodium sulfate (Na2SO4), the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 23 as a desired product (VVZ-024; 242.4 mg, 81% yield).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:27][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH2:25][CH3:26])=[CH:19]4)(=O)=O)=CC=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[C:38]1[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=1>CS(C)=O.C(OCC)(=O)C>[CH2:25]([C:20]1[NH:21][C:22]2[C:18]([CH:19]=1)=[C:17]1[O:27][CH:13]([CH2:12][N:41]3[CH2:42][CH:43]=[C:38]([C:32]4[C:31]5[C:35](=[CH:36][CH:37]=[C:29]([F:28])[CH:30]=5)[NH:34][CH:33]=4)[CH2:39][CH2:40]3)[CH2:14][O:15][C:16]1=[CH:24][CH:23]=2)[CH3:26]
Reactant: CCc1cc2c3c(ccc2[nH]1)OC[C@H](COS(=O)(=O)c1ccc(C)cc1)O3
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)O3

Procedure:
A solution of 0.41 g (0.1.1 mmole) of [(2R)-8-ethyl-2,3-dihydro-7H-[1,4]-dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.71 g (3.3 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 25 mL of DMSO were heated at 75-80° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 0-2% methanol in methylene chloride as eluant. The product fractions were combined and concentrated in vacuum, and the residue triturated with ether/hexane (1:1) to give 0.090 g of the (S)-enantiomer of the title compound as a yellow solid hydrate, m.p. 81-82° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:35][NH:36][NH2:37]>C(O)C>[CH:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([N:36]([CH3:35])[NH2:37])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CNN
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: CCO
Product: CN(N)C(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Yield: 9 %

Procedure:
A solution of 2,2,2-trichloro-1-[(10-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-1-ethanone of Example 7 (2.32 g) in absolute ethanol (50 mL) was treated with methylhydrazine (0.626 g). The mixture was refluxed for four hours and then all volatiles were removed in vacuo. The residue was treated with water and extracted with dichloromethane. The extracts were filtered through a short column of Magnesol®. The eluate was evaporated to dryness to provide the title compound as an amorphous yellow solid (0.18 g).