Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].Cl([O-])=[O:13].[Na+].O.O.P([O-])([O-])(O)=O.[Na+].[Na+].Cl>C(O)(C)(C)C.O>[C:4]([C:3]1[CH:6]=[C:7]([CH:8]=[CH:9][C:2]=1[F:1])[C:10]([OH:13])=[O:11])#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: N#Cc1cc(C(=O)O)ccc1F
Yield: 90 %

Procedure:
To a stirred solution of 15.0 g (97.6 mmol) 2-fluoro-5-formyl-benzonitrile (Aldrich), 150 ml dest. water and 630 ml t-butanol were added 40.8 g (361 mmol) sodium chlorite and 35.9 g (230 mmol) sodium hydrogen phosphate dihydrate. The reaction mixture was stirred over night and poured into a diluted aqueous hydrogen chloride solution (pH=3.5). The pH value was readjusted to pH=3.5 by aqueous hydrogen chloride. The aqueous solution was extracted trice with dichloromethane/isopropanol (10:1). The combined organic phases were dried (sodium sulphate) and concentrated. The residue was purified by extraction with sodium hydrogen carbonate solution and dichloromethane, acidification with aqueous solution and subsequent filtering. The solid crude product 2a was obtained in 90% yield (14.5 g, 87.8 mmol) and was used for the next step without purification.
Reaction SMILES: [C:1]1(C([O-])=O)[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.[NH2:12][N+:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[NH2:20].[CH:21]([N:24](C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C=O>[Cl:19][C:15]1[C:14]2[N:13]([N:12]=[C:21]([NH:24][C:1]3[CH:2]=[C:3]([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=3)[N:20]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(C)cc(C(=O)[O-])c1
Reactant: Nc1c(Cl)ncc[n+]1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(Nc2nc3c(Cl)nccn3n2)c1
Reaction time: 1 h
Yield: 53.7 %

Procedure:
To a solution of 3,5-dimethylisothiocyanate (200 mg, 1.2 mmol) in dichloro-methane and N,N-dimethylformamide (1:1) (5.0 mL) were added 1,2-diamino-3-chloro-pyrazinium mesitylenate (0.59 g, 0.0017 mol) and diisopropylethylamine (791 mg, 6.1 mmol). The reaction mixture was stirred for 1 hour. EDCl (93 mg, 5 mmol) was added and the solution stirred for 2 hours at room temperature before being concentrated to dryness. The residue was taken up in water and stirred for 5 minutes and the solid precipitated was filtered, washed with water, dried to get the product as a light brown solid (0.25 g, 75%). TLC: pet ether/ethyl acetate (6/4) Rf-0.4. LCMS (method A): mass found (M+H+, 274.0), Rt (min): 4.47 area % 98.0 (max), 98.47 (254 nm); 1H NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 8.95 (d, J=4.28 Hz, 1H), 7.91 (d, J=4.32 Hz, 1H), 7.28 (s, 2H), 6.58 (s, 1H), 2.24 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH3:25][O:26][CH2:27][C:28]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11])=[O:29]
Reactant: COCC(=O)Cl
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CC(OC(C)=O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.5 mmol) and methoxyacetyl chloride (0.38 g, 3.5 mmol) in tetrahydrofuran (20 mL) is heated at reflux for 1 hour. The solvent is removed in vacuo to give 3-[4-(2-methoxyacetylamino)-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=2)[O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[C:34](OC)=[O:35])=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>O1CCCC1.CO>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[C:12]([NH:14][C:15]1[CH:40]=[CH:39][CH:38]=[C:17]([O:18][C:19]2[CH:33]=[CH:32][C:22]3[N:23]=[C:24]([NH:26][C:27]([CH:29]4[CH2:31][CH2:30]4)=[O:28])[S:25][C:21]=3[C:20]=2[CH2:34][OH:35])[CH:16]=1)=[O:13])([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1c(Oc2cccc(NC(=O)c3cccc(C(C)(C)C#N)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3CO)c2)c1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
To a solution of methyl 6-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]-2-[(cyclopropylcarbonyl)amino]-1,3-benzothiazole-7-carboxylate (200 mg, 0.369 mmol) produced in Example 46(iv) in tetrahydrofuran (8 mL) were added triethylamine (101 μL, 0.738 mmol) and isobutyl chloroformate (96 μL, 0.738 mmol) at 4° C., and the mixture was stirred at 4° C. for 30 min. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (2 mL), sodium borohydride (42 mg, 1.10 mmol) and methanol (2 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (20 mL), washed successively with 1N hydrochloric acid (5 mL), 5% aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80→60/40), and the obtained solution was concentrated under reduced pressure to give the title compound (108 mg, 55%) as a pale-yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9]Cl)=[CH:4][CH:3]=1.[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>COCCOC.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9][N:18]2[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CN(CCCl)Cc1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: COCCOC
Product: CN1CCN(CCN(C)Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Yield: 69.1 %

