Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH3:11][OH:12]>>[CH3:11][O:12][C:3]([OH:4])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1]
Reactant: CO
Reactant: O=C(C(F)(F)F)C(F)(F)F
Product: COC(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
Into 1.82 g of dry methanol was introduced 18.86 g of hexafluoroacetone, and the mixture was stirred at room temperature. After 6 hours, the reaction mixture was distilled under a reduced pressure, to obtain 11.2 g of hexafluoroacetone methylhemiacetal as an intermediate fluorinated hemiacetal. Next, in 50 mL of THF was dissolved 11.2 g of hexafluoroacetone methylhemiacetal, and the mixture was cooled to −78° C. To the solution was added dropwise 35.5 mL of a n-butyllithium solution in hexane (concentration: 1.6 mol/L). After stirring for one hour, 5.14 g of acryloyl chloride was added dropwise thereto. After stirring for 4 hours under ice cooling, precipitated lithium chloride was filtered off and the filtrate was concentrated in vacuo. To the residue was added 200 mL of ether, and the ethereal layer was sequentially washed with a saline solution and water. The ethereal layer was dried over anhydrous magnesium sulfate. After evaporation of ether under a reduced pressure, the residue was distilled under a reduced pressure to obtain 3.06 g of the desired acrylate 3 (yield: 21%, colorless liquid).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1.[C:24](#[N:27])[CH:25]=[CH2:26]>>[CH3:23][N:16]1[C:15]2[C:10]3[C:11](=[C:4]4[C:5](=[N:8][C:9]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=3)[CH:6]=[CH:7][C:2](/[CH:26]=[CH:25]/[C:24]#[N:27])=[CH:3]4)[CH:12]=[CH:13][CH:14]=2
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cccc1c23
Reactant: C=CC#N
Product: CN1c2ccccc2-c2nc3ccc(/C=C/C#N)cc3c3cccc1c23
Yield: 62 %

Procedure:
The general procedure (Method M) applied to 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridine, 28 (300 mg, 0.94 mol) and acrylonitrile (0.144 mL, 2 eq) gave the title compound (193 mg, 0.58 mmol, 62%).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>>[F:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)cc1
Product: O=C(Cl)c1ccc(F)cc1
Temperature: 60 °C

Procedure:
Separately, thionyl chloride (5 ml) is added to 4-fluorobenzoic acid (1.2 g) and the mixture is warmed at 60° C. for 3 hours, followed by distilling off excess thionyl chloride under reduced pressure to obtain 4-fluorobenzoyl chloride. To this chloride is added a solution of trans-4-(4'-heptylphenyl)cyclohexanol obtained above (2 g) in pyridine (2 ml) and toluene (50 ml), followed by vigorous shaking. The resulting reaction liquid is allowed to stand at room temperature overnight, followed by pouring it into water (50 ml) and further adding toluene (50 ml) to carry out extraction. The toluene layer is washed with 6N hydrochloric acid and then with 2N aqueous solution of sodium hydroxide, followed by washing with water until the layer becomes neutral, drying over anhydrous sodium sulfate and distilling off toluene under reduced pressure. The residual oily substance is recrystallized from ethanol to obtain the objective 4-fluorobenzoic acid trans-4-(4"-heptylphenyl)cyclohexyl ester. Yield: 2.6 g, 90.0%, C-Sm: 62.0°-62.3° C., Sm-N point: 78.4° C., N-I point: 102.1°-102.7° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)(=[O:11])=[O:10])[O:4][N:3]=1.[H][H]>[Pd].CO>[NH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[O:4][N:3]=[C:2]([CH3:1])[C:6]=1[CH3:7])(=[O:11])=[O:10]
Reactant: [H][H]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2N)c1C
Yield: 111.1 %

Procedure:
To a suspension of 135 mg of 10% palladium on carbon in 20 mL of methanol under argon, 0.9 g (3.03 mmol) of N-(3,4-dimethyl-5-isoxazolyl)-2-nitrobenzenesulfonamide (Example 9)in 20 mL of methanol was added. The solution was hydrogenated with a balloon filled with hydrogen for 90 minutes. The mixture was filtered through Celite® and the filtrate was concentrated to afford 0.9 g of a gum. This material was chromatographed on silica initially with 9:1 methylene chloride:methanol and then with 1:1 hexanes:ethyl acetate to provide 0.2 g (24%) of Example 10 as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:6]([CH2:7]Br)=[CH:5][S:4][CH:3]=1.[C:9]([O-:12])(=[O:11])[CH3:10].[K+].O>CC(C)=O>[C:9]([O:12][CH2:7][C:6]1[C:2]([Br:1])=[CH:3][S:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: BrCc1cscc1Br
