Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].I[C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.N1CCCCC1>[NH:10]1[CH2:9][CH2:8][CH2:3][CH:2]([C:6]2[CH:12]=[CH:11][C:9]([NH:10][CH2:12][C:6]#[CH:7])=[CH:8][CH:7]=2)[CH2:1]1
Reactant: C#CCBr
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: C#CCNc1ccc(C2CCCNC2)cc1
Temperature: 0 °C
Yield: 15 %

Procedure:
Under nitrogen gas, to a pre-cooled (0° C., ice-bath) flask containing 400 mL piperidine, a number of reagents were added, including 14.2 mL of propargyl bromide (80 wt. % solution in toluene, 127 mmol), 22.0 g of 4-iodoaniline (100 mmol), 1.4 g of tetrakis(triphenylphosphine)palladium O) (1.2 mmol) and 200 mg copper(I) iodide (1.05 mmol). The mixture was heated for 18 h (40-45° C., oil bath temperature). The reaction mixture was filtered through Celite and the solvent (piperidine) was removed. The crude solid was redissolved with 125 mL AcOEt. The acetate solution was extracted with water (2×450 mL) and dried with brine (2×250 mL). Flash column chromatography on aluminum oxide (Brockmann I, basic, Aldrich #19,944-3, CH2Cl2) supplied 4-(3-piperidinyl)-propargyl-aniline as a light yellow solid (3.1 g; yield: 15%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:18][C:19](=[O:20])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(CC(=O)O)cc1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2)cc1

Procedure:
4-Phenylureidophenylacetic acid was prepared using procedure C with 4-amino-phenylacetic acid and phenyl isocyanate: 1H NMR (CD3SOCD3, 300 MHz, ppm) 8.72-8.64 (m, 2H), 7.44 (d, 2H), 7.36 (d, 2H), 7.28 (d, 2H), 7.16 (d, 2H), 6.96 (t, 1H), 3.52 (s, 2H); m/z 272.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11](OS(C(F)(F)F)(=O)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3c(OC(C)C)n2)n[nH]1
Reactant: C1COCCN1
Product: Cc1cc(Nc2cc3cc(N4CCOCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in the example 363 was used, starting from Trifluoro-methanesulfonic acid 1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl ester and Morpholine to give 5 mg of (1-Isopropoxy-6-morpholin-4-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine as a yellow solid. LC-MS m/e 368 (MH+).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>ClCCl>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
2.1 ml of 2,2,2-trifluoroethanol and 4.4 ml of triethylamine were added to 100 ml of dichloromethane, and 5.0 g of p-toluenesulfonyl chloride in batches under ice-bath condition. Upon the end of the addition, the mixture was warmed to room temperature and stirred overnight. The mixture was washed with water and then with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and distilled to remove the solvent to obtain 5.9 g of light yellow oily liquid, yield 98.7%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=O)=[CH:14][CH:13]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:11][C:12]1[N:17]=[CH:16][C:15](/[C:18](/[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:1](\[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)/[CH2:2][CH3:3])=[CH:14][CH:13]=1
Reactant: CCC(=O)c1ccccc1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Temperature: 80 °C
Yield: 41 %

Procedure:
To a stirred mixture of Zn powder (8.06 g, 6 eq) in dry THF at rt under N2 was slowly added TiCl4 (6.8 mL, 3 eq). The resulting mixture was heated to 80° C. and refluxed for 1 h. After cooling to rt, a mixture of propiophenone (8.2 g, 3.0 eq) and (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (6.5 g, 1.0 eq) in dry THF was added. The resulting mixture was refluxed for additional 2 h, then quenched with saturated aq. Na2CO3 solution, extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give a Z/E mixture of the product (6.3 g, 92%, Z/E=1/1). The Z/E mixture was recrystallized in petroleum ether/CH2Cl2 to give the pure Z-isomer (2.8 g, 41% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.06-7.25 (m, 8H), 6.97 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 2H), 2.51 (q, J=7.6 Hz, 2H), 0.94 (t, J=7.6 Hz, 3H); m/z=336 [M+1]+.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]1[C:44]2[CH:43]([C:45](O)=[O:46])[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][CH:33]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:45]([CH:43]1[C:44]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:46])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(O)C1c2ccccc2-c2ccccc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Product: O=C(C1c2ccccc2-c2ccccc21)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Yield: 83.3 %