Procedure:
To a solution of 73 (3.5 g, 13.3 mmol) in DME (20 ml) was added N-methylpiperazine (3.33 g, 2.5 eq, 33.3 mmol) and tetrabutylammonium bromide (cat). The reaction mixture was heated to reflux for 3 hrs, then cooled to RT and concentrated. The crude was dissolved in EtOAc, washed well with water and the organic phase was collected, dried over Na2SO4 and filtered then concentrated. Purification by column chromatography (20% MeOH in EtOAc+1% TEA) afforded 74 as colorless oil (3.0 g, 69% yield). MS (m/z): 326.0/328.0 (M+H).
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[C:22]([F:23])=[C:21]([OH:24])[C:20]([F:25])=[C:19]([F:26])[C:5]=1[C:6]([C:8]1[C:13](F)=[C:12]([F:15])[C:11](F)=[C:10]([F:17])[C:9]=1[F:18])=[O:7].O.Cl.[CH3:29]O>C(O)(C)C>[CH3:29][O:24][C:21]1[C:20]([F:25])=[C:19]([F:26])[C:5]2[C:6](=[O:7])[C:8]3[C:13]([O:3][C:4]=2[C:22]=1[F:23])=[C:12]([F:15])[C:11]([OH:1])=[C:10]([F:17])[C:9]=3[F:18]
Reactant: CO
Reactant: [OH-]
Reactant: O=C(c1c(O)c(F)c(O)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Agent: Cl
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1c(F)c(F)c2c(=O)c3c(F)c(F)c(O)c(F)c3oc2c1F

