Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][O:8][CH2:9][C:10]([O:12]C)=[O:11])=[O:6])[CH3:3].[OH-].[K+].Cl>CO>[CH3:3][C:2]([CH3:14])([O:4][C:5]([NH:7][O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6])[CH3:1]
Reactant: COC(=O)CONC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NOCC(=O)O

Procedure:
[(1,1-Dimethylethoxy)carbonyl]aminooxyacetic acid, methyl ester (18.0 g, 0.087 mole) and potassium hydroxide (7.4 g, 0.13 mole) were stirred in 60 ml of methanol for one hour at ambient temperatures. The mixture was neutralized with concentrated hydrochloric acid and evaporated to dryness in vacuo. The residue was taken up in 100 ml of water and acidified to pH 2.5. Extraction with ethyl acetate, drying over magnesium sulfate and evaporation gave the title compound as 6.8 g of a colorless solid, m.p. 95°-98° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH:9]=2)=[CH:6][N:7]=1>CO.[Pd]>[NH2:1][C:2]1[C:3]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([F:24])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: COC(=O)c1ccc(-c2nc(C3=CNCCC3)cnc2N)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2nc(C3CCCNC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To methyl 4-(3-amino-6-(1,4,5,6-tetrahydropyridin-3-yl)pyrazin-2-yl)-2-fluorobenzoate (115 mg, 0.350 mmol) in MeOH (10 mL) was added Pd/C (93 mg, 0.088 mmol). The reaction mixture was stirred at room temperature for 24 h under H2 balloon. The reaction mixture was filtered through Celite and washed with DCM. The filtrate was evaporated and dried to yield the desired product. The crude product was proceeded for the next step (115 mg, 95%). LCMS (m/z): 331.2 (MH+), 0.492 min.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21]2[C:22]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[C:18]([CH:19]=[O:20])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1>CO>[F:3][C:4]1[CH:5]=[C:6]([C:21]2[C:22]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[C:12]2[C:18]([CH2:19][OH:20])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1
Reactant: CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]cc(C=O)c3c2)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]cc(CO)c3c2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 (4.45 mg, 0.13 mmol) was added to 3′-fluoro-4′-(3-formyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methyl-[1,1′-biphenyl]-2-sulfonamide (18 mg, 0.044 mmol) in MeOH (0.52 mL). The mixture was stirred at rt for 1 h and then concentrated to dryness. The residue was subjected to FCC purification to give the title compound. MS (ESI): mass calcd. for C21H18FN3O3S, 411.11; m/z found, 412.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 9.36 (s, 1H), 8.34 (s, 1H), 8.23 (dd, J=7.9, 1.2, 1H), 8.12 (s, 1H), 7.68-7.61 (m, 1H), 7.61-7.54 (m, 1H), 7.42-7.30 (m, 5H), 5.21 (s, 1H), 4.88 (s, 2H), 2.52 (dd, J=13.9, 5.3, 3H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.CCOC(/N=N/C(OCC)=O)=O.[CH2:37]([O:39][C:40](=[O:60])[C@@H:41]([OH:59])[CH2:42][CH2:43][C:44]1[C:45](O)=[N:46][C:47]([NH:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)=[N:48][C:49]=1[OH:50])[CH3:38]>CN(C=O)C>[OH:50][C:49]1[C:44]2[CH2:43][CH2:42][C@H:41]([C:40]([O:39][CH2:37][CH3:38])=[O:60])[O:59][C:45]=2[N:46]=[C:47]([NH:51][CH:52]2[CH2:57][CH2:56][O:55][CH2:54][CH2:53]2)[N:48]=1
Reactant: CCOC(=O)[C@@H](O)CCc1c(O)nc(NC2CCOCC2)nc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CCc2c(O)nc(NC3CCOCC3)nc2O1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
A flask was charged with PPh3 (0.807 g, 3.08 mmol), anhydrous THF (20 mL) and DEAD (0.655 g, 3.08 mmol). The solution was stirred for 10 min under N2 then a solution of 400, THF (5 mL) and DMF (5 mL) was added and solution stirred 18 h. The solution was concentrated in vacuo to afford an orange oil. The crude product was purified by reverse phase chromatography (SP4 biotage 40M C18 using a C18 Biotage 40 samplet) and eluted with a MeCN/H2O gradient (0-60% MeCN) to afford a light yellow oil which solidified under high vacuum. The crude product was re-purified by SiO2 chromatography (SNAP 25) eluting with DCM/MeOH (95:5) to afford 0.42 g (60%) of Obtained (R)-ethyl 4-hydroxy-2-(tetrahydro-2H-pyran-4-ylamino)-6,7-dihydro-5H-pyrano[2,3-d]pyrimidine-7-carboxylate (402) as a clear oil: m/z (APCI-pos) M+1=324.0
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([O:35]CC5C=CC=CC=5)=[C:30]([NH:32][CH:33]=[O:34])[CH:31]=4)[OH:25])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd]>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][CH2:21][NH:22][CH2:23][C@@H:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:35])=[C:30]([NH:32][CH:33]=[O:34])[CH:31]=4)[OH:25])[CH:17]=[CH:18][CH:19]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=CNc1cc([C@@H](O)CNCCc2cccc(OCCC34CC5CC(CC(C5)C3)C4)c2)ccc1OCc1ccccc1
Agent: [Pd]
Product: O=CNc1cc([C@@H](O)CNCCc2cccc(OCCC34CC5CC(CC(C5)C3)C4)c2)ccc1O

