Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH2:14][S:15]([CH3:17])=[O:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.[CH2:46]([NH2:54])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]>ClCCl>[CH3:17][S:15]([CH2:14][CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([NH:54][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:12])=[O:16]
Reactant: CS(=O)CCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)C(CCS(C)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 92 %

Procedure:
To a mixture of 2-((tert-butoxycarbonyl)amino)-4-(methylsulfinyl)butanoic acid (10.0 g, 37.7 mmol) and HOBt (6.35 g, 41.5 mmol) in dichloromethane (200 mL) at 0° C. was added triethylamine (10.5 mL, 75.4 mmol) and EDAC (7.95 g, 41.5 mmol). After stirring for 20 minutes octylamine was added and the solution was allowed to warm to room temperature and stirred for 3 days. The reaction was washed with saturated sodium bicarbonate (2×100 mL), 1N HCl (2×100 mL), and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give an oil which solidified upon standing. The solid was purified by silica gel chromatography with 0-5% methanol/dichloromethane to give a white solid (13.1 g, 92%). m/z 377 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([NH:11][C:12](=[O:40])[CH2:13][NH:14][C:15]([C:17]1[CH:18]=[C:19]([N:26]2[CH2:31][C@@H:30]3[CH2:32][C@H:27]2[CH2:28][N:29]3C(OC(C)(C)C)=O)[CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])=[O:16])([CH3:10])[CH3:9]>ClCCl>[C@H:27]12[CH2:32][C@H:30]([NH:29][CH2:28]1)[CH2:31][N:26]2[C:19]1[CH:20]=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([CH:18]=1)[C:15]([NH:14][CH2:13][C:12]([NH:11][CH:8]([CH3:10])[CH3:9])=[O:40])=[O:16]
Reactant: CC(C)NC(=O)CNC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)CNC(=O)c1cc(N2C[C@@H]3C[C@H]2CN3)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 83.7 %

Procedure:
2,2,2-Trifluoroacetic acid (4.6 g, 39.5 mmol) was added to a solution of (1S,4S)-tert-butyl 5-(3-(2-(isopropylamino)-2-oxoethylcarbamoyl)-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (Intermediate 5A) (1.5 g, 3.25 mmol) in dichloromethane (15 mL). The resulting solution was stirred overnight. The resultant crude material was purified using a 20 g SCX cartridge to afford 5-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-N-(2-(isopropylamino)-2-oxoethyl)-2-nitrobenzamide (984 mg, 2.72 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:10][C:11]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[Cl:10][C:11]1[CH:18]=[C:17]([O:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(C#N)c(Cl)c2)cc1Cl
Temperature: 120 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a solution of 3-chloro-4-methylphenol (7.5 g) and 2-chloro-4-fluorobenzonitrile (8.14 g) in N,N-dimethylacetamide (23 ml) was added potassium carbonate (8.55 g). The mixture was stirred for 5 hours at 120° C. The mixture was poured into ice water and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness to give the title compound (14.42 g) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[O:10][CH:11]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=3)[N:29]([CH2:39][CH3:40])[CH:28]=2)=[O:26])=[CH:5][CH:4]=1.[C:56]1(=[O:62])[O:61][C:59](=[O:60])[CH2:58][CH2:57]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH:11]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:12]2[N:13]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]3[C:36](=[O:37])[C:35]4[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=4)[N:29]([CH2:39][CH3:40])[CH:28]=3)=[O:26])[CH2:14][CH:15]([O:17][C:56](=[O:62])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH2:16]2)=[CH:53][CH:52]=1
Reactant: CCn1cc(C(=O)NCCCCCC(=O)N2CC(O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)NCCCCCC(=O)N2CC(OC(=O)CCC(=O)O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 27, Compound 99 (1.48 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.606 g, 0.96 mL, 6 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 101.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.Cl.N1CCCNCC1.[I-].[Na+].CS(O[CH2:24][CH2:25][CH:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)=O>C(O)C>[C:27]1([CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:25][CH2:24][N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C1CNCCNC1
Reactant: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(CCN2CCCNCC2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of 126 mg of homopiperazine. 218 mg of homopiperazine dihydrochloride, 3 mL of ethanol was heated to 70° C. into a solution. 378 mg of sodium iodide and 289 mg of 3,3-diphenylpropyl methanesulfonate were added sequentially to the solution and the solution was stirred at 70° C. for 15 hours. After the solution was cooled to room temperature, the ethanol was removed under reduced pressure followed by adding 20 mL of aqueous 2N sodium hydroxide and extracting with 20 mL×2 of ethyl acetate. The organic layers were combined, washed with 20 mL of saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give 1-(3,3-diphenylpropyl)homopiperazine.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>O1OCCCC1>[C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)([O:6][CH3:7])=[O:5]
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccccc1Br
Agent: C1CCOOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccccc1N1CCNCC1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
To a solution of methyl 2-bromobenzoate (1.63 g, 17.8 mmol) in 1,6-dioxane (100 ml) at room temperature was added piperazine (15.3 g, 178 mmol) and K2CO3 (4.92 g, 35 mmol). The resulting mixture was heated to reflux for 7 days after which the reaction mixture was cooled to room temperature. The solvent and the excess piperazine were removed in vacuo along with heating with a hot water bath. The residue was dissolved in 1N NaOH solution, extracted with CH2Cl2 (6×30 ml), and dried over Na2SO4. The solvent was removed in vacuo to obtain 1-(2-carbomethoxyphenyl)-piperazine as a yellow oil (1.0 g, 26%).
Reaction SMILES: Cl([O-])(=O)(=O)=O.Cl[C:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C:9](=[N+:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:8]=1.[CH3:20][S:21]([CH2:24][C:25]#[N:26])(=[O:23])=[O:22].C(N(CC)CC)C>C(O)C>[CH3:13][C:11]1([CH3:14])[CH2:10][C:9]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:8][C:7](=[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])[C:25]#[N:26])[CH2:12]1
Reactant: CC1(C)CC(Cl)=CC(=[N+]2CCCC2)C1
Reactant: CS(=O)(=O)CC#N
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CC(N2CCCC2)=CC(=C(C#N)S(C)(=O)=O)C1