Procedure:
A solution of sodium hydroxide (125 mg, 3.14 mmol) in 5 mL methanol is added dropwise to a solution of Compound 46 (450 mg, 1.25 mmol) in 10 mL methanol. The reaction mixture is then heated at reflux for 15 hours. The reaction mixture is then poured into 50 mL water and hydrochloric acid is added to a solution pH of 2, and the resulting solution is extracted with ethyl acetate (50 mL×2). The combined organic layers are washed with brine (30 mL), dried over magnesium sulfate and concentrated in vacuo to yield 387 mg (88%) of crude Compound 47. An analytically pure sample is obtained by recrystallization from isopropyl alcohol. mp: 270-272° C. dec. 1H-NMR (d6-DMSO) 4.23 (s). 19F-NMR (d6-DMSO) 141.39 (dd, J=13.0, 20.3 Hz, 1F); 141.85 (dd, J=11.4, 21.6 Hz, 1F); 151.65 (d, J=10.4 Hz, 1F); 154.34 (d, J=20.3 Hz, 1F); 155.46 (t, J=7.9 Hz, 1F); 156.68 (dd, J=6.4, 20.3 Hz, 1F). Anal. calc. for C14H4F6O4: C, 48.02; H, 1.15. Found: C, 47.09; H, 1.07.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[N:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:21](O)=[O:22])[C:5]2=[N:6][CH:7]=1.[F:24][CH2:25][CH2:26][NH2:27].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]3[C:17]([CH3:18])=[C:16]([O:19][CH3:20])[N:15]=[CH:14][N:13]=3)[CH:9]=[C:8]([C:21]([NH:27][CH2:26][CH2:25][F:24])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(F)cc32)c1C
Reactant: NCCF
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: COc1ncnc(Cn2cc(C(=O)NCCF)c3ncc(F)cc32)c1C
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
See FIG. 20(c). 6-fluoro-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (20 mg, 0.06 mmol) and 2-fluoroethanamine (7.18 mg, 0.11 mmol), TEA (0.026 mL, 0.19 mmol) was added. After 3 min, 1-Propanephosphonic acid cyclic anhydride (50.3 mg, 0.16 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water.DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 6-fluoro-N-(2-fluoroethyl)-1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (20.00 mg, 88%). ES+MS m/z: 362. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.24 (s, 3 H ) 3.57-3.70 (q, 1 H ) 3.70-3.80 (q, 1 H ) 3.94 (s, 3 H ) 4.43-4.58 (t, 1 H ) 4.66 (t, J=4.99 Hz, 1 H ) 5.68 (s, 2 H ) 8.03 (dd, J=9.89, 2.54 Hz, 1 H ) 8.29 (s, 6 H ) 8.40 (s, 1 H ) 8.53 (t, J=2.07 Hz, 1 H ) 8.71 (t, J=5.84 Hz, 1 H ).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1Cl)(=[O:12])=[O:11].[SH:23][CH2:24][CH2:25][OH:26]>O>[OH:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[S:23][CH2:24][CH2:25][OH:26])(=[O:12])=[O:11]
Reactant: OCCS
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCO)c(S(=O)(=O)CCO)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
58.75 g of potassium carbonate are added at 22° C. to a suspension of 132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone in 100 ml of water and 80 g of 2-mercaptoethanol in the course of 1.5 hours, and the mixture is stirred at room temperature for 4 hours. The reaction mixture is then filtrated with suction, and the filter residue is washed with water until neutral. Drying these gives 124.3 g of 2-β-hydroxyethylmercapto-5-nitrophenyl hydroxyethyl sulfone having a melting point of 116°-118° C. (purity about 99%), which corresponds to a yield of 81% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=O.[F:15][CH2:16][C:17](=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20].[NH2:24][C:25]([CH3:33])=[CH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>>[Cl:1][C:2]1[C:3]([C:11]([F:14])([F:13])[F:12])=[C:4]([CH:5]2[C:26]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])=[C:25]([CH3:33])[NH:24][C:17]([CH2:16][F:15])=[C:18]2[C:19]([O:21][CH3:22])=[O:20])[C:7]([F:10])=[CH:8][CH:9]=1
Reactant: COC(=O)CC(=O)CF
Reactant: O=Cc1c(F)ccc(Cl)c1C(F)(F)F
Reactant: CC(N)=CC(=O)OC(C)C
Product: COC(=O)C1=C(CF)NC(C)=C(C(=O)OC(C)C)C1c1c(F)ccc(Cl)c1C(F)(F)F
Reaction time: 1.5 h
Yield: 7.5 %

Procedure:
3-Chloro-6-fluoro-2-(trifluoromethyl)benzaldehyde (1.3 g, 5.7 mmoles), methyl 4-fluoro-3-oxobutanoate (0.77 g, 5.7 mmoles) and 1-methylethyl 3-amino-2-butenoate (0.82 g, 5.7 mmoles) were heated under nitrogen with stirring for 1.5 hours at 90°, followed by 1.5 hours at 100° and then 1 hour at 110°. The cooled reaction mixture was chromatographed twice on silica first using methylene chloride as eluent and then toluene/ethyl acetate mixtures. The title compound (0.2 g) was obtained after crystallisation from petroleum ether (60°-80°) mp 142°-3°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[OH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[OH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:13]1[CH2:14][CH2:15][N:16]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=2)[CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OC(c1ccccc1)C1CCNCC1
Product: Nc1ccc(N2CCC(C(O)c3ccccc3)CC2)nc1

Procedure:
Intermediate B-24 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-(hydroxyphenylmethyl)piperidine as starting materials. MS (M+1): 284.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](Cl)=[O:31])=[CH:24][CH:23]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=C[CH:34]=1>O>[CH3:34][CH:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=1)[C:30]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)=[O:31]
Reactant: c1ccncc1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: CCCCCCOc1ccc(CCC(=O)Cl)cc1
Solvent: O
Product: CCCCCCOc1ccc(CC(C)C(=O)Oc2ccc(-c3ccc(F)cc3)cc2)cc1
Reaction time: 8 h
Yield: 48 %