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1cscc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 3-bromo-4-methylthiophene (8.85 g), N-bromosuccinimide (8.85 g), 2,2'-azobis(isobutyronitrile) (0.16 g) and carbon tetrachloride (100 ml) was stirred under reflux for 6 hours. The mixture was concentrated under reduced pressure to give a crude product of 3-bromo-4-bromomethylthiophene. A suspension of this crude product of 3-bromo-4-bromomethylthiophene and potassium acetate (30 g) in acetone (100 ml) was stirred at room temperature for 5 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 4-acetoxymethyl-3-bromothiophene. This crude product was dissolved in tetrahydrofuran (50 ml), and 1N aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-4-hydroxymethylthiophene (5.33 g) as oil. 3-Bromo-4-hydroxymethylthiophene was dissolved in methylene chloride (100 ml), and manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 4-bromo-3-thiophenecarbaldehyde. The crude product of 4-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added. Further, sodium chlorite (3.7 g) in water (40 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalified with 1N aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromo-3-thiophenecarboxylic acid (3.40 g) as crystals.
Reaction SMILES: [SH3+].[H-].[Na+].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]=[O:12].[CH3:13]S(C)=O>>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH:11]1[CH2:13][O:12]1
Reactant: CS(C)=O
Reactant: O=Cc1ccncc1Br
Agent: [H-]
Agent: [Na+]
Agent: [SH3+]
Product: Brc1cnccc1C1CO1
Reaction time: 0.25 h

Procedure:
To a solution of sulfonium salt (7.39 g, 33.6 mmol) in DMSO (40 mL) was added sodium hydride (60% in oil, 1.236 g, 30.9 mmol) at room temperature. After 15 min of stirring, 3-Bromo-pyridine-4-carbaldehyde (930 mg, 5 mmol) in DMSO (20 was added slowly at this temperature. After addition, the resulting mixture was stirred for another 30 min, and was subsequently quenched with brine. The mixture was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the title compound was obtained (200 mg).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:33]4[CH:34]=[CH:35][O:31][CH:32]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccoc1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(-c2c(-c3ccoc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 80.3 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (70 mg, 0.134 mmol) (Example 33), 3-furanylboronic acid (22.43 mg, 0.20 mmol), sodium carbonate (28.3 mg, 0.267 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.44 mg, 0.013 mmol) in acetonitrile (1 mL) and water (250 μl) was heated at 80° C. under nitrogen for 1.5 h. The reaction mixture was cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in isohexane, afforded the title compound (55 mg). LCMS (A) m/z: 511 [M+1]+, Rt 1.51 min (acidic), Rt 0.98 min (basic).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12](Cl)=[O:13].Cl.[C:16](=[NH:26])([O:23][CH2:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([N:26]=[C:16]([O:23][CH2:24][CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: O=C(Cl)c1cccc2c(Br)cccc12
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=NC(=O)c1cccc2c(Br)cccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
According to the procedure of Soto et al, Synthesis, 483 (1983), a solution of 5-bromo-1-naphthoyl chloride (10.7 g, 39.8 mmol) in dry toluene (30 mL) was added dropwise to a mixture of ethyl benzimidate hydrochloride (7.4 g, 39.8 mmol) and triethylamine (8.9 g, 12.2 mL, 87.6 mmol) in dry toluene (100 mL). The mixture was stirred for 18 hours at room temperature, then heated to 70° C. for 60 hours. The mixture was cooled to room temperature and the preciptated salt removed by filtration and washed with toluene. The filtrate was concentrated in vacuo to give a red oil which crystallized upon drying in vacuo (15.2 g, guant.). This material was of sufficient purity to be used in the subsequent reaction.
