Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:29])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][O:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (32 g, 74.2 mmol) and Et3N (22.5 g, 226 mmol) in CH2Cl2 (400 mL) was added a solution of MsCl (10.1 g, 89 mmol) in CH2Cl2 (50 mL) at 0-5° C. After addition, the reaction mixture was allowed to warm to rt and stir for 1 hr. The reaction was washed with water (200 mL) and the aqueous layer was extracted with CH2Cl2 (3×150 mL). The combined organic layers was washed with 10% citric acid (60 mL), sat. NaHCO3 (60 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to give (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-(methylsulfonyloxy)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (37.7 g, 100%), which was used in the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH:20]([NH2:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:23][CH:20]([CH2:21][CH3:22])[CH2:19][O:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:16]=2)[N:7]=1
Reactant: CCC(N)COc1cccc(C(F)(F)F)c1
Reactant: CC(C)c1nc(N)nc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(COc1cccc(C(F)(F)F)c1)Nc1nc(N)nc(C(C)C)n1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
2.6 g (0.015 mol) of 2-amino4-chloro-6-isopropyl-1,3,5-triazine, 4.0 g (0.015 mol) of 1-(3-trifluoromethylphenoxy)-2-aminobutane hydrochloride and 6.2 g (0.045 mol) of potassium carbonate were added to 50 ml of dimethylformamide (DMF). The mixture was heated at 80° C. for 3 hours, added into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) gave 4.2 g (76%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[CH2:6][O:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16].[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1.C(Cl)Cl>[Br:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]3[CH:12]=[CH:13][N:14]=[C:7]3[CH2:6][O:5][C:4]=2[C:3]=1[C:15]([O:17][CH3:18])=[O:16])(=[O:29])=[O:28]
Reactant: COC(=O)c1c(N)ccc2c1OCc1nccn1-2
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1nccn1-2
Temperature: 25 °C
Reaction time: 17 h
Yield: 80.9 %

Procedure:
A mixture of methyl 7-amino-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (Intermediate 26, 0.379 g) and 2-bromo-4-fluorobenzenesulfonyl chloride (0.466 g) in pyridine (10 mL) and DCM (10 mL) was stirred at room temperature for 17 hours. A further amount of 2-bromo-4-fluorobenzenesulfonyl chloride (0.190 g) was added and the mixture was stirred at room temperature for 5 hours. The resultant mixture was concentrated in vacuo and the residue was dissolved in DCM and water and passed through a phase separator. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with ethyl acetate to give a white solid which was triturated with ether to give methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-5-oxa-3,9b-diazacyclopenta[a]naphthalene-6-carboxylate (0.603 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:8]=2)[CH:6]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:30]=1[OH:37].B(O)O>O1CCOCC1.CC(N(C)C)=O>[CH3:36][O:35][C:31]1[CH:32]=[C:33]([C:6]2[N:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[N:8]=3)[CH:4]=[N:3][CH:2]=2)[CH:34]=[C:29]([O:28][CH3:27])[C:30]=1[OH:37]
Reactant: Brc1cn(-c2ccnc(N3CCOCC3)n2)cn1
Reactant: COc1cccc(OC)c1O
Agent: O=P([O-])([O-])[O-]
Agent: OBO
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)N(C)C
Product: COc1cc(-c2cncn2-c2ccnc(N3CCOCC3)n2)cc(OC)c1O
Temperature: 170 °C
Yield: 96.3 %

Procedure:
To a solution of 4-[4-(4-Bromo-imidazol-1-yl)-pyrimidin-2-yl]-morpholine (0.20 g, 0.65 mmol) in anhydrous dioxane (6 ml) and anhydrous DMA (0.6 m) was added tripotassium phosphate (0.28 g, 1.3 mmol) and 2,6-dimethoxy-phenol-boronic acid (0.18 g, 0.91 mmol). The resultant mixture was degassed with sonication for 10 minutes before the addition of bis(tri-butylphospine)palladium (0.017 g, 0.033 mmol) and degassing for a further 5 minutes. The reaction vessel was sealed and heated under the influence of microwave radiation (170° C., 11 min, low absorption setting). Upon completion, the reaction was filtered through a thin silica plug which was then washed with 10% methanol/CH2Cl2. The filtrate was concentrated in vacuo and the crude residue purified by flash chromatography (SiO2) (1:1—EtOAc:Hexanes) to give the desired product (0.24 g, 96%) as a white crystalline solid in analytically pure form. m/z (LC-MSW, ESP):384.4 [M+H]+, R/T=2.90 mins.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=O)=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30]>N1C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=[N:29][OH:30])=[C:9]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Sc2cccc(C=O)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1c(Sc2cccc(C=NO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzaldehyde (0.225 g, 0.57 mmol) was dissolved in pyridine (10 mL) and then hydroxylamine hydrochloride (0.235 g, 3.42 mmol). The reaction stirred at room temperature for 45 minutes and was submitted to an aqueous workup to provide the title compound, which was taken to the next step without further purification.