Procedure:
Obtained from Intermediate 61 (0.8 g, 1.41 mmol) and palladium on charcoal (10%, 0.15 g) by the same procedure described in Example 1 (reaction time: 3 hours). The crude was purified by column chromatography with silica gel, eluting with methylen chloride/methanol (from 98:2 to 9:1) and the title compound was obtained as a solid (0.32 g, 47%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][C:10](=[O:15])[NH:11][C:12](=[O:14])[CH2:13]2)=[CH:6][C:7]=1[Br:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CC(=O)NC(=O)C2)cc1
Solvent: ClCCl
Product: Nc1ccc(C2CC(=O)NC(=O)C2)cc1Br
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A solution of 106 mg (0.519 mmol) of 4-(4-amino-phenyl)-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (20 mL) was cooled to 0° C. and treated with 92.4 mg (0.519 mmol) of NBS for 35 min. The mixture was diluted with CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (2×40 mL) and water (1×40 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford 138 mg (94%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C11H11N2O2Br, 283.0/285.0 (M+H). found 283.1/285.1.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: BrCc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of 4-iodo-benzyl bromide (9.04 g, 30.4 mmol) in DMF (316 mL) was added phthalimide (4.47 g, 30.4 mmol) and cesium carbonate (14.86 g, 45.6 mmol). The reaction stirred at room temperature overnight under nitrogen atmosphere. The next day, the reaction mixture was quenched with water. The product precipitated from the quenched reaction mixture and was filtered off, washed with water, and collected as a white solid (9.5 g, 86% yield). 1H NMR (600 MHz, CDCl3): δ 7.84 (m, 2H), 7.71 (m, 2H), 7.63 (d, 2H, J=8.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 4.77 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 168.1, 138.0, 136.2, 134.3, 132.2, 130.8, 123.6, 93.7, 41.3.
Reaction SMILES: C[N:2]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=[CH:15][N:14]=1)[C:3](=O)OC(C)(C)C.[C:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=O)[CH2:35][CH3:36]>>[CH3:3][NH:2][CH2:10][CH2:11][CH2:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:35][CH3:36])=[CH:17][CH:18]=1
Reactant: CN(CCCc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cn1)C(=O)OC(C)(C)C
Reactant: CCC(=O)c1ccccc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(CCCNC)nc1)c1ccccc1
Yield: 19.5 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, tert-butyl methyl(3-(5-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)pyridin-2-yl)propyl)carbamate (100 mg, 0.22 mmol) was reacted with propiophenone (88 mg, 0.66 mmol) to give 16 mg desired product (20% yield, Z/E=1/1). m/z=373[M+1]+.
Reaction SMILES: [C:1]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].B#B>CCCCCC>[CH2:1]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Nc1ccccc1
Agent: B#B
Solvent: CCCCCC
Product: CCCCCCCCCCCCNc1ccccc1