Reaction SMILES: OCCN1CCN(CC(NC2C(SC)=NC(C)=CC=2SC)=O)CC1.O[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:36])[CH2:30][CH2:29]1.SC1NC2C=CC=CC=2N=1.[SH:65][C:66]1[O:67][C:68]2[C:69]([N:74]=1)=[N:70][CH:71]=[CH:72][CH:73]=2>>[O:67]1[C:68]2[C:69](=[N:70][CH:71]=[CH:72][CH:73]=2)[N:74]=[C:66]1[S:65][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]([NH:37][C:38]2[C:39]([N:50]3[CH2:51][CH2:52][CH2:53][CH2:54]3)=[N:40][C:41]([CH3:49])=[CH:42][C:43]=2[N:44]2[CH2:45][CH2:46][CH2:47][CH2:48]2)=[O:36])[CH2:32][CH2:33]1
Reactant: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCO)CC2)c(N2CCCC2)n1
Reactant: Sc1nc2ncccc2o1
Agent: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Agent: Sc1nc2ccccc2[nH]1
Product: Cc1cc(N2CCCC2)c(NC(=O)CN2CCN(CCSc3nc4ncccc4o3)CC2)c(N2CCCC2)n1

Procedure:
The reaction and treatments of Example 12 were repeated, except that 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide was replaced by 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(pyrrolidin-1-yl)-6-methylpyridin-3-yl]acetamide, and 2-mercaptobenzimidazole was replaced by 2-mercaptooxazolo[4,5-b]pyridine, to thereby yield the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:25]([O:31][CH2:32][CH3:33])(=[O:30])[CH2:26][C:27]([O-])=[O:28].C1(N=C=NC2CCCCC2)CCCCC1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[CH3:22][C:21]([CH3:24])([O:20][C:18]([N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:27](=[O:28])[CH2:26][C:25]([O:31][CH2:32][CH3:33])=[O:30])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[O:19])[CH3:23]
Reactant: CC(C)(C)OC(=O)NCCCN(CCCCN)C(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)NCCCCN(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
After stirring for 0.5 hour, a solution of 1.04 g (3×10-3 mol) of 1,1-dimethylethyl 10-amino-6-[(1,1-dimethylethoxy)carbonyl]-2,6-diazadecanoate in 5 ml of anhydrous chloroform is added dropwise at 0° C. The mixture is stirred for 5 hours at room temperature and 1.06 g (8×10-3 mol) of ethyl malonate and 1.64 g (8×10-3 mol) of 1,3-dicyclohexylcarbodiimide are added. The mixture is stirred for 1 hour and the solvent is evaporated off under reduced pressure. The pasty residue obtained is chromatographed on silica using an ethyl acetate/hexane mixture (1/1 v/v) and then ethyl acetate as the eluent to give 0.95 g (yield: 69%) of the expected product in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH:17]2[CH2:19][CH2:18]2)[C:4](=[O:20])[CH:3]=1.[CH3:21][N:22]([CH3:25])[CH:23]=O.COC(OC)N(C)C.C(O)(C)C>O>[CH:17]1([N:5]2[C:4](=[O:20])[CH:3]=[C:2]([N:1]=[CH:21][N:22]([CH3:25])[CH3:23])[N:7]([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:6]2=[O:16])[CH2:18][CH2:19]1
Reactant: Nc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CC(C)O
Product: CN(C)C=Nc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Under a nitrogen atmosphere, to 6-amino-3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-1H-pyrimidine-2,4-dione 75 (178 g) were added N,N-dimethylformamide (356 ml) and N,N-dimethylformamide dimethylacetal (178 ml), and the mixture was stirred at room temperature for 2 hrs. Isopropanol (178 ml) was added with stirring at room temperature, and water (1068 ml) was added dropwise. The mixture was stirred at room temperature for 2 hrs, and the precipitated crystals were collected by filtration and dried to give N′-[1-cyclopropyl-3-(2-fluoro-4-iodo-phenyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl]-N,N-dimethyl-formamidine 76 (188 g, yield 92%) as yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][S:4]([C:7]1[CH:18]=[C:11]2[C:12]([O:14]C(=O)[NH:16][C:10]2=[CH:9][CH:8]=1)=O)(=[O:6])=[O:5])[CH3:2].[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CC(C)=O.C(O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:12](=[O:14])[C:11]2[C:10](=[CH:9][CH:8]=[C:7]([S:4](=[O:5])(=[O:6])[NH:3][CH2:1][CH3:2])[CH:18]=2)[NH2:16])[CH2:22][CH2:21]1