Reaction SMILES: [OH-:1].[Na+].[NH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.O.OO>O>[NH2:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:4]([NH2:3])=[O:1])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: N#Cc1ccc(CN)cc1
Agent: OO
Agent: [Na+]
Solvent: O
Product: NCc1ccc(C(N)=O)cc1
Temperature: 25 °C
Yield: 809 %

Procedure:
In a reactor equipped with a motor-driven stirrer, 45 g of water, 1.38 g of sodium hydroxide (reagent, purity: 96%) and 43.56 g of p-aminomethylbenzonitrile were charged in this sequence and then stirred at room temperature. 74.8 g of 30 wt % hydrogen peroxide water was gradually added so that the reaction temperature reaches 30° C. or lower, followed by mixing with stirring. After foaming and temperature rise were terminated, the reaction solution was cooled to 5° C. The deposited crystal was collected by filtration and then dried to obtain 41.92 g of p-aminomethylbenzamide (yield based on p-aminomethylbenzonitrile: 81%). The purity of p-aminomethylbenzamide determined by analyzing using high-performance liquid chromatograph was 97%.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([NH2:14])[CH:11]=[C:10]([NH:15][C:16]3[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:26][CH:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:14][C:12]1[CH:11]=[C:10]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[N:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([NH:26][CH:27]3[CH2:31][CH2:30][NH:29][C:28]3=[O:32])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: NC1CCNC1=O
Reactant: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(F)nc2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNC3=O)nc2)c1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
6′-Fluoro-N6-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridine-4,6-diamine (50 mg, 0.143 mmol), 3-aminopyrrolidin-2-one (39.1 mg, 0.286 mmol), tribasic potassium phosphate (60.8 mg, 0.286 mmol), and N,N-diisopropylethylamine (0.050 ml, 0.286 mmol) were dissolved in dimethylsulfoxide (0.5 mL). The mixture was heated to 130° C. with stirring for three days. After allowing to cool to room temperature, the reaction mixture was partitioned between ethyl acetate (30 mL) and saturated aqueous sodium bicarbonate solution (15 mL). The layers were separated, and the organic layer was washed with water (3×5 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified using reverse phase HPLC (15 to 85% acetonitrile/water with 0.1% TFA gradient). The fractions containing the product were partitioned between 10% isopropanol/chloroform and 1:1 saturated aqueous sodium bicarbonate solution:brine. The layers were separated, and the aqueous layer was extracted with additional 10% isopropanol/chloroform. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-[(4-amino-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)amino]pyrrolidin-2-one. MS ESI calcd. for C20H19F3N7O [M+H]+ 430. found 430. 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.88 (dd, J=2.4, 8.8 Hz, 1H), 7.83 (s, 1H), 7.08 (d, J=5.3 Hz, 1H), 6.94 (d, J=7.3 Hz, 1H), 6.61 (d, J=8.8 Hz, 1H), 6.53 (d, J=1.6 Hz, 1H), 6.46 (s, 1H), 5.97 (s, 2H), 4.60-4.52 (m, 1H), 3.25-3.20 (m, 2H), 2.52-2.46 (m, 1H), 1.87-1.79 (m, 1H). rhSyk IC50=4 nM.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[CH3:16][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:19])=[O:18].Cl>CN(C=O)C.C(O)C>[CH3:19][P:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[CH:3]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:5]=[C:6]([CH3:8])[N:7]=2)=[C:22]([O:27][CH3:28])[CH:21]=1)([CH3:16])=[O:18]