Procedure:
200 mg (0.467 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted in analogy to Example 4a with 78 mg (0.562 mmol) of 9-fluorene carboxylic acid, 143 mg (0.561 mmol) of bis-(2-oxo-3-oxazolidinyl)phosphinic chloride and 144 μl (1.03 mmol) of triethylamine. The title compound (241 mg, 82%) is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.58, FD-MS: M+ =619.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)[CH3:22]>>[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:8]1[C:7]2[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=2[C:5]2[C:4]3[CH:3]=[C:2]([OH:1])[CH:14]=[CH:13][C:12]=3[NH:11][C:10]=2[CH:9]=1)[CH3:22]
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CCc1ccccc1B(O)O
Product: CCc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 69 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-ethylbenzeneboronic acid according to the procedure described in example 8 gave 4-(2-Ethylphenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (501) (I; Ar=2-ethylphenyl) in a 69% yield; mp (MeOH/CH2Cl2/hexane) 273–275° C. 1H NMR [(CD3)2SO] δ 11.73 (br s, 1H), 10.95 (br s, 1H), 9.25 (s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.44 (s, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.36 (td, J=7.2, 1.5 Hz, 1H), 7.33 (dd, J=8.1, 2.2 Hz, 1H), 7.25 (td, J=7.0, 1.8 Hz, 1H), 7.20 (dd, J=7.5, 1.2 Hz, 1H), 7.07 (dd, J=8.7, 2.5 Hz, 1H), 2.42 (m, 2H), 0.96 (t, J=7.6 Hz, 3H). Found: C, 73.83; H, 4.46; N, 7.82. C22H16N2O3 requires C, 74.15; H, 4.53; N, 7.86.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.Cl>[CH2:28]([O:27][C:25]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][C:7]=2[CH2:8][CH2:9]1)=[O:26])[CH3:29]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Example 36, step (a) (5 g, 26.0 mmol) dissolved in DCM (75 ml), DIEA (6.8 ml, 39 mmol) was added. The reaction mixture was cooled to 0° C. and ethyl chloroformate was added (3.0 ml, 31.2 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature. The reaction mixture was diluted with 2N HCl (150 ml) and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 50% EtOAc in hexane) gave the sub-title compound as a light yellow solid (4.7 g). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=2.4 Hz, 1H); 8.01 (dd, J=8.1 Hz, 2.4 Hz, 1H); 7.45 (d, J=8.1 Hz, 1H); 4.07 (q, J=6.9 Hz, 2H); 3.54-3.51 (m, 4H); 3.04-3.01 (m, 4H); 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:33][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]([CH3:15])=[C:13]2[CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:32])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH3:31])[CH2:18][CH2:17]1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3ccccc3OC)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1NC(=O)N1CCC(c2c(C)c(CC(=O)O)cc3ccc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (107.6 mg, 0.232 mmol) in THF (8.0 mL) was added a solution of lithium hydroxide monohydrate (111.1 mg, 2.6 mmol) in water (2.0 mL) at room temperature. The resulting solution was stirred overnight at room temperature under a nitrogen atmosphere. The solvent was evaporated. Water (˜25 mL) was added and the mixture was acidified with 1.0 N aqueous HCl (4.6 mL). The resulting white precipitate was collected by filtration and dried under high vacuum to provide {6-fluoro-4-[1-(2-methoxy-phenylcarbamoyl)-piperidin-4-yl]-3-methyl-naphthalen-2-yl}-acetic acid (86.4 mg, 83%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.45 (b. s, 1H), 7.90 (dd, J=9.23, 6.59 Hz, 1H), 7.78 (br. s., 1H), 7.65-7.72 (m, 2H), 7.35 (t, J=8.01 Hz, 1H), 6.99-7.06 (m, 2H), 6.86-6.95 (m, 1H), 4.23 (m, 2H), 3.82 (s, 3H), 3.78 (br. s., 2H), 3.32 (br. s., 3H), 3.09 (br. s., 2H), 2.43 (s, 3H), 1.66 (m, 2H). MS cald. for C26H28FN2O4 [(M+H)+]: 451, obsd. 451.2.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Nc1cnccn1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cnccn2)c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 13.7 %