Procedure:
N-dodecylaminobenzene was prepared from the N-dodecanoylaminobenzene of (a) by reduction with diborane by a procedure similar to that of Example 1(b). A yield of 74% of white crystals from hexane, m.p. 26.7°-27.2° C. was obtained.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1)[CH3:5].C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[I:12][C:9]1[CH:8]=[CH:7][C:6]([CH:4]([NH:3][O:2][CH3:1])[CH3:5])=[CH:11][CH:10]=1
Reactant: CON=C(C)c1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CONC(C)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
To a stirred solution of 1-(4-iodo-phenyl)-ethanone O-methyl-oxime (2.17 g, 7.83 mmol) in glacial acetic acid (22 ml), Sodium cyano borohydride (1.54 g, 24.39 mmole) was added portion wise at 15° C. and stirred for 12 hours at ambient temperature. Acetic acid was removed by distillation. The resulting reaction mass was basified with 10% aq. NaOH solution at 10-15° C. Aqueous layer was extracted with EtOAc (3×30 ml). The combined organic layer was washed with brine (2×30 ml) and dried over sodium sulfate. The organic layer was concentrated under vacuum to give pale yellow liquid, which was purified by chromatography to afford 2.1 g (96% of theory) of N-[1-(4-Iodo-phenyl)-ethyl]-O-methyl-hydroxylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=C)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CC([OH:26])C>O.O=[Os](=O)(=O)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH2:20][CH:21]=[O:26])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C=CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)O
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCOC(=O)C1(CCC=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 6 h

Procedure:
4-But-3-enyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (13.5 g, 43.48 mmol, 1 eq) was dissolved in i-PrOH (217 mL) and a solution of NaIO4 (20.23 g, 94.6 mmol, 2.18 eq) in 217 mL of water was added followed by OsO4 (37 mg, 0.144 mmol, 0.003 eq). The reaction mixture was vigorously stirred for 6 h. The reaction mixture was then quenched with 1500 mL of water, transferred to a separatory funnel and extracted with ethyl acetate (3×200 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (300 g column, 30% EtOAc in heptanes; 50 mL/min). This affords 8.5 g (63%) of the title compound as a beige oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]2)[CH:7]=1.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccn(Cc2cc(Cl)ccc2OCc2ccccc2)n1
Temperature: 85 °C

Procedure:
1-({5-Chloro-2-[(phenylmethyl)oxy]phenyl}methyl)-3-nitro-1H-pyrazole (for a preparation see Intermediate 54)(159 mg, 0.46 mmol) was dissolved in ethanol (10 ml). Stannous chloride (hydrated) (522 mg, 2.31 mmol) was added and the reaction was stirred and heated to 85° C. overnight under nitrogen. The reaction mixture was treated with saturated aqueous sodium bicarbonate solution. The mixture was partitioned between water and ethyl acetate. The mixture was filtered to remove the solid tin residues. The ethyl acetate layer was separated, and the aqueous layer was extracted with further ethyl acetate (2×50 ml). The combined organic fractions were concentrated in vacuo to give the title compound as an off-white solid (156 mg);
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][C@@H:17]([CH3:20])[NH:16][C:15](=[O:21])[C@H:14]1[CH3:22])=[O:12])=O)(C)(C)C.[ClH:33]>O1CCOCC1>[ClH:33].[NH2:8][C@H:9]([CH2:23][C:24]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=1[F:32])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][C@@H:17]([CH3:20])[NH:16][C:15](=[O:21])[C@H:14]1[CH3:22])=[O:12]
Reactant: C[C@@H]1CCN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)[C@H](C)C(=O)N1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CCN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)[C@H](C)C(=O)N1

