Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23](=[O:31])[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>O1CCCC1>[C:3]([CH:2]([CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][CH:20]([C:23](=[O:31])[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCCl)CC1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(C)=O
Temperature: 20 °C

Procedure:
A solution of 5.45 g of ethyl acetoacetate in 20 ml of tetrahydrofuran is added at 0° C. to a suspension of 1.68 g of sodium hydride at a concentration of 60% in oil in 100 ml of anhydrous tetrahydrofuran. The medium is maintained at 20° C. for 1 hour 30 minutes. 6.3 g of sodium iodide are added, followed by the addition at 0° C. of 11.3 g of 1-(2-chloroethyl)-4-(4-fluorobenzoyl)piperidine in 100 ml of tetrahydrofuran. The reaction mixture is brought to reflux for 15 hours. It is concentrated under vacuum. The residue is taken up in water and the product is extracted with dichloromethane.
Reaction SMILES: [CH3:1][CH:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:17]([O:20][CH2:21][CH2:22][CH:23]=O)([CH3:19])[CH3:18].[H][H]>CO.[Pt]=S>[CH:17]([O:20][CH2:21][CH2:22][CH2:23][NH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:11][CH:12]=1)([CH3:19])[CH3:18]
Reactant: [H][H]
Reactant: CCCCCCC(C)Nc1ccc(N)cc1
Reactant: CC(C)OCCC=O
Agent: S=[Pt]
Solvent: CO
Product: CCCCCCC(C)Nc1ccc(NCCCOC(C)C)cc1
Temperature: 25 °C

Procedure:
A mixture of 20 g. of N-(2-octyl)-p-phenylenediamine, 14 g. of 3-isopropoxypropionaldehyde and 0.3g. of 5% platinum sulfide on carbon catalyzt is shaken in a rocker bomb at 150°C under 600 psi hydrogen for 5 hours. After allowing the mixture to cool to room temperature, the contents of the bomb are dissolved in methanol and filtered through celite. The filtrate is evaporated in vacuo and the residue is taken up in ether and treated with an excess of dry hydrogen chloride gas. The resulant solid is collected by filtration and recrystallized from methanol-acetone to yield the product N-(3-isopropoxypropyl)-N'-(2-octyl)-p-phenylenediamine in dihydrochloride salt form (mp 200°-202°C).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Cl:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[N:59]([CH3:66])[CH:60]1[CH2:65][CH2:64][N:63]([C:11](=[O:13])[CH2:10][NH:9][C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:62][CH2:61]1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Reactant: CN(c1ccccc1Cl)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CN(c1ccccc1Cl)C1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 8 h
Yield: 26.4 %