Procedure:
To a stirred solution of 75 mg (0.261 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 37 mg (0.392 mmol) of aminopyrazine was added. The resulting mixture was stirred at room temperature during 3 days and the final product was collected by filtration and washed with diethylether to yield the title compound (12 mg, 13.6% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[I:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[I:27])[N:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: NCc1ccccc1I
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3ccccc3I)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.1 %

Procedure:
To a solution of {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (100 mg, 0.26 mmol) in a mixture of CH2Cl2 (2 mL) and DMF (1 mL) were added 2-iodobenzylamine (192 mg, 0.82 mmol) and DIPEA (135 μL, 1.04 mmoL). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The resulting residue was diluted with EtOAc and washed with water (×3) and then with brine. The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel preparative TLC using 98:2 CH2Cl2:MeOH as an eluent to afford 97 mg (64%) of (4-{[2-(2-iodo-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][NH:10][C:9](=[O:12])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>O1CCOCC1>[CH2:20]([O:19][C:17]([CH2:16][N:10]1[CH2:11][C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]1=[O:12])=[O:18])[CH3:21]
Reactant: O=C1C[C@H](c2ccccc2)CN1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)CN1C[C@@H](c2ccccc2)CC1=O
Temperature: 90 °C
Yield: 63.9 %

Procedure:
The solution of 4(R)-phenyl-2-pyrrolidinone (1) (345 mg, 2.14 mM) in 1,4-dioxane (30 ml) was added to the suspension of sodium hydride (56 mg, 2.35 mM) in 1,4-dioxane (30 ml). The mixture was heated at 80÷90° C. during 30 min and then cooled to room temperature. Ethyl bromoacetate (393 mg, 2.37 mM) was added and the reaction mixture was refluxed at 110÷120° C. for 6 hours. Obtained mixture was concentrated under reduced pressure. Residue was purified by column chromatography on silicagel with ethylacetate-hexane mixture 1:1, giving N-ethoxycarbonylmethyl-4(R)-phenyl-2-pyrrolidinone (3) (338 mg, 64%). [α]D20=+4.6° (c=3; MeOH). 1H NMR (CDCl3), δ: 1.28 (3H, t, CH2CH3); 2.59 (1H, d, d, 3-CH2); 2.87 (1H, d, d, 3-CH2); 3.54 (1H, t, 5-CH2); 3.64 (1H, quintet, 4-CH); 3.83 (1H, t, 5-CH2); 4.11 (2H, s, NCH2CO); 4.20 (2H, q, CH2CH3); 7.20-7.39 (5H, m, C6H5).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12]([Si:14]([C:19]#[CH:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:15]([Si:14]([C:12]#[C:13][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)([CH2:19][CH3:20])[CH2:17][CH3:18])[CH3:16]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C#C[Si](CC)(CC)CC
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc(C(=O)OC)nc1)(CC)CC
Temperature: 70 °C
Yield: 87.8 %

Procedure:
A glass microwave reaction vessel was charged with methyl 5-bromopyridine-2-carboxylate (0.95 ml, 6.94 mmol, Alfa Aesar), (triethylsilyl) acetylene (3.73 ml, 20.81 mmol, Sigma-Aldrich), tetrakis(triphenylphosphine) palladium (0.61 g, 0.527 mmol, Strem Chemicals), triethylamine (4.82 ml, 34.7 mmol, Sigma-Aldrich Chemical), and copper (I) iodide (0.04 ml, 1.040 mmol, Sigma-Aldrich). The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 70° C. for 30 min. The reaction mixture was filtered through celite and concentrated. The reaction mixture was diluted with saturated NH4Cl and extracted with EtOAc. The organic extract was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was adsorbed onto a plug of silica gel and chromatographed through a silica gel column, eluting with a gradient of 0% to 40% EtOAc in hexane, to provide methyl 5-((triethylsilyl)ethynyl)picolinate (1.68 g, 6.09 mmol, 88% yield). MS m/z [M+H]+=276.0. Calculated from C15H21NO2Si: 275.418
Reaction SMILES: [OH:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21]Br>C(#N)C>[N:5]1[N:6]2[C:2]([O:1][CH2:19][CH2:20][CH2:21]2)=[CH:3][C:4]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrCCCBr
Reactant: CCOC(=O)c1cc(O)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(n1)CCCO2
Temperature: 25 °C
Yield: 61.6 %