Procedure:
N-(3-Chloro-5,5-dimethylcyclohex-2-en-1-ylidene)-pyrrolidinium perchlorate (4.7 g., 0.015 mol.), methylsulfonylacetonitrile (1.8 g., 0.015 mol.) and triethylamine (4.6 ml.) are dissolved in ethanol (15 ml.) and heated at reflux for 5 minutes. After chilling, the crude dye is collected on a filter, washed with methanol and dried. After one recrystallization from pyridine/methanol, the yield of purified dye is 1.2 g. (27%), m.p. 260°-261°C. with decomposition. The above dye compound has excellent absorption characteristics in the ultraviolet region of the spectrum as shown in Table 1 below.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:7]=[C:8]([C:10]2[CH:11]=[N:12][NH:13][CH:14]=2)[CH:9]=1.[CH3:26][C:27]1([C:30]([O:32]C)=[O:31])[O:29][CH2:28]1>CN(C=O)C.CCOC(C)=O>[OH:29][C:27]([CH3:28])([CH2:26][N:12]1[CH:11]=[C:10]([C:8]2[CH:7]=[C:6]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][N:17]=3)[CH:5]=[C:4]([CH3:3])[CH:9]=2)[CH:14]=[N:13]1)[C:30]([OH:32])=[O:31]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: COC(=O)C1(C)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnn(CC(C)(O)C(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (23.5 mg, 0.59 mmol) at 0° C. was added to an oven-dried vial containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.24 mmol) in DMF (0.8 mL). The mixture was stirred for 10 minutes, and then methyl 2-methylglycidate (0.03 mL, 0.24 mmol) was added. The reaction was warmed to room temperature and stirred overnight, followed by subsequent heating to 70° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (3×), then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier) to afford racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C19H18F3N5O3 [M+H]+ 422. found 422.
Reaction SMILES: [Br:1][C:2]1[C:3](OC)=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O=P(Cl)(Cl)[Cl:13]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([Cl:13])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ncc(Br)cc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ncc(Br)cc1Br
Temperature: 0 °C
Yield: 66.2 %