Procedure:
4-Hydroxy-4'-fluorobiphenyl (2.1 g, 0.012 mol) was dissolved in pyridine (10 ml), and to the solution was added β-(4-hexyloxyphenyl)propionic acid chloride (3.0 g, 0.01 mol) with sufficient shaking, followed by allowing the resulting reaction solution to stand overnight, thereafter pouring it in water (100 ml), extracting the resulting oily material with toluene (100 ml), washing the toluene layer with 6N-HCl and then with 2N-NaOH, further washing with water till the washing liquid became neutral, filtering, distilling off toluene under reduced pressure, and recrystallizing residual crystals from ethanol to obtain the objective 4'-fluoro-4-biphenylyl α-methyl-β-(4-hexyloxyphenyl)propionate (2.1 g, yield 48%). m.p.: 78.4°-79.5° C. N-I point: 38.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[Cl:14]C(OCC(C)C)=O.[C:22]([C:25]1[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=1[NH:27][C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:24])[NH2:23].Cl.Cl.C(O)C>CN(C)C=O.C(N(CC)CC)C>[OH2:2].[ClH:14].[C:22]([C:25]1[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=1[NH:27][C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]([C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:32][CH2:31]1)(=[O:24])[NH2:23]
Reactant: CC(C)COC(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: NC(=O)c1ccccc1NC(=O)CN1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(CC(=O)Nc3ccccc3C(N)=O)CC2)cc1OC
Product: O

Procedure:
3.3 Grams of 3,4-dimethoxybenzoic acid was dissolved in 30 ml of dimethylformamide, and to this solution was added 2.4 g of triethylamine. Under ice-cooled condition with stirring, 2.75 g of isobutyl chloroformate was added dropwise and the mixture obtained was stirred for 30 minutes. To this reaction mixture was added dropwise a dimethylformamide solution of 5.5 g of o-carbamoyl-α-(1-piperazinyl)acetanilide and was stirred for 5 hours. The reaction mixture was concentrated to dryness and extracted with chloroform-1N sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried and chloroform was removed by distillation, the residue thus obtained was purified by a silica gel column chromatography and the product obtained was converted into a hydrochloride by adding hydrochloric acid-ethanol, recrystallized from water-acetone to obtain 1.5 g of o-carbamoyl-α-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]acetanilide monohydrochloride monohydrate in the form of colorless needle-like crystals. Melting point: 122.0°-125.0° C. (decomposed).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[C:21]([NH:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([Cl:26])=[N:18][CH:17]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[C:11]1[O:12][C:15]([C:16]2[CH:17]=[N:18][C:19]([Cl:26])=[CH:20][C:21]=2[NH:22][CH:23]([CH3:24])[CH3:25])=[N:14][N:13]=1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1cc(Cl)ncc1C(=O)NNC(=O)C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)Nc1cc(Cl)ncc1-c1nnc(C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)o1
Temperature: 50 °C

Procedure:
tert-butyl (3-((tert-butyldimethylsilyl)oxy)-1-(2-(6-chloro-4-(isopropylamino)nicotinoyl)hydrazinyl)-1-oxopropan-2-yl)carbamate (54) (100 mg, 0.18 mmol) in DCM (5 mL) was stirred at room temperature. Added triphenyl phosphine (0.56 mmol, 3 equiv.), Et3N (1.5 mol, 8 equiv.) and CCl4 (0.56 mmol, 3 equiv.). The reaction mixture was heated at 50° C. for 3 h. Reaction mixture was diluted using DCM. The DCM layer was washed with water. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and EtOAc: Pet. Ether as eluent to provide the desired compound, tert-butyl (2-((tert-butyldimethylsilyl)oxy)-1-(5-(6-chloro-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate (55). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 2.567 min; LCMS (ES-API), m/z 512.3 (M+H).
Reaction SMILES: [CH3:1][C:2]12[C:8]([CH3:10])([CH3:9])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@@H:17]([CH2:18][O:19][CH3:20])[C@@:16]3([CH3:35])[C:21]3[CH:30]=[CH:29][C:28]4[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=4[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:36].[CH3:37][C:38]12[C:44]([CH3:46])([CH3:45])[C:41]([C:47]([O:49][CH2:50][C@@H:51]3[C@H:53]([CH2:54][O:55][CH3:56])[C@:52]3([CH3:71])[C:57]3[CH:66]=[CH:65][C:64]4[C:63]([CH3:68])([CH3:67])[CH2:62][CH2:61][C:60]([CH3:70])([CH3:69])[C:59]=4[CH:58]=3)=[O:48])([CH2:42][CH2:43]1)[O:40][C:39]2=[O:72].[CH3:73]COC(C)=O>CCCCCC>[CH3:1][C:2]12[C:8]([CH3:9])([CH3:10])[C:5]([C:11]([O:13][CH2:14][C@H:15]3[C@H:17]([CH2:18][O:19][CH2:20][CH3:37])[C@@:16]3([CH3:35])[C:21]3[CH:30]=[CH:29][C:28]4[C:27]([CH3:32])([CH3:31])[CH2:26][CH2:25][C:24]([CH3:34])([CH3:33])[C:23]=4[CH:22]=3)=[O:12])([CH2:6][CH2:7]1)[O:4][C:3]2=[O:36].[CH3:37][C:38]12[C:44]([CH3:45])([CH3:46])[C:41]([C:47]([O:49][CH2:50][C@@H:51]3[C@@H:53]([CH2:54][O:55][CH2:56][CH3:73])[C@:52]3([CH3:71])[C:57]3[CH:66]=[CH:65][C:64]4[C:63]([CH3:68])([CH3:67])[CH2:62][CH2:61][C:60]([CH3:70])([CH3:69])[C:59]=4[CH:58]=3)=[O:48])([CH2:42][CH2:43]1)[O:40][C:39]2=[O:72]
Reactant: COC[C@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(C)=O
Reactant: COC[C@@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Solvent: CCCCCC
Product: CCOC[C@@H]1[C@@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: CCOC[C@H]1[C@H](COC(=O)C23CCC(C)(C(=O)O2)C3(C)C)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 42 %
Yield: 42 %