Procedure:
To a stirred solution of [(biphenyl-4-carbonyl)-amino]-acetic acid (0.0659 g, 0.00025 mol) in DMF (1 mL), was added DIPEA (0.0911 g, 0.0007 mol), HOBt (0.0318 g, 0.00023 mol) and EDCI.HCl (0.054 g, 0.00028 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-methyl-piperidin-4-yl-amine hydrochloride (0.07 g, 0.00023 mol) was added and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with aqueous sodium bicarbonate solution followed by brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue obtained was purified by column chromatography using basic aluminium oxide (10-30% ethyl acetate in hexane) to afford 0.028 g (23%) of biphenyl-4-carboxylic acid (2-{4-[(2-chloro-phenyl)-methyl-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 462.1 (M+1)+, 96.19%, 1H NMR (DMSO-d6): δ 8.6 (t, 1H), 7.95 (d, 2H), 7.75 (m, 3H), 7.5 (t, 2H), 7.42 (m, 2H), 7.3-7.2 (m, 2H), 7.05 (m, 1H), 4.4 (d, 1H), 4.2 (m, 2H), 3.95 (d, 1H), 3.05 (t, 1H), 2.65 (s, 3H), 1.6 (bs, 3H), 1.6-1.4 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=1
Reactant: Cc1cc(-c2cccc(Br)n2)c(C)[nH]1
Reactant: OB(O)c1ccc(F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccc(-c3ccc(F)c4ccccc34)n2)c(C)[nH]1
Yield: 700.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 404 mg (2.13 mmol) 4-fluoronaphthalene-1-boronic acid, 534 mg (2.13 mmol) 2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg (8.51 mmol) sodium carbonate, 150 mg tetrakistriphenylphosphine, 10 mL ethanol, and 2 mL water. The reaction was refluxed overnight, cooled, poured into water, and extracted into ethyl acetate. After combining with another run on a larger scale, the combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 4.72 g (85%) of an oil. 1H-NMR (δ, CDCl3): 2.25 (s, 6H), 5.92 (s, 2H), 7.1-7.2 (m, 2H), 7.4-7.6 (m, 4H), 7.95 (t, J=8, 1H), 8.12 (d, J=8, 1H), 8.19 (d, J=8, 1H); 13C-NMR (δ, CDCl3): 13.41, 106.97, 108.82, 109.02, 120.18, 120.78, 120.84, 123.42, 123.81, 123.96, 125.48, 126.20, 127.32, 127.68, 127.76, 128.56, 132.35, 133.90, 138.22, 151.87, 157.82, 158.30, 160.34; MS (%): 317 (parent+1, 100); HRMS Calculated. for C21H18N2F (parent+1): 317.1454, Found: 317.1462.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O-:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[C:29]([Cl:30])=[CH:28][C:16]2[N+:17]([CH2:26][CH3:27])=[C:18]([CH3:25])[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:15]=2[CH:14]=1.CCO[CH:34]=[N:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1CCCCC1>CN(C)C(=O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([O-:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH:35]([CH:34]=[CH:25][C:18]1[N:19]([CH2:20][C:21]([F:23])([F:24])[F:22])[C:15]2[CH:14]=[C:13]([Cl:12])[C:29]([Cl:30])=[CH:28][C:16]=2[N+:17]=1[CH2:26][CH3:27])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC[n+]1c(C)n(CC(F)(F)F)c2cc(Cl)c(Cl)cc21
Reactant: CCOC=Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CC(=O)N(C)C
Solvent: C1CCCCC1
Product: CC[n+]1c(C=CNc2ccccc2)n(CC(F)(F)F)c2cc(Cl)c(Cl)cc21
Temperature: 150 °C

Procedure:
A slurry of 30 g (0.062 mole) of the 5,6-dichloro-1-ethyl-2-methyl-3-(2,2,2-trifluoroethyl)benzimidazolium p-toluenesulfonate in 150 mL of N,N-dimethylacetamide was treated with 45 g (about 0.3 mole, a large excess) of ethyl iso-formanilide, i.e., N-(ethoxymethylene)aniline, the mixture stirred and heated to 150° C., allowed to cool to 120° C. where it was maintained for 5 minutes, and then allowed to cool slowly to 30° C. The solution was poured into 1.5 L of cyclohexane, stirred, allowed to settle, and the dark reddish oil was separated. The oil was washed with another 500 mL of cyclohexane, separated, treated with 200 mL of methyl ethyl ketone, warmed to a uniform solution and cooled in a freezer to produce a bright yellow-orange solid. The solid was collected by filtration, washed with cold methy ethyl ketone, and dried to produce 23 g melting at 215°-217° C. The mass spec. and NMR spec. are consistent with the assigned structure.
Reaction SMILES: C(N(C(C)C)CC)(C)C.ClCCl.[NH2:13][C:14]1[C:19]([OH:20])=[C:18]([F:21])[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]=1[C:29]#[N:30].CC([O:34][C:35]1[C:40]([C:41](Cl)=O)=[CH:39][CH:38]=[CH:37][CH:36]=1)=O>O>[F:21][C:18]1[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH3:28])[C:15]([C:29]#[N:30])=[C:14]2[C:19]=1[O:20][C:41]([C:40]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:34])=[N:13]2
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(-c3ccccc3O)nc2c1C#N
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Diisopropylethylamine (435 μl, 2.5 mmol) was added to a dichloromethane (10 ml) solution of 4-amino-6-fluoro-5-hydroxy-2-methyl-biphenyl-3-carbonitrile (I-41) (353 mg, 1.46 mmol), then after cooling with ice, O-acetylsalicyloyl chloride (318 mg, 1.6 mmol) was added, followed by stirring at the same temperature for 30 minutes. With cooling with ice, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. In xylene (30 ml) and in the presence of a catalytic amount of p-tosylic acid, the resulting residue was heated under reflux for 2 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, and the resulting residue was dissolved in chloroform, washed with saturated sodium bicarbonate water, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was washed with a mixed solvent of isopropyl ether and ethanol, and the solid was collected by nitration to obtain the entitled compound (320 mg, 64%) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+].C1COCC1.CO>O>[Br:17][C:13]1[CH:12]=[C:11]([C:6]2([C:4]([OH:5])=[O:3])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(c2cccc(Br)c2)CCCC1
Reaction time: 18 h
Yield: 80.7 %