Reactant: CCNS(=O)(=O)c1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CN1CCNCC1
Solvent: CCO
Solvent: CC(C)=O
Product: CCNS(=O)(=O)c1ccc(N)c(C(=O)N2CCN(C)CC2)c1

Procedure:
In a manner analogous to that described in Example 1, the reaction of 5-(N-ethylsulfamoyl)-isatoic anhydride with 1-methylpiperazine yields 5-(N-ethylsulfamoyl)-anthranilic acid (4-methyl)-piperazide with a melting point of 175°-177° (from acetone/ethanol).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=O)=[CH:15][CH:14]=1)#[N:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[N:10]=[C:17]([C:16]3[CH:20]=[CH:21][C:13]([C:11]#[N:12])=[CH:14][CH:15]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: NC(=NO)c1cccnc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: N
Product: N#Cc1ccc(-c2nc(-c3cccnc3)no2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using N′-hydroxynicotinimidamide (Aldrich) and 4-cyanobenzoyl chloride (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.65 (ddd, J=8.0, 4.9, 1.0 Hz, 1 H), 8.02 (d, J=8.8 Hz, 2 H), 8.42 (d, J=8.8 Hz, 2 H), 8.57 (dt, J=8.1, 1.9 Hz, 1 H), 8.75 (dd, J=4.7, 1.7 Hz, 1 H), 9.31 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4Cl)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:28][C@@H:29]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:30][OH:31].CN1CCOCC1>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([CH3:27])[C:13]3[N:17]=[C:16]([C:18]4[C:19](=[O:25])[NH:20][CH:21]=[CH:22][C:23]=4[NH:28][C@H:29]([CH2:30][OH:31])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:15][C:14]=3[CH:26]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(N[C@H](CO)Cc5ccccc5)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a solution of 3-[6-(4-acetyl-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-4-chloro-1H-pyridin-2-one (1 g, 2.6 mmol) in DMF (10 mL) was added (S)-(−)-2-amino-3-phenyl-propanol (0.78 mg, 5.2 mmol) and N-methyl morpholine (2 mL). The reaction mixture was heated to 80° C. for 12 h, cooled to room temperature and concentrated with high vacuum. The residue was purified by flash column chromatography (10% MeOH/CH2Cl2) to yield the title compound (0.90 g, 69%). 1H NMR (400 MHz, CD3OD) δ 7.36 (1H, s), 7.02–7.23 (6H, m), 6.80 (1H, s), 5.98 (1H, d, J=7.5 Hz), 4.10–4.12 (3H, m), 3.67–3.78 (6H, m), 3.06–3.11 (3H, m), 2.90 (1H, dd, J=7.8, 13.6 Hz), 2.54 (3H, s), 2.12 (3H, s). LCMS (M+H)+ m/z 501 (t=1.30 min.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:18])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[Br:19]Br>CC(O)=O>[Br:19][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:18]
Reactant: O=C(CCc1ccc(Cl)cc1)c1cccc(Cl)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(c1cccc(Cl)c1)C(Br)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 20 %

Procedure:
To a solution of 1-(3-chlorophenyl)-3-(4-chlorophenyl)propan-1-one (1.39 g, 5 mmol) in HOAc (15 mL) at 0° C. was added Br2 (800 mg, 5 mmol) dropwise. The reaction was refluxed for 8 h, cooled to RT, concentrated then diluted with EA (25 mL) and water (5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give a residue which was purified by chromatography eluted with PE/EA (50:1) to give 2-bromo-1-(3-chlorophenyl)-3-(4-chlorophenyl)propan-1-one (358 mg, 20% yield) as a brown solid. LCMS: MH+ 359 and TR=2.029 min.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CN1CCOCC1.[C:31]([NH:34][NH2:35])(=[O:33])[CH3:32]>C1COCC1>[C:31]([NH:34][NH:35][C:21]([CH:18]1[CH2:19][CH2:20][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:15])[CH2:17]1)=[O:23])(=[O:33])[CH3:32]