Procedure:
Following a procedure similar to that for the preparation of Intermediates 8a and 9a but using intermediate 7b as the starting material and 10% EtOAc in hexane as normal phase HPLC eluent afforded Intermediate 10b (49 mg, 42% yield) and Intermediate 11b (48 mg, 42% yield) from 7b as colorless oils:
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])(O)=[O:2].Cl.[CH2:29]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.C(Cl)CCl>CN(C=O)C>[CH2:29]([O:36][C:37](=[O:42])[C@H:38]([CH2:40][OH:41])[NH:39][C:1](=[O:2])[CH:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][Si:18]([CH:19]([CH3:21])[CH3:20])([CH:25]([CH3:26])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[CH:15][CH:16]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C(=O)O
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)CC(Cc1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1)C(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Yield: 0.1 %

Procedure:
To a solution of methyl (±)-3-carboxy-4-[4-(triisopropylsilyloxy)phenyl]butanoate (5.00 g, 12.67 mmole) in dry DMF (60 mL) at RT was added serine benzyl ester hydrochloride (3.52 g, 15.21 mmole), HOBt (2.06 g, 15.21 mmole), Et3N (5.3 mL, 38.01 mmole), and EDC (2.92 g, 15.21 mmole). After 18 hr the mixture was concentrated. The residue was chromatographed on silica gel (80% EtOAc/hexanes) to give the title compound (5.76 mg, 79%) as a pale yellow oil: MS (ES) m/e 572 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17]Cl)[CH:5]=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccncc1
Reactant: Fc1cccc(-n2c(CCl)nc3ccccc32)c1
Solvent: CCO
Product: Fc1cccc(-n2c(CNc3ccncc3)nc3ccccc32)c1
Yield: 20.5 %

Procedure:
A ethanol (8 ml) solution of 1-(3-fluorophenyl)-2-chloromethylbenzimidazole (1.0 g, 4 mmol) prepared in the preceding step (b) and 4-aminopyridine (1.3 g, 7.4 mmol) was refluxed for 1.5 hours. The reaction mixture was concentrated in vacuo and crystallized from acetone and recrystallized from ethanol-acetone, then the objective compound (0.3 g, 0.82 mmol) was obtained.
Reaction SMILES: N1C2C(=CC([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=CC=2)C=N1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[CH:26][CH:25]=1>>[CH3:33][Si:32]([C:31]#[C:30][C:27]1[CH:28]=[CH:29][C:24]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:25][CH:26]=1)([CH3:34])[CH3:35]
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]ncc3c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Yield: 67 %

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 62.4, except ((4-bromophenyl)ethynyl)trimethylsilane (compound 76.1, 850 mg, 3.36 mmol) was used in place of 5-bromo-1H-indazole to yield the title compound as a yellow oil (0.80 g, 67%).