Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4ccccn4)cc2)CCO3)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(-c4cccc[n+]4[O-])cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 14.5 %

Procedure:
To a suspension of N-[4—(2-pyridyl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (400 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.25 g) at 0° C., and the mixture was stirred at room temperature for 70 hours. To the mixture was added sodium thiosulfate solution, and the mixture was stirred for minutes. The mixture was extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, and dried with magnesium sulfate. The mixture was concentrated, purified with column chromatography (ethanol/ethyl acetate=1:1) to give crystals, which were dissolved in chloroform. The mixture was concentrated, and to the residue was added ethanol. Precipitated crystal was collected by filtration to give crystals, which were washed with ethanol to give N-[4—(1-oxidopyridin-2-yl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 160) (60 mg) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:8]=1[C:9]#[N:10].C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>CN(C1C=CN=CC=1)C.ClCCl.CCOC(C)=O>[C:9]([C:8]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:25](=[O:27])[CH3:26])#[N:10]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OCCCCN)cccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCCCOc1cccc([N+](=O)[O-])c1C#N
Reaction time: 8 h
Yield: 57 %

Procedure:
To a solution of 2-(4-aminobutoxy)-6-nitrobenzonitrile (Example 234d) (235 mg, 1.0 mmol), triethylamine (3 equiv.), and DMAP (0.1 equiv.) in dry dichloromethane (20 mL) was added dropwise acetyl chloride (1.5 equiv.) at 0° C. under nitrogen. The reaction mixture was then stirred at 0° C.—RT overnight. The reaction was diluted with EtOAc, washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound (158 mg, 57%). MS 278 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]=O)=[C:6]2[CH2:7][CH2:8][CH2:9][O:10][C:5]2=[CH:4][CH:3]=1.[F:14][C:15]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:16]=1[NH2:17].[BH4-].[Na+].Cl>CO.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:11]=1[CH2:12][NH:17][C:16]1[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:15]=1[F:14]
Reactant: O=Cc1c(O)ccc2c1CCCO2
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Oc1ccc2c(c1CNc1ccc(F)cc1F)CCCO2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.7 %

Procedure:
A mixture of 6-hydroxy-3,4-dihydrobenzopyran-5-carboxaldehyde (299 mg, 1.68 mmol) and 2,4 -difluoroaniline (219 mg, 1.68 mmol) in methanol (8 mL) was heated to reflux for 20 minutes during which time the intermediate Schiff's base crystallized, and, after cooling to room temperature, was collected by filtration and dried. The isolated Schiff's base (175 mg, 36%) was suspended in methanol (8 mL) and sodium borohydride (25 mg, 0.66 mmol) was added. The mixture was stirred at room temperature for 5 minutes, poured into water (50 mL) and carefully neutralized (pH=7) with 2.5 N HCl. The product was collected by filtration and dried to afford 6-hydroxy-5-(2,4-difluorophenyl)aminomethyl-3, 4-dihydrobenzopyran, (170 mg, 96.6%), m.p. 120°-121° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][Cl:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[NH:20][C:21]2[C:26]([C:27]=1[CH3:28])=[CH:25][C:24]([OH:29])=[CH:23][CH:22]=2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:29][C:24]3[CH:25]=[C:26]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([CH3:18])=[C:27]4[CH3:28])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCCCl
Temperature: 90 °C
Yield: 67.3 %

Procedure:
A mixture of 4-chloro-7-(2-chloroethoxy)-6-methoxyquinazoline (5.0 g), prepared as described in Example 7, 2,3-dimethyl-5-hydroxyindole (3.5 g), (Arch. Pharm. 1972, 305, 159), and potassium carbonate (4.0 g) in DMF (70 ml) was stirred and heated at 90° C. for 3 hours. The mixture was filtrated and the solvent was removed by evaporation under vacuum. The residue was purified by column chromatography on silica using the solvent mixture dichloromethane/ethyl acetate/methanol (50/48/2). The solvent was evaporated under vacuum to give 7-(2-chloroethoxy)-4-[(2,3-dimethyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (4.9 g) as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:18]3[CH:35]=[CH:34][C:21]([C:22]([NH:24][CH2:25][CH:26]([OH:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:23])=[CH:20][CH:19]=3)[CH2:15][C:16]#[CH:17])[CH:8]=2)[N:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>CN(C=O)C>[C:36]([O:33][CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:25][NH:24][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N:14]([CH2:13][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[NH:11][C:10]3=[O:12])[CH2:15][C:16]#[CH:17])=[CH:35][CH:34]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(O)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)c1ccc(C(=O)NCC(OC(C)=O)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
p-[N-(2-Methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]-N-(2-hydroxy-2-phenylethyl)benzamide (0.105 g) was dissolved in DMF (3 ml) and acetic anhydride (34 mg) and pyridine (37 mg) were added in turn. The mixture was stirred at 20° C. for 24 hours. The mixture was evaporated and the residue was triturated with water (5 ml). The solid was filtered off, washed with water and dried in air to give N-(2-acetoxy-2-phenylethyl)-p-[N-(2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamide (0.095 g; containing 1 equivalent of water), m.p. 203°-205° C.
Reaction SMILES: [C:1]([O:14][CH2:15]Cl)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[I-:17].[Na+].O>CC(C)=O>[C:1]([O:14][CH2:15][I:17])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: [I-]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCCl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)OCI