Procedure:
3,5-Dibromo-2-methoxy-pyridine (427) (1.5 g, 5.62 mmol) was dissolved in anhydrous DMF (14 mL) and chilled to 0° C. While stirring, POCl3 (2.1 mL, 22.48 mmol) was added drop wise over a period of 5 minutes. The mixture was stirred at 0° C. for 1 h. The mixture was then heated to 100° C. under N2, for 16 h. TLC indicated complete reaction at this point. Ice-chips (10 g) were added to the cooled solution and the mixture was stirred for 20 minutes. The mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and brine (2×50 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by column chromatography gave the desired product (428) as an off white solid upon concentration (1.01 g, 3.722 mmol, 66.2% yield). 1H NMR (400 MHz, CDCl3): δ 8.07 (d, 1H, J=2 Hz), 8.38 (d, 1H, J=1.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:48]=[CH:47][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:46])[C:10]3[C:15]([C:16]=2[C:17]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:23][CH2:22]2)=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]([CH3:46])[C:10]3[C:15]([C:16]=2[C:17]([CH2:19][CH2:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:47][CH:48]=1
Reactant: Cn1c(COc2ccc(Cl)cc2)c(C(=O)CCC2CCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=CO
Product: Cn1c(COc2ccc(Cl)cc2)c(C(=O)CCC2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere 2-[(4-chlorophenoxy)methyl]-1-methyl-3-[[2-(1-tritylpiperidin-4-yl)ethyl]carbonyl]-1H-indole (0.2723 g, 0.417 mmol) was dissolved in 2.1 ml of methylene chloride. To this solution formic acid (0.079 ml, 0.096 g, 2.084 mmol) was added and the resulting mixture was stirred at room temperature for about 2.5 hours. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:6][C:7]1[CH:24]=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([C:25](=[O:34])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=1
Reactant: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(OS(=O)(=O)C(F)(F)F)ccc4[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCCNC(=O)C1=CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Yield: 87.2 %

Procedure:
About 2.05 g of compound 3a (m=6) was dissolved in a mixture of methanol (90 ml) and water (10 ml). About 1.6 g of solid potassium carbonate (K2CO3) was added and the reaction mixture was refluxed for 2.5 h. After removal of most of the methanol, 50 ml of 1N HCl was added to the reaction mixture. The precipitate formed was filtered and washed with water, yielding the phenol 4a (1.34 g, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[CH:16][N:15]=2)=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2)nc1
Reaction time: 20 h
Yield: 61.3 %

Procedure:
5-[(4-fluorophenyl)sulfonyl]-2-[(E)-2-(4-fluorophenyl)vinyl]-pyridine (Example 2, 0.42 g, 1.18 mmol) was taken up in ethanol (5 mL) and ethyl acetate (5 mL) and palladium (10% wt. on activated carbon, 60 mg) was added. The suspension was shaken in a Parr apparatus at 20 psi hydrogen for 6 hours, followed by 40 psi hydrogen for 3 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was taken up in acetic acid (25 mL) and platinum(IV) oxide (20 mg) was added. The suspension was stirred under a balloon of hydrogen for 20 hours. Further platinum(IV) oxide (20 mg) was added and stirring under hydrogen continued for 24 hours. The catalyst was removed by filtration and most of the solvent removed in vacuo. The residue was partitioned between ethyl acetate and 4N sodium hydroxide solution. The organic phase was dried over MgSO4 and concentrated in vacuo while loading onto silica. Eluting through a plug of silica using 20% ethyl acetate/isohexane gave the title compound as a yellow solid (0.26 g, 61%). δH (500 MHz, d6 DMSO): 9.04 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=2.4, 8.3 Hz), 8.09–8.07 (2H, m), 7.49–7.45 (3H, m), 7.22–7.19 (2H, m), 7.04 (2H, t, J=8.8 Hz), 3.11–3.09 (2H, m), 2.98–2.95 (2H, m); m/z (ES+) 360 [MH+].
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2c(/C=C/c3ccccc3)nc3ccccc32)nc1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-Chloro-5-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate-hexane to give the titled compound. MW: 347.85; mp: 245.0-247.0° C.; 1H-NMR (DMSO-d6) δ: 8.66 (1H, d, J=1.8 Hz), 8.19 (1H, d, J=16.1 Hz), 8.08 (1H, dd, J=8.1, 2.1 Hz), 7.87 (1H, d, J=8.8 Hz), 7.76 (1H, d, J=8.1 Hz), 7.71-7.66 (2H, m), 7.57-7.52 (2H, m), 7.49-7.44 (4H, m), 7.19 (1H, d, J=16.1 Hz), 2.50 (3H, s).
Reaction SMILES: C[Mg]Cl.[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14].[Cl-].[NH4+].[C:17](OCC)(=O)C>C1COCC1>[F:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:17])=[CH:7][C:6]=1[O:13][CH3:14]
Reactant: COc1cc(C=O)ccc1F
Reactant: CCOC(C)=O
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(C)O)ccc1F
Reaction time: 2 h