Procedure:
A solution of (3R,7R)-4-[(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3,7-dimethyl-1,4-diazepan-2-one (175 mg, 0.38 mmol) in 4 mL of 4N hydrogen chloride in dioxane (4 mL, 4N) was stirred for 2 h and concentrated. The residue was dried under vacuum overnight to yield the title compound as a white solid. MS 358.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[NH:5][C:6](=[O:14])[C:7](=[N:12][OH:13])[CH2:8][CH:9]([CH3:11])[CH3:10].[H-].[Na+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)[NH:5][C:6](=[O:14])[C:7](=[N:12][O:13][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:8][CH:9]([CH3:10])[CH3:11]
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@H](Cc1cc(OC)c(OC)c(OC)c1)NC(=O)C(CC(C)C)=NO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1cc(OC)c(OC)c(OC)c1)NC(=O)C(CC(C)C)=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.50 g of N-(2-hydroxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine methyl ester in dried dimethylformamide (150 ml) was added 0.9 g of sodium hydride (60%), and the mixture was stirred at room temperature for 1 hour. Then 2.75 ml of benzyl bromide was added to the reaction mixture and further stirred at room temperature for 2 hours. The reaction mixture was transferred to an aqueous solution saturated with ammonium chloride under an ice-cooling condition, then was extracted with ethyl acetate. The organic layer was washed with an aqueous solution saturated with sodium chloride in three times, and was dried with magnesium sulfate, and the solvent was removed by distillation, the resulting residue was purified by means of a silica gel column chromatography (eluent: ethyl acetate:n-hexane=l:3) to obtain 8.35 g of N-(2-benzyloxyimino-4-methylpentanoyl)-(3,4,5-trimethoxy)phenylalanine methyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][NH2:9])[N:5]=[CH:4][N:3]=1.[N:10]1([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1>O>[NH:8]([C:6]1[CH:7]=[C:2]([N:18]2[CH2:19][CH2:20][CH:15]([N:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:16][CH2:17]2)[N:3]=[CH:4][N:5]=1)[NH2:9]
Reactant: NNc1cc(Cl)ncn1
Reactant: c1cc(N2CCCC2)ccn1
Solvent: O
Product: NNc1cc(N2CCC(N3CCCC3)CC2)ncn1

Procedure:
A mixture of 2.0 g (13.8 mmol) of the compound from Example 7A and 4.3 g (27.7 mmol) 4-pyrrolidin-1-ylpyridine is stirred in 20 ml water at 100° C. for 16 h. The solid which has precipitated out is filtered off, washed first with ethanol and then with diethyl ether and dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCc2c(Br)cc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc(Br)c2c(c1)C(=O)NC2
Yield: 100 %

Procedure:
A mixture of Example 104B (103 mg, 0.45 mmol), Cs2CO3 (164 mg, 0.5 mmol) and t-butyl bromoacetate (0.075 mL, 0.5 mmol) in DMF (2.2 mL) was stirred overnight at room temperature, diluted with water, and filtered. The filter cake was dried to give 154 mg (45%) of the desired product. MS (ESI(+)) m/e 342,344 (M+H)+.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OC([N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O)=O)(C)(C)C.Br[C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[C:27]([NH:38][C:39]([C:41]2[CH:42]=[N:43][CH:44]=[C:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:46]=2)=[O:40])[CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:47]1([C:45]2[CH:46]=[C:41]([C:39]([NH:38][C:27]3[CH:26]=[C:25]([C:17]4[NH:16][CH:20]=[CH:19][CH:18]=4)[CH:37]=[CH:36][C:28]=3[C:29]([OH:31])=[O:30])=[O:40])[CH:42]=[N:43][CH:44]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(-c2ccc[nH]2)ccc1C(=O)O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Tripotassium phosphate (0.12 g), 1-(tert-butoxycarbonyl)-1H-pyrrole-2-boronic acid (56 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1 mg), and palladium(II) acetate (1 mg) were added to a toluene (3.0 mL) solution of tert-butyl 4-bromo-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g), followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and tripotassium phosphate (47 mg), 1-(tert-butoxycarbonyl)-1H-pyrrole-2-boronic acid (47 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1 mg), and palladium(II) acetate (1 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Dioxane (1.5 mL), methanol (1.5 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.29 mL) were sequentially added to the obtained residue, followed by stiffing at 50° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were sequentially added thereto. The solid substance was collected by filtration to obtain 39 mg of 2-(5-phenylpyridine-3-carboxamido)-4-(1H-pyrrol-2-yl)benzoic acid as a white solid.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=O)=O)C.C(=O)(O)O.[NH2:21][C:22]([NH2:24])=[NH:23]>C1(C)C(C)=CC=CC=1>[NH2:23][C:22]1[NH:24][C:4](=[O:3])[C:6]2[CH2:15][CH2:14][C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=2[N:21]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CCc2ccccc2C1=O
Agent: O=C(O)O
Solvent: Cc1ccccc1C
Product: Nc1nc2c(c(=O)[nH]1)CCc1ccccc1-2
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A mixture of 2-ethoxycarbonyl-1-tetralone (0.65 g) and guanidine carbonate (0.65 g) in xylene (15 ml) was refluxed overnight and, after cooling to room temperature, the tan solid was collected by filtration, washed with water and alcohol, and then dried to yield 0.24 g of tan solid, m.p.>300° C. The solid was dissolved in Con.-HCl, concentrated in vacuo to dryness, and recrystallized from ethanol to yield a colorless solid product, (0.28 g).
Reaction SMILES: BrC1C=C([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[N:21][C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[C:13]3[C:12]([CH2:29][CH3:30])=[CH:11]2)C=CC=1C#N.NC1CCN(C)CC1.C(C1C2C(=NC=CC=2C2C=NC3C(C=2)=CC=CC=3)N([C:60]2[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[C:62]([NH:68][CH:69]3[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]3)[CH:61]=2)C=1)C>>[CH2:29]([C:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([C:61]2[C:62]([NH:68][CH:69]3[CH2:74][CH2:73][N:72]([CH3:75])[CH2:71][CH2:70]3)=[C:63]([CH:66]=[CH:67][CH:60]=2)[C:64]#[N:65])[CH:11]=1)[CH3:30]
Reactant: CCc1cn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3cnc4ccccc4c3)c12
Reactant: CCc1cn(-c2ccc(C#N)c(NC3CCN(C)CC3)c2)c2nccc(-c3cnc4ccccc4c3)c12
Agent: CN1CCC(N)CC1
Product: CCc1cn(-c2cccc(C#N)c2NC2CCN(C)CC2)c2nccc(-c3cnc4ccccc4c3)c12
Yield: 62 %