Procedure:
C4F9OCH2Cl (50 g, 0.175 mole, isomer ratio n/i=95:5) was combined with sodium iodide (52.5 g, 0.38 mole) in acetone (200 g) and heated to reflux overnight. Water was added and the acetone distilled from the reaction vessel using a Dean-Stark apparatus. The product was washed with water to remove residual acetone. Glc of the residue (52.6 g) revealed it to be 82.6 wt. % of the desired product C4F9OCH2I, which was further purified by distillation. The distillation fraction boiling at 110-15° C. was found to be 97.8 wt. % of the desired product with a 96/4 normal to iso ratio.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C=[O:44])C>>[Si:32]([O:44][CH:17]1[O:16][C:15](=[O:25])[N:14]([C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(CCCC(O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C=O
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)OC1OC(=O)N(C(=O)CCCCc2ccc(F)cc2)C1c1ccccc1
Temperature: 25 °C

Procedure:
30 g of 3-[5-(4-Fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one are dissolved in 50 ml of DMF. 14.3 g of imidazole and 19 g of tert-butyidimethylsilyl chloride in 25 ml of DMF are added, and the mixture is then stirred at room temperature until the reaction has gone to completion (2–4 h). The reaction solution is concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated, giving 10:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1>C(#N)C.CN(C)C=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 85 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (1.46 g, 7.0 mmol) and trans-4-aminocyclohexane carboxylic acid (1.0 g, 7.0 mmol) were dissolved in a mixture of acetonitrile (42 mL), dimethylformamide (21 mL), and water (7 mL). The resulting solution was heated to 85° C. and then maintained at this temperature overnight. After cooling to room temperature, the mixture was partly concentrated under vacuum, diluted with ethyl acetate (50 mL), and washed with water (30 mL). The aqueous phase was acidified to pH 4 by the addition of 1 M HCl. This formed a precipitate, which was isolated by filtration. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under vacuum to afford a solid. Both solids were combined and dried under vacuum. The desired product was isolated as a yellow solid (2.4 g, quantitative yield).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][SH:5].C[O-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1>CO>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][S:5][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CN(C)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCSc1ccc2nccn2n1
Temperature: 150 °C
Yield: 57.6 %