Reactant: CC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(=O)NNC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Isobutyl chloroformate (152 μL, 1.16 mmol) was added to a stirred solution of 1-(tert-butoxycarbonyl)pyrrolidine-3-carboxylic acid (237 mg, 1.10 mmol) and 4-methylmorpholine (182 μL, 1.65 mmol) in THF (5.50 mL) at −78° C. After 15 min, added acetic hydrazide (2.0 mg, 1.10 mmol), and the resulting mixture was warmed slowly to rt. After 1 h, the reaction mixture was quenched with 0.5 M HCl and extracted with EtOAc. The combined organics were dried (sodium sulfate) and concentrated in vacuo to afford the title compound i-8a. m/z (ES) 272 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12.[C:25]1([CH2:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH:8][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[S:36])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12
Reactant: Cn1cnc(-c2cc3nccc(Nc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cn1cnc(-c2cc3nccc(Nc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a stirred solution of 418 (200 mg, 0.59 mmol) in a mixture of anhydrous toluene/ethanol (15mL/15mL) was slowly added a solution of 2-phenylacetyl isothiocyanate (522 mg, 2.95 mmol) in a mixture of anhydrous toluene/ethanol (5mL/5mL). The reaction mixture was stirred at room temperature for 4 hrs under nitrogen, concentrated, and adsorbed on silica gel. The crude material was purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2 from 5/95 to 10/90) followed by trituration with AcOEt (with traces of acetone)/hexanes, to afford title compound 415 (183 mg, 60% yield) as a pink solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.51 (s, 1H), 11.81 (s, 1H), 8.82 (bs, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.91 (dd, J=12.4, 2.3 Hz, 1H), 7.79 (d, J=1.1 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.53 (s, 1H), 7.44 (dd, J=8.6, 2.2 Hz, 1H), 7.40-7.24 (m, 6H), 6.42 (dd, J=5.55, 2.22 Hz, 1H), 3.83 (s, 2H), 3.71 (s, 3H). LCMS: 517.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:27][CH2:28][CH3:29])[CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:27][CH2:28][CH3:29])[CH2:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:8][CH2:9]1
Reactant: CCCC(O)CC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCC(=O)CC1CCC(c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 60.2 %

Procedure:
4'-(4-(2-Hydroxypentyl)cyclohexyl)-4-trifluoromethoxybiphenyl (12.3 mmol) was added at 0 or below in the absence of a solvent to a mixture of PCC (13.5 mmol), 3 g of silica gel, and 70 ml of methylene chloride, and the mixture was stirred at room temperature for 7 hr to give a black suspension. 500 ml of toluene was added thereto, and the mixture was stirred. The precipitated insolubles were filtered off through Celite, and the solvent was distilled off from the resultant black solution under reduced pressure to give a dark brown crude product. The crude product was purified by silica gel column chromatography (eluting solution: toluene) to give 4'-(4-(2-oxopentyl)cyclohexyl)-4-trifluoromethoxybiphenyl (7.4 mmol, yield 66%) as a white crystal.