Procedure:
According to Example 1(6), a crude product of 4-{(3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}-2-(1-methylpiperidin-4-ylamino)benzonitrile was prepared using compound (41h) instead of compound (1e) and using 4-amino-1-methylpiperidine instead of trans-aminocyclohexanol and was used in the subsequent reaction without being purified. According to Example 1(7), compound (71) (the second stage yield: 62%) was prepared as a white solid using 4-{3-ethyl-4-(quinolin-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl}-2-(1-methylpiperidin-4-ylamino)benzonitrile instead of compound (1f).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=3[CH3:19])[C:6]=2[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=1.C[O:27][B:28](OC)[O:29]C>>[Cl:18][C:14]1[C:13]([CH3:19])=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:7]1[C:6]2[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:3]=[C:2]([B:28]([OH:29])[OH:27])[C:10]=2[N:9]=[CH:8]1
Reactant: Cc1c(Cl)cccc1Cn1cnc2c(Br)cc(N3CCOCC3)cc21
Reactant: COB(OC)OC
Product: Cc1c(Cl)cccc1Cn1cnc2c(B(O)O)cc(N3CCOCC3)cc21

Procedure:
The titled compound was prepared from 4-(4-bromo-1-(3-chloro-2-methylbenzyl)-1H-benzo[d]imidazol-6-yl)morpholine (400 mg, 0.951 mmol) using Method A with trimethylborate to give the product (23 mg, 6%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.41 (s, 3H) 3.12-3.18 (m, 4H) 3.82-3.90 (m, 4H) 5.61 (s, 2H) 6.89 (d, J=7.07 Hz, 2H) 7.17 (t, J=7.83 Hz, 1H) 7.27 (d, J=2.27 Hz, 1H) 7.42 (d, J=8.08 Hz, 1H) 8.39 (s, 1H); LC/MS: MS (ES+) m/e 386 [M+H]+.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[S:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=C(C)C=1>[CH3:16][C:13]1[S:12][C:11]2[CH:10]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:1][C:15]=2[CH:14]=1
Reactant: CCOC(=O)C(=Cc1ccc(C)s1)N=[N+]=[N-]
Solvent: Cc1cccc(C)c1
Product: CCOC(=O)c1cc2sc(C)cc2[nH]1
Yield: 85.9 %

Procedure:
Ethyl 2-azido-3-(5-methylthiophen-2-yl)acrylate (3.38 g) was dissolved in m-xylene (30 mL) and the mixture was heated at reflux for 1 hour. The reaction solution was concentrated under reduced pressure. To the residue was added n-hexane and the residue was washed with n-hexane. The solid was collected by filtration, and dried under reduced pressure to give the title compound (2.56 g).