Procedure:
To 20 ml of methanol is dissolved 2.8 g of 2-dimethylaminoethanethiol. To this, 20 ml of 2M solution of sodium methoxide in methanol and 3 g of 6-chloroimidazo-[1,2-b]pyridazine are added successively and the mixture is heated in a sealed tube for 4 hours at 150° C. After cooling, the solvent is evaporated and the residue is treated with water. The mixture is then extracted with methylene chloride. The organic layer is separated, washed with saturated aqueous solution of sodium chloride and dried over MgSO4. Evaporation of the solvent gives 2.5 g of the title compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17]([O:19]C)=O)[CH:10]=2)[C:5]([F:21])=[CH:4][N:3]=1.Cl.[CH3:23][NH2:24].C([N:28]([CH:31](C)C)CC)(C)C>CO.O>[F:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([C:17]([NH:28][CH3:31])=[O:19])[CH:10]=2)=[N:7][C:2]([NH:24][CH3:23])=[N:3][CH:4]=1
Reactant: CN
Reactant: COC(=O)c1cc(Nc2nc(Cl)ncc2F)ccc1OC
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: O
Solvent: CO
Product: CNC(=O)c1cc(Nc2nc(NC)ncc2F)ccc1OC
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-5-fluoro-N4-(3-methyloxycarbonyl-4-methoxyphenyl)-4-pyrimidineamine (0.15 g, 0.4 mmol), methylamine hydrochloride (0.324 g, 48 mmol) and diisopropylethylamine (0.84 mL, 48 mmol) in MeOH (2 mL) was heated in a sealed tube at 100° C. for 24 h (followed by TLC). The reaction was cooled to room temperature and diluted with H2O (20 mL). The solid was filtered, washed with H2O and dried to obtain 5-fluoro-N4-(3-methylaminocarbonyl-4-methoxyphenyl)-N2-methyl-2,4-pyrimidinediamine R940304. 1H NMR (DMSO-d6): δ 10.65 (1H, s), 8.48 (1H, s), 8.29 (2H, m), 7.93 (1H, m), 7.28 (1H, d, J=9 Hz), 4.00 (3H, s), 2.94 (3H, s), 2.90 (3H, d, J=4.5 Hz); purity: 90%; MS (m/e): 306 (MH+);
Reaction SMILES: [Cl:1][C:2]([Cl:4])=[CH2:3].[Br:5][C:6]1[CH:7]=[C:8]([CH3:14])[C:9]([Cl:13])=[C:10](N)[CH:11]=1.[ClH:15]>C(#N)C>[Br:5][C:6]1[CH:11]=[C:10]([CH2:3][C:2]([Cl:15])([Cl:4])[Cl:1])[C:9]([Cl:13])=[C:8]([CH3:14])[CH:7]=1
Reactant: Cl
Reactant: Cc1cc(Br)cc(N)c1Cl
Reactant: C=C(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Br)cc(CC(Cl)(Cl)Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
CuCl2 (8.0 g, 0.06 mol) and tert-butylnitrile (8.9 mL, 0.074 mol) are suspended in acetonitrile (60 mL). 1,1-dichloroethylene is added dropwise at 20° C. 5-Bromo-2-chloro-3-methyl-phenylamine (11.0 g, 0.05 mol), dissolved in acetonitrile (60 mL), is added and the reaction is stirred at RT for 3 h. The mixture is poured into aqueous 20% HCl (150 mL) and the aqueous phase is extracted with CH2Cl2 (2×150 mL). The organic phase is dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (hexane/CH2Cl2 9:1) to afford 5-bromo-2-chloro-1-methyl-3-(2,2,2-trichloro-ethyl)-benzene. The intermediate is redissolved in MeOH (80 mL) and heated to 70° C. A solution of 5.4 M NaOMe in MeOH (28.4 mL) is added dropwise and the reaction is stirred at 70° C. for 3 h. The reaction is cooled to RT and concentrated H2SO4 (10 mL) is added. The reaction is stirred at reflux for 1 h. The mixture is diluted with H2O (200 mL) and extracted with CH2Cl2 (2×200 mL). The combined organic phases are dried over Na2SO4 and the solvent is evaporated. The residue is purified by FCC (hexane/CH2Cl2 9:1 to 1:1) to afford (5-bromo-2-chloro-3-methyl-phenyl)-acetic acid methyl ester. 1H NMR (CDCl3, 400 MHz) δ 2.26 (s, 3H), 3.61 (s, 3H), 3.63 (s, 2H), 7.15 (s, 1H), 7.21 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:8]=2[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18]C(C)(C)C)=[O:17])=[CH:14][CH:13]=2)=[O:10])=[C:4]([CH3:35])[CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:23][CH:24]=2)=[O:10])=[C:4]([CH3:35])[CH:3]=1
Reactant: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1Oc1ccc(C(F)(F)F)cc1C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
tert-Butyl 4-[[2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)benzoyl]amino]benzoate (43.8 mg, 0.09 mmol) was suspended in dichloromethane (1.45 mL) and TFA (1.45 mL) was added and the mixture stirred 0.5 h at room temperature. The reaction mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile and water (10-99%) and HCl as a modifier to yield 4-(2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamido)benzoic acid (28) (24.71 mg, 67%). ESI-MS m/z calc. 433.09, found 434.3 (M+1)+; Retention time: 2.00 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 12.78 (s, 1H), 10.83 (s, 1H), 8.01 (d, J=2.1 Hz, 1H), 7.94 (d, J=8.7 Hz, 2H), 7.80 (dd, J=15.4, 5.6 Hz, 3H), 7.18 (m, 3H), 6.83 (d, J=8.7 Hz, 1H), 2.14 (s, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[NH:7][C:6]1=[O:16].C(=O)([O-])[O-].[Ca+2].[Br-:23].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1>CO.ClCCl>[Br:23][C:11]1[C:12]([O:14][CH3:15])=[CH:13][C:8]2[NH:7][C:6](=[O:16])[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:17])[C:9]=2[CH:10]=1
Reactant: [Br-]
Reactant: COc1ccc2c(c1)[nH]c(=O)n2CCN(C)C
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2[nH]c(=O)n(CCN(C)C)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 157 %