Procedure:
To the stirred suspension of ethyl 5-hydroxy-1H-pyrazole-3-carboxylate (10.34 g, 0.66 mol) and 36.62 g of potassium carbonate in 500 ml of acetonitrile was added 14.7 g of 1,3-dibromopropane, and refluxed for 16 hours. The reaction mixture was allowed to cool to room temperature, then filtered, the solid was washed with acetonitrile. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and extracted with water. The organic phase was dried over MgSO4 and evaporated to dryness. 8.80 g of the desired product was obtained (68%), m.p. 44-46° C. (M+H)+ 197.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: Oc1ncc(Br)cc1I
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A solution of 5-bromopyridin-2-ol (5.22 g, 30.0 mmol) and N-iodosuccinimide (7.42 g, 33.0 mmol) in acetonitrile (150 mL) was heated under reflux under a nitrogen atmosphere for 1 hr. After being allowed to cool to room temperature, the resulting solid was collected and washed with acetonitrile to give the title compound (7.07 g, yield 79%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH2:6][O:7]2.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]1[O:21][CH:5]1[CH2:6][O:7]2
Reactant: Fc1ccc(F)c2c1C=CCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(F)c2c1OCC1OC21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.9 %

Procedure:
5,8-Difluoro-2H-chromene (35 g, 0.21 mole) was dissolved in 500 ml DCM and MCPBA (77%, 93 g, 0.42 mole) was added. The reaction was stirred at room temperature for 30 minutes. 50 g Na2S2O3 in 500 ml water was added to quench the reaction. The organic layer was washed with 2N NaOH solution (2×500 ml), brine (200 ml), dried over Na2SO4 and concentrated. The residue was recrystallized from EtOAc/Hexane solution to give rise to 21.6 g pure product. The residue from mother liquor was purified by column chromatography (EtOAc/hexane from 0/100 to 25/75 in 55 minute, additional 1.4 g obtained). Total Yield: 23 g, 60%. 1H NMR (CDCl3 400 MHz δ 7.00 (m, 1H), 6.63 (m, 1H), 4.67 (d, J=12.4 Hz, 1H), 4.27 (m, 2H), 3.84 (d, J=4.4 Hz, 1H).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:17][C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([CH:24]([CH3:26])[CH3:25])[N:19]=1>C1C=CC=CC=1>[CH3:17][C:18]1[C:22]2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:8][C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[N:23][C:21]=2[N:20]([CH:24]([CH3:26])[CH3:25])[N:19]=1
Reactant: Cc1cc(N)n(C(C)C)n1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccncc1
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccncc2)nc2c1c(C)nn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 64 using ethyl 2,4-dioxo-4-(4-pyridinyl)butanoate (766 mg, 2.87 mmol), benzene (6 mL), and 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (400 mg, 2.87 mmol). The crude product was purified using column chromatography (Silica gel, eluent: 0 to 30% MeOH/DCM) to give 95 mg (10%) of product. LCMS E-S (M+H)=325.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48-1.56 (m, 3 H), 1.61-1.73 (m, 6 H), 2.77 (s, 3 H), 4.56 (q, J=7.2 Hz, 2 H), 5.37-5.50 (m, 1 H), 8.02-8.16 (m, 3 H), 8.76-8.83 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19](O)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([NH:26][CH2:27][CH2:28][N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) and dry tetrahydrofuran (100 ml) was stirred at room temperature for 2 hours with nitrogen bubbling through it. The reaction mixture was then heated at 55° C. for 2 hours under nitrogen and cooled to room temperature. A solution of N,N-dimethylethylenediamine (4.41 g, 0.050 mole) in tetrahydrofuran (5.5 ml) was added and the reaction mixture was stirred at room temperature under nitrogen over the weekend. The reaction mixture was evaporated to a white solid and triturated with water (100 ml). The solid was collected by filtration, rinsed once with a 5% potassium hydroxide solution, and washed twice more with water to give 4.9 g of a white solid (79%). A second crop of white solid was obtained from the mother liquor of the above solid. The second crop was dried under high vacuum at 70° C. to give a white solid, mp 141.5°-143° C.