Procedure:
A mixture of 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid ethyl ester [3.42 g, 11.51 mmol], lithium hydroxide (579 mg, 13.81 mmol), THF (13 mL), MeOH (13 mL) and water (13 mL) is vigorously stirred for 18 hours. The mixture is concentrated and the residue is diluted with water (50 mL). The aqueous mixture is acidified with concentrated HCl to pH 1 and extracted twice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 1-(3-bromo-phenyl)-cyclopentanecarboxylic acid [2.5 g, 80.6%] as a solid, which is used without further purification.
Reaction SMILES: [OH:1][C:2]([C:26]1[N:30](COCC[Si](C)(C)C)[C:29]2[CH:39]=[C:40]([C:43]#[N:44])[CH:41]=[CH:42][C:28]=2[N:27]=1)([C:4]1[C:12](SC)=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2S(C1C=CC(C)=CC=1)(=O)=O)[CH3:3].OC(C1N(COCC[Si](C)(C)C)C2C=CC(C#N)=CC=2N=1)(C1C(SC)=CC(C)=C2C=1C=CN2[S:60]([C:63]1C=CC(C)=CC=1)(=[O:62])=[O:61])C>>[OH:1][C:2]([C:26]1[NH:27][C:28]2[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][C:29]=2[N:30]=1)([C:4]1[C:12]([S:60]([CH3:63])(=[O:62])=[O:61])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)[CH3:3]
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Reactant: CSc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(C)(O)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Product: Cc1cc(S(C)(=O)=O)c(C(C)(O)c2nc3cc(C#N)ccc3[nH]2)c2cc[nH]c12

Procedure:
A mixture of (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(1-hydroxy-1-(7-methyl-5-(methylthio)-1-tosyl-1H-indol-4-yl)ethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile was transformed into the title compound using the same reaction conditions as described in Example 10-B and Example 10-C. 1H NMR (400 MHz, DMSO-d6) δ 12.24-12.49 (m, 1H), 11.46 (br. s., 1H), 8.17-8.32 (m), 7.70-7.84 (m, 2H), 7.54 (m, 1H), 7.45 (m), 7.18 (t, J=2.91 Hz, 1H), 6.49-6.69 (m, 1H), 5.63 (dt, J=1.83, 3.82 Hz, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 2.27 (s, 3H). HRMS calcd. for C20H18N4O3S (M+H)+ 395.1173. found 395.1173.
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[CH:11][NH:10][C:9]=1[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:20][CH:21]1[CH:23]([C:24](O)=[O:25])[C:22]1([CH3:28])[CH3:27])[CH2:16][CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C=O)C>[CH2:15]([O:20][CH:21]1[CH:23]([C:24]([O:14][CH2:13][C:9]2[NH:10][CH:11]=[CH:12][C:8]=2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:25])[C:22]1([CH3:27])[CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCOC1C(C(=O)O)C1(C)C
Reactant: OCc1[nH]ccc1Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCOC1C(C(=O)OCc2[nH]ccc2Cc2ccccc2)C1(C)C
Reaction time: 2 h

Procedure:
To a stirred solution of 3-benzylpyrrolylmethyl alcohol (1.8 mmol), 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylic acid (2.0 mmol) and 4-dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of DMF is added N,N'-dicyclohexylcarbodiimide (2 mmol). The reaction mixture is stirred, under nitrogen, for about two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph eluting with ether/hexane to yield 3-benzylpyrrolylmethyl 3-(n-pentyloxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[N:21]O)[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1>[Pd].C(O)C>[NH2:21][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=1)[OH:10]
Reactant: O=C(C(=NO)c1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: NC(c1ccnc(F)c1)C(O)c1cccc(C(F)(F)F)c1
Reaction time: 10 h