Procedure:
To a solution of 1,3-dihydro-1-(2-dimethylaminoethyl)-5-methoxy-2H-benzimidazol-2-one (0.28 g) in methanol (10 ml) and dichloromethane (15 ml) were added calcium carbonate (0.25 g) and benzyltrimethylammonium tribromide (0.49 g). The reaction mixture was stirred at room temperature for 16 hours and the insoluble matter was filtered off. The solvent was then distilled off under reduced pressure and the residue was diluted with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent: chloroform:methanol=10:1) to give 0.35 g of 6-bromo-1,3-dihydro-1-(2-dimethylaminoethyl)-5-methoxy-2H-benzimidazol-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])[S:5][CH:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][S:7][C:4]=2[S:5][CH:6]=1
Reactant: CC(C)=CCSc1cc(C)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc2c1C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
A solution of 17.36 g (0.088 mol) of the title compound of Step A in 300 mL of methylene chloride was added dropwise to 300 mL of trifluoroacetic acid under nitrogen. After stirring at room temperature overnight, the mixture was evaporated to dryness. The residue was dissolved in 500 mL of methylene chloride, washed with 5% sodium bicarbonate (2×500 mL), dried (MgSO4), filtered, and evaporated to dryness. The crude product was chromatographed on silica gel eluting with hexane to yield 8.26 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 1.32 (s,6H), 2.0 (m,2H), 2.3 (s,3H), 3.0 (m,2H), 6.6 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18](=[NH:22])OCC)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1.C(N(CC)CC)C.Cl.Cl[CH2:32][CH2:33][CH2:34][CH:35]([C:40]1[CH:45]=[CH:44][C:43]([N:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=1)[C:36]([NH:38][NH2:39])=O>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]2[N:22]=[C:36]3[CH:35]([C:40]4[CH:45]=[CH:44][C:43]([N:46]([CH3:48])[CH3:47])=[CH:42][CH:41]=4)[CH2:34][CH2:33][CH2:32][N:38]3[N:39]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: CN(C)c1ccc(C(CCCCl)C(=O)NN)cc1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3c2ccc(N(C)C)cc2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
A solution of 4 N hydrochloric acid in ethyl acetate (2.64 mL) was added to tert-butyl N′-[5-chloro-2-(4-dimethylaminophenyl)pentanoyl]hydrazinecarboxylate (106.9 mg), and the reaction solution was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure to obtain 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride. A solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate hydrochloride (77.6 mg) and triethylamine (0.16 mL) in ethanol (1.25 mL) was added to a solution of the resulting 5-chloro-2-(4-dimethylaminophenyl)pentanoic acid hydrazide hydrochloride and triethylamine (0.291 mL) in ethanol (1.25 mL), and the reaction solution was stirred at 80° C. in a nitrogen atmosphere for 22 hours. The reaction solution was cooled to room temperature, and then the solvent was evaporated from the reaction solution under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1→ethyl acetate→ethyl acetate:methanol=9:1) and further purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=9:1) to obtain 26.6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].CC(C)N=C=NC(C)C.O[CH2:83][P:84](=[O:89])([O:87]C)[O:85]C.C[Si](Br)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH2:83][P:84](=[O:85])([OH:89])[OH:87])=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Reactant: COP(=O)(CO)OC
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCn1c(C)c(C(=O)OCP(=O)(O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a solution of BM-957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added dimethyl (hydroxymethyl)phosphonate (40 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TMSBr (248 uL, 1.9 mmol). The solution was stirred at room temperature for 20 h until no starting material was observed by MS. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 8 (salt with TFA, 74 mg, yield 68% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. 1H NMR (300 M Hz, CD3OD): δ 7.92 (s, 1H), 7.73-7.70 (m, 2H), 7.34-6.82 (m, 17H), 4.28 (d, J=8.6 Hz, 2H), 4.06-3.35 (m, 14H), 3.20-2.92 (m, 5H), 2.65 (s, 3H), 2.24-1.67 (m, 6H), 1.10 (t, J=7.0 Hz, 3H). MS (ESI): m/z 1259.50 (M+H)+.