Procedure:
Methyl magnesium chloride (3 M tetrahydrofuran solution, 7.8 mL) was added to a solution of 4-fluoro-3-methoxybenzaldehyde (3 g) in THF (200 mL) while cooling with ice, and the reaction solution was stirred for 2 hours while cooling with ice. A saturated aqueous solution of ammonium chloride and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent:heptane-ethyl acetate system) to obtain 2.65 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1I)[CH3:2].FC1C=CC(B(O)O)=CC=1.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[CH2:1]([C:3]1[C:4]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[C:5]([CH:9]=[O:10])[NH:6][C:7]=1[C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=1)[CH3:2]
Reactant: CCc1c(I)[nH]c(C=O)c1C(=O)OCc1ccccc1
Reactant: Cc1cccc(B(O)O)c1
Agent: OB(O)c1ccc(F)cc1
Product: CCc1c(-c2cccc(C)c2)[nH]c(C=O)c1C(=O)OCc1ccccc1

Procedure:
Following the procedures described in Example 5, replacing methyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate with benzyl 4-ethyl-2-formyl-5-iodo-1H-pyrrole-3-carboxylate and 4-fluorophenylboronic acid with 3-methylphenylboronic acid, the title compound was obtained. Proton NMR for the product was consistent with the title compound. HRMS (ES) exact mass calculated for C22H22NO3 (M+H): 348.1594. Found 348.1611
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)=[CH:5][CH:4]=[N:3]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.[NH2:49][C@@H:50]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:73])([F:72])[F:71])[CH2:51][N:52]1[C:60](=[O:61])[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53]1=[O:62]>C(Cl)Cl>[O:61]=[C:60]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:53](=[O:62])[N:52]1[CH2:51][C@@H:50]([NH:49][C:12]([C:10]1[S:11][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)=[CH:8][CH:9]=1)=[O:14])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[C:70]([F:72])([F:71])[F:73]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1ccc(C(=O)O)s1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nccc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)s1
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (100 mg, 0.48 mmol), PyBrOP (270 mg, 0.58 mmol) and diisopropylethyl amine (420 μL, 2.4 mmol) in DCM (5 mL) at 25° C. was added 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (168 mg, 0.48 mmol) [from Preparation 6]. After 16 h, the solution was partitioned between H2O and washed with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (74 mg, 28%) as a white solid: LC-MS (ES) m/z=539 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>CN(C=O)C.O>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[O:12])[CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 110.5 %

Procedure:
Indole-5-carboxylic acid (1.00 g, 6.21 mmol) was dissolved in DMF (10 mL) and the solution was added with EDCI (2.38 g, 12.4 mmol), HOBT monohydrate (839 mg, 6.21 mmol) and 1-(tert-butoxycarbonyl)piperazine (1.73 g, 9.29 mmol), followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, 1 mol/L hydrochloric acid, and saturated brine, and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 5-[4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indole (2.26 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][S:8][C:9]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:17](=[O:26])[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:30][OH:31]>C(O)(=O)C.N#N.CCOC(C)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:17](=[O:26])[C:16]3[C:11](=[CH:12][C:13]([C:27](=[N:30][OH:31])[NH2:28])=[CH:14][CH:15]=3)[N:10]=[C:9]2[S:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:29])=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C#N)ccc2c(=O)n1-c1ccc(F)cc1
Reactant: NO
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C(N)=NO)ccc2c(=O)n1-c1ccc(F)cc1

Procedure:
A solution of tert-butyl-2-(7-cyano-3-(4-fluorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10A, 0.05 g, 0.12 mmol) in 50% NH2OH aqueous solution (3 mL) and 20 μL acetic acid was microwaved under high absorption in N2 atmosphere 105° C. for 40 minutes. The reaction was diluted with EtOAc and washed with water. The organic was concentrated to yield tert-butyl 2-(3-(4-fluorophenyl)-7-(N′-hydroxycarbamimidoyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetate (10B), MS (M+H)=445.