Procedure:
10% palladium on carbon (3.0 g) was added to a solution of the 1-(2-fluoropyridin-4-yl)-2-(3-trifluoromethylphenyl)-ethane-1,2-dione 1-oxime (4) (8.0 g, 27 mmol) in ethanol (400 mL) at ambient temperature. The reaction vessel was vacuum purged with hydrogen and vigorously stirred for 10 hrs. After the reaction was complete, the solution was filtered through a pad of celite, and concentrated to give a yellow solid. The residue could be purified by recrystalization from methylene chloride and hexane. Alternatively, non polar impurities could be removed by filtration though silica gel starting with 5% methanol in methylene chloride to 5% methanol, 0.5% ammonium hydroxide in methylene chloride. Colorless solid (91%): mp 128-129° C.; 1H NMR (300 MHz, CD3OD) d 8.01 (d, J=5.0 Hz, 1 H, Ar), 7.53 (m, 1 H, Ar), 7.49 (m, 2 H, Ar), 7.43 (s, 1 H, Ar), 7.06 (d, J =5.0 Hz, 1 H, Ar), 6.86 (s, 1 H, Ar), 4.96 (d, J=5.0 Hz, 1 H, CH), 4.12 (d, J=5.0 Hz, 1 H, CH).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.Br[C:12]1[CH:13]=[CH:14][C:15]([F:19])=[C:16]([CH3:18])[CH:17]=1>>[F:19][C:15]1[CH:14]=[CH:13][C:12]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]2)=[CH:17][C:16]=1[CH3:18]
Reactant: Cc1cc(Br)ccc1F
Reactant: COC(=O)C1CCNCC1
Product: COC(=O)C1CCN(c2ccc(F)c(C)c2)CC1

Procedure:
starting with 10.6 g (74.0 mmol) of methyl piperidine-4-carboxylate and 4.67 g (24.7 mmol) of 5-bromo-2-fluorotoluene, the general procedure [E] gives 2.74 g (40% of theory) of product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[CH:15]=[C:16]([C:30]#[C:31][CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20])=[O:13].Cl.O1CCOCC1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:13])[C:14]1[CH:15]=[C:16]([C:30]#[C:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:17]=[C:18]([N:21]([CH2:28][CH3:29])[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:19]=1[CH3:20]
Reactant: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(c1cc(C#CC2CCNCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-((3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methylphenyl)ethynyl)piperidine-1-carboxylate (250 mg, 0.413 mmol) in DCM (3 mL) was added 4M HCl in 1,4-dioxane (3 mL, 12.0 mmol) at 20° C. The mixture was stirred at 20° C. for 1 h. LCMS indicated that the reaction was completed. The reaction mixture was directly concentrated and the residue was dissolved in DCM and then neutralized with sat. NaHCO3/brine. The organic layer was dried (Na2SO4) and filtered. And the filtrate was concentrated. The residue was used for alkylation without further purification (209 mg, 100%). 1H-NMR (500 MHz, CD3OD) δ ppm 7.21 (brs, 1H), 7.07 (brs, 1H), 6.11 (s, 1H), 4.46 (s, 2H), 3.95-3.89 (m, 2H), 3.39-3.34 (m, 2H), 3.08 (q, J=7.0 Hz, 2H), 3.06-2.98 (m, 3H), 2.79-2.72 (m, 1H), 2.72-2.65 (m, 2H), 2.38 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 1.94-1.88 (m, 2H), 1.73-1.68 (m, 2H), 1.68-1.56 (m, 4H), 0.85 (t, J=7.0 Hz, 3H); MS (ESI) [M+H]+505.5.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:20]=[C:21]([C:22]#[N:23])[C:4]=2[N:3]=1.[C:30]([NH:33][NH2:34])(=O)[CH3:31].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(O)CCC.O>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[C:5]2[CH:18]=[C:19]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:20]=[C:21]([C:22]3[NH:34][N:33]=[C:30]([CH3:31])[N:23]=3)[C:4]=2[N:3]=1
Reactant: CC(=O)NN
Reactant: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c(-c2cc(N3CCOCC3)cc3c2nc(C)n3Cc2cccc3ccccc23)n1
Yield: 26.1 %