Reactant: Cc1nc(Cl)cc(Nc2ccccc2)n1
Reactant: COc1cc(P(C)(C)=O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1cc(P(C)(C)=O)ccc1Nc1cc(Nc2ccccc2)nc(C)n1

Procedure:
To a solution of 6-chloro-2-methyl-N-phenylpyrimidin-4-amine (0.35 mmol) and 4-(dimethylphosphoryl)-2-methoxyaniline (60 mg, 0.30 mmol) in 1 mL of DMF, is added 0.36 mL of 2.5M HCl in Ethanol. The reaction mixture can be heated in a sealed tube at 140 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and can be purified by Prep-HPLC.
Reaction SMILES: [CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH2:3][C:2]2=[O:8].[Li+].CC([N-]C(C)C)C.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>C1COCC1>[CH:1]12[CH2:7][CH:6]1[CH2:5][CH2:4][CH:3]=[C:2]2[O:8][Si:18]([CH3:20])([CH3:19])[CH3:17]
Reactant: O=C1CCCC2CC12
Reactant: C[Si](C)(C)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCCC2CC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
Add dropwise bicyclo[4.1.0]heptan-2-one (43.3 g, 0.393 mol) in dry THF (50 mL) to a solution of LDA (237 mL, 0.472 mol) in THF (500 mL). Stir the reaction mixture for 30 min and then add dropwise TMSCl (64.2 g, 0.59 mol) to the reaction mixture. Stir the resultant solution for additional 1 hour. Pour the mixture into ice water (92 mL) and extract the aqueous mixture with EtOAc (100 mL×3). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford crude (bicyclo[4.1.0]hept-2-en-2-yloxy)-trimethyl-silane (68.0 g, 95.0%) as yellowish oil, MS (m/z): 181 (M−1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][PH:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]1([CH2:7][CH2:8][P:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([NH:20][C@H:21]([C:29]([NH:31][C@H:32]([C:37]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:30])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=[PH](CCc1ccccc1)OCc1ccccc1
Agent: Cl
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NP(=O)(CCc1ccccc1)OCc1ccccc1)C(=O)OCc1ccccc1

Procedure:
(2-Phenylethyl)phosphinic acid, phenylmethyl ester is reacted with L-phenylalanyl-L-leucine, phenylmethyl ester, hydrochloride salt according to the procedure of Example 1(c) to yield N-[N-[(2-phenylethyl)(phenylmethoxy)phosphinyl]-L-phenylalanyl]-L-leucine, phenylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[H-].[Na+].Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(Cc2ccccn2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of 5-bromoisatin (10.0 g, 44.4 mmol) in anhydrous N,N-dimethylformamide (100 mL) at 0° C. was added slowly sodium hydride (60% w/w dispersion in mineral oil, 3.90 g, 97.7 mmol). The solution was stirred for 30 min and 2-(bromomethyl)pyridine hydrobromide (11.2 g, 44.4 mmol) was added. The solution was stirred at ambient temperature for 16 h and poured into ice water (1.3 L) with vigourous stirring, causing a precipitate to be deposited. The solid was collected by filtration to afford 5-bromo-1-(pyridin-2-ylmethyl)-1H-indole-2,3-dione (4.93 g, 35%) as a orange solid: 1H NMR (300 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 7.72-7.56 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.18 (m, 1H), 6.93-6.88 (m, 1H), 5.03-4.99 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=O)[O:10]2)=[CH:5][CH:4]=1.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:7]3[CH2:18][NH:17][CH2:16][C@@H:8]3[CH2:9][O:10][C:11]=2[CH:12]=1