Procedure:
To the suspension of 2-methyl-6-(4-morpholinyl)-1-(1-naphthalenylmethyl)-1H-benzimidazole-4-carbonitrile (120 mg, 0.314 mmol) in n-butanol (15 mL) was added in acetic hydrazide (232 mg, 3.14 mmol) and potassium carbonate (434 mg, 3.14 mmol). The reaction was stirred at reflux temperature for 4 days. DCM (50 mL) and water (50 mL) were added in. The organic phase was washed with Brine (50 mL×3), dried (MgSO4), and the solvent was removed. The crude was purified by reverse phase purification to provide the desired product (36 mg, 25%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.71 (br. s., 3H), 1.78 (br. s., 3H), 2.21-2.37 (m, 4H), 2.90-3.08 (m, 4H), 5.20 (s, 2H), 5.74 (d, J=7.33 Hz, 1H), 6.17 (br. s., 1H), 6.51 (t, J=7.71 Hz, 1H), 6.75-6.95 (m, 3H), 7.04 (d, J=8.08 Hz, 1H), 7.17 (d, J=8.08 Hz, 1H), 7.43 (d, 1H). MS (ES+) m/e 439.1[M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34](S(C)(=O)=O)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:49][CH2:48][C:47]4[CH:50]=[CH:51][C:44]([O:43][CH3:42])=[CH:45][CH:46]=4)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1nccc(-c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2nccc(-c3[nH]c(C4CCN(C(=O)OCc5ccccc5)CC4)nc3-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 140 °C
Yield: 92.4 %

Procedure:
A mixture of 4-[5-(2-methylsulfonylpyrimidin-4-yl)-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1.5 g, 0.00256 mole) and 4-methoxybenzylamine (3.51 g, 0.026 mole) was heated in a pressure tube at 140° C. for 10 minutes. The mixture was allowed to cool and the residue column chromatographed on silica using 5% methanol/methylene chloride to give 1.52 g of a yellow powder upon concentration in vacuo of product containing fractions.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])=[C:4]([F:11])[S:5][C:6]=1[CH2:7][C:8]([OH:10])=[O:9].[CH2:23](O)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:12]2[C:13](=[O:22])[C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]2=[O:21])=[C:4]([F:11])[S:5][C:6]=1[CH2:7][C:8]([O:10][CH2:23][CH3:24])=[O:9]
Reactant: O=C(O)Cc1sc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1Cl
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)Cc1sc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1Cl

Procedure:
To a solution of 2-(4-chloro-2-fluoro-5-carboxymethylthiophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (1.2 g) and ethanol (1.0 g) in toluene (20 ml), there was added a small amount of p-toluenesulfonic acid, and the mixture was refluxed for 3 hours. Water was added to the reaction mixture. The toluene layer was separated, dried and concentrated. The residue was purified by silica gel chromatography to give 0.1 g of 2-(4-chloro-2-fluoro-5-ethoxycarbonylmethylthiophenyl-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. nD18 1.5670.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH3:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH2:13]([O:20][C:21](=[O:27])[NH:22][CH:23]([CH3:26])[CH2:24]Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[CH2:13]([O:20][C:21](=[O:27])[NH:22][CH:23]([CH3:24])[CH2:26][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=2)[C:2]([Cl:1])=[N:3]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)n[nH]c2c1
Reactant: CC(CBr)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cl)nn(CC(C)NC(=O)OCc3ccccc3)c2c1
Reaction time: 18 h
Yield: 72.2 %

Procedure:
To a solution of the product from Step C (0.18 g, 1 mmol) and (2-bromo-1 methyl-ethyl)-carbamic acid benzyl ester (0.27 g, 1 mmol) in DMF (2 mL) was added potassium carbonate (0.17 g, 1.2 mmol) and the mixture stirred at 75° for 18 h. Ethyl acetate (20 mL) and water (20 mL) were added to the reaction mixture and the aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (30 mL), dried (MgSO4), and evaporated to a residue that was purified by chromatography (silica, hexane to 15% ethyl acetate in hexane) to give a syrup (0.27 g): APCl/LCMS m/z 374 (M+H)+.