Reactant: COc1ccc2ccc(=O)oc2c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: COc1ccc2c(c1)OC[C@H]1CNC[C@@H]21

Procedure:
From 7-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C: 1H NMR (300 MHz, CDCl3), δ 1.92 (br s, 1H), 2.60 (m, 1H), 2.81 (m, 2H), 3.17 (q, 1H), 3.29 (dd, 1H), 3,40 (dd, 1H), 3.77 (s, 3H), 3.78 (t, 1H), 4.10 (dd, 1H), 6.43 (d, 1H), 6.52 (dd, 1H), 7.03 (d, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2=[N:14][C:15]3[C:20]([N:21]=[C:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=[CH:19][CH:18]=[CH:17][CH:16]=3.[C:22]1(=O)[O:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23]1>>[C:22]1(=[O:28])[N:1]([CH2:2][CH2:3][CH2:4][N:5]2[C:13]3=[N:14][C:15]4[C:20]([N:21]=[C:12]3[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:26](=[O:27])[CH2:25][CH2:24][CH2:23]1
Reactant: NCCCn1c2ccccc2c2nc3ccccc3nc21
Reactant: O=C1CCCC(=O)O1
Product: O=C1CCCC(=O)N1CCCn1c2ccccc2c2nc3ccccc3nc21

Procedure:
6-(3-aminopropyl)-6H-indolo(2,3-b)quinoxaline (2.77 g, 0.01 mole) is heated (3 hours, 170° C.) with glutaric acid anhydride (1.14 g, 0.01 mole) and then the melt is allowed to cool and recrystallization from acetonitrile is carried out. Yield: 3,43, (92%) mp. 312°-314° C.
Reaction SMILES: [NH2:1]C1SC(C)=NN=1.C(O[C:13]1[C:21](OC)=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=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:17]([NH2:1])(=[O:18])[C:16]1[CH:20]=[CH:21][CH:13]=[CH:14][CH:15]=1
Reactant: CCCCOc1c(OC)cc(C(=O)O)cc1OC
Reactant: Cc1nnc(N)s1
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:
A compound represented by Formula 110, that is, 2-amino-5-methyl-1,3,4-thiadiazole (314.6 mg, 2.73 mmol, purchased from TCI Co.) was slowly added to 4-n-butoxy-3,5-dimethoxybenzoic acid represented by Formula 90 (772 mg, 3.04 mmol) prepared in Preparative Example 2 and diisopropylethylamine (1.64 mL, 10.92 mmol) in DMF (15 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, 1.15 g, 3.04 mmol) thereto, the mixture was agitated at room temperature for 24 hours. The reaction solvent was removed under reduced pressure and chloroform (30 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 24 as a desired product (VVZ-025; 545.7 mg, 56.8% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=2[CH3:19])=[CH:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[CH2:30][N:31]1[C@@H:35]([CH3:36])[C@@H:34]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[O:33][C:32]1=[O:43].[Cl:44]C1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.O=P(Cl)(Cl)Cl>[Cl:44][C:39]1[CH:38]=[C:37]([C@H:34]2[O:33][C:32](=[O:43])[N:31]([CH2:30][C:21]3[CH:22]=[C:23]([C:26]([F:28])([F:29])[F:27])[CH:24]=[CH:25][C:20]=3[C:4]3[CH:5]=[C:6]([C:9]4[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][C:10]=4[CH3:19])[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[C@H:35]2[CH3:36])[CH:42]=[CH:41][N:40]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccncc4)[C@@H]3C)c2)c(C)c1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4ccnc(Cl)c4)[C@@H]3C)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 4′-methoxy-2-methyl-2″-{[(4S,5R)-4-methyl-2-oxo-5-pyridin-4-yl-1,3-oxazolidin-3-yl]methyl}-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (175 mg, 0.296 mmol) in CH2Cl2 (15 mL) at 0° C. under N2, was added 3-chloroperbenzoic acid (146 mg, 0.593 mmol) as a powder. The mixture was stirred at 0° C. for 15 min. Then it was allowed to warm up to room temperature and stirred for 2 h. The reaction mixture was diluted with CH2Cl2 and washed with satd Na2SO3 (1×) followed satd K2CO3 (2×). The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue obtained was dissolved in POCl3 (10 mL). The resulting solution was heated at 110° C. under N2 for 2 h. Then it was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated in vacuo. The residue was diluted with EtOAc (50 mL) and water (10 mL) and washed with satd NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (2×40 mL). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 2″-{[(4S,5R)-5-(2-chloropyridin-4-yl)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]methyl}-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. LCMS calc.=625.2; found=625.0 (M+1)−. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 8.40 (s, 0.5 H); 8.39 (s, 0.5 H); 7.97 (s, 1 H); 7.90 (t, J=5.8 Hz, 1 H); 7.72 (s, 0.5 H); 7.69-7.63 (m, 1.5 H); 7.48 (d, J=11.8 Hz, 0.5 H); 7.44 (s, 0.5 H); 7.43-7.37 (m, 1 H); 7.32-7.26 (m, 1 H); 7.24 (s, 0.5 H); 7.20 (s, 0.5 H); 7.16 (d, J=2.2 Hz, 0.5 H); 7.14 (d, J=2.2 Hz, 0.5 H); 7.12-7.06 (m, 1.5 H); 7.05 (d, J=5.1 Hz, 0.5H); 5.42 (d, J=8.1 Hz, 0.5H); 5.18 (d, J=8.1 Hz, 0.5 H); 4.92 (dd, J=15.9, 18.5 Hz, 1 H); 4.19 (d, J=15.8 Hz, 0.5 H); 3.99 (d, J=15.8 Hz, 0.5 H); 3.95 (s, 3 H); 3.88 (s, 3 H); 3.81-3.75 (m, 1 H); 2.39 (s, 1.5 H); 2.35 (s, 1.5 H); 0.60 (d, J=6.5 Hz, 1.5 H); 0.49 (d, J=6.5 Hz, 1.5 H).
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16](OS(C2C=CC(C)=CC=2)(=O)=O)[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C>C(#N)C>[N:29]1([C:16]2[C:5]3[CH2:6][CH2:7][CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]=3[N:3]=[C:2]([NH2:1])[N:17]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: C1CNCCN1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1nc2c(c(N3CCNCC3)n1)CCCCc1ccccc1-2

Procedure:
A solution of Example 20C (80 mg 0.20 mmol), piperazine (26 mg, 0.30 mmol) and triethylamine (0.1 mL, 0.72 mmol) in anhydrous acetonitrile (3 mL) was heated at 160° C. in a microwave reactor for 20 minutes. The mixture was concentrated under reduced pressure and chromatographed on silica gel eluting with NH4OH:MeOH:CH2Cl2 (0.6:6:94) to provide the title compound. 1H NMR (CD3OD) δ 1.45 (m, 2H), 1.86 (m, 1H), 2.00-2.15 (m, 2H), 2.34 (m, 1H), 2.73 (dd, J=14.58, 8.48 Hz, 1H), 2.80-3.02 (m, 5H), 3.37 (m, 4H), 7.22 (m, 1H), 7.24-7.31 (m, 2H), 7.33-7.41 (m, 1H). MS (M+H)+ m/z 310.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[CH2:34][CH2:35][CH2:36][OH:37].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:34][CH2:35][CH2:36][OH:37])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NCCCO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCCO)C1
Yield: 60 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]amino}-piperidine-1-carboxylic acid tert-butyl ester and 3-amino-propan-1-ol, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (70 mg, 60%); LCMS (method B): RT=3.37 min, M+H+=504.