Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:19](=[O:21])[CH3:20])[N:1]=[CH:2]1
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1-c1cnc[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of 2-(1H-imidazol-5-yl)aniline (18 mg, 0.113 mmol) in dichloromethane (3 mL) was added pyridine (47 μL, 0.339 mmol) and acetyl chloride (19 μL, 0.271 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-30% MeOH/DCM as eluent) to afford the desired product as a white solid (10 mg, 0.050 mmol, 44%). 1H NMR (MeOH-d4): 2.17 (s, 3H), 7.05-7.26 (m, 2H), 7.46 (s, 1H), 7.62 (d, 1H, J=7.8 Hz), 7.78 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCNCC4)ccc23)CC1
Yield: 97 %

Procedure:
A solution of 4-{2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (0.202 g, 0.385 mmol) in trifluoroacetic acid (5 ml) was stirred at 23° for 3 h. The solvent was evaporated in vacuo and the residue was triturated with ether to give the title compound as an off-white solid (0.228 g, 97%)
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[C:5](=[O:12])[N:4]2[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:3]=12.[CH3:18][Si](C=[N+]=[N-])(C)C>CO.CCOCC>[CH:9]([N:6]1[C:7](=[O:8])[C:2]([O:1][CH3:18])=[C:3]2[C:16](=[O:17])[NH:15][CH2:14][CH2:13][N:4]2[C:5]1=[O:12])([CH3:10])[CH3:11]
Reactant: CC(C)n1c(=O)c(O)c2n(c1=O)CCNC2=O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COc1c2n(c(=O)n(C(C)C)c1=O)CCNC2=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 9-hydroxy-7-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (1.0 g, 4.2 mmol) in MeOH (30 mL) was added trimethylsilyldiazomethane (7 mL of a 2.0 M solution in ether, 14 mmol). The mixture was stirred at ambient temperature for 24 h. The solvent was removed in vacuo and the residue was triturated in MeOH and the solid was collected by filtration to give the title compound as a solid. HPLC RT=2.07 min (Method A); ES MS (M+H)=254; 1H NMR (400 MHz, DMSO-d6) δ 8.64 (2, 1H), 5.03 (septet, J=7 Hz, 1H), 3.86 (m, 2H), 3.66 (s, 3H), 3.37 (m, 2H), 1.38 (d, J=7 Hz, 6H).
Reaction SMILES: [OH:1]O.[F:3][C:4]1([F:12])[CH2:7][CH:6]([CH2:8][N:9]([CH3:11])[CH3:10])[CH2:5]1.O=O>CO.O.[Pd]>[OH2:1].[F:3][C:4]1([F:12])[CH2:7][CH:6]([CH2:8][N+:9]([O-:1])([CH3:11])[CH3:10])[CH2:5]1
Reactant: OO
Reactant: CN(C)CC1CC(F)(F)C1
Agent: [Pd]
Agent: O=O
Solvent: CO
Solvent: O
Product: C[N+](C)([O-])CC1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30% Aqueous H2O2 (18 mL) was added dropwise to a stirred solution of 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine (12 g, 80 mmol) prepared in Part B in methanol (100 mL) at 5 to 22° C. over 2 h. After stirring at RT for 20 h, additional 30% H2O2 (18 mL) was added. After 3 h, Pd black slurry (150 mg) in water (3 mL) was added to the stirred reaction mixture in small portions such that the temperature could be maintained between 5 to 25° C. with a cooling bath. The reaction mixture was stirred at RT for 1 h until the O2 evolution ceased. After filtration, the filtrate was concentrated in vacuo to give 1-(3,3-difluorocyclobutyl)-N,N-dimethylmethanamine oxide hydrate as a thick colorless oil (15 g, semisolid). 1H NMR (400 MHz, CD3OD) δ ppm 3.47 (2H, d, J=5.29 Hz), 3.16 (6H, s), 2.75-2.92 (3H, m), 2.42-2.58 (2H, m).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1.[NH:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=[O:23].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:27]4\[NH:21][C:22](=[O:23])[NH:24][C:25]\4=[O:26])=[C:9]3[N:8]=[C:7]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)Nc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 35 %

Procedure:
To methyl 7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylcarbamate (33 mg, 0.12 mmol) in 1.0 mL ethanol was added hydantoin (12 mg, 0.12 mmol) and piperidine (11 ul). The reaction was heated at 80° C. for two hours. The reaction was cooled to room temperature, the yellow precipitate was filtered, and washed with ethanol to yield 15 mg (40% yield) (Z)-methyl 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylcarbamate. LCMS (M+1=358)
Reaction SMILES: C=O.[O:3]([CH2:10][C@@H:11]1[NH:16][CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:33](Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:33][N:16]1[CH2:15][CH2:14][N:13]([C:17]2[C:26]3[CH:25]=[C:24]([CH3:27])[S:23][C:22]=3[NH:21][C:20]3[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=3[N:18]=2)[CH2:12][C@@H:11]1[CH2:10][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(Cl)Cl
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](COc2ccccc2)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](COc2ccccc2)C1
Reaction time: 0.03 h
Yield: 63.3 %

Procedure:
Add aqueous 37% formaldehyde (1.1 eqiv) to a solution of (R)-10-(3-phenoxymethyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (520 mg) in dichloroethane (60 mL per 1 mmol non-alkylated starting material). Stir the mixture 2 minutes and add sodium triacetoxyborohydride (1.5 mmol per 1 mmol non-alkylated starting material). Stir the suspension for 30 minutes and quench with a saturated aqueous solution of sodium bicarbonate. Extract the aqueous phase 3 times with dichloromethane and combine the organic phases, dry over magnesium sulfate, filter and concentrate. Purify the residue via chromatography on silica gel (methylene chloride/methanol (90:10) to provide the title compound as a yellow solid (265 mg, 49%): mp 74-88° C.; 1H NMR (CDCl3) δ 2.28 (s, 3H), 2.47 (s, 3H), 2.50-2.39 (m, 1H), 2.66-2.58 (m, 1H), 2.91 (dt, 1H), 3.11 (dd, 1H), 3.26 (dt, 1H), 3.93 (bd, 1H), 4.14-4.03 (m, 3H), 4.91 (bs, 1H), 6.31-6.29 (m, 1H), 6.59 (dt, 1H), 7.00-6.86 (m, 5H), 7.03 (dd, 1H), 7.32-7.27 (m, 2H); MS (APCI) m/z (rel intensity) 419.3 (100).
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:39][N:40]([CH3:45])[CH2:41][C:42](O)=[O:43].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([C:28]4[N:29]=[C:30]([CH:33]5[CH2:38][CH2:37][N:36]([C:42](=[O:43])[CH2:41][N:40]([CH3:45])[CH3:39])[CH2:35][CH2:34]5)[S:31][CH:32]=4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncnn2c(-c3csc(C4CCNCC4)n3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(c2nc(-c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)cs2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.9 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(2-piperidin-4-yl-1,3-thiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.17 mmol), N,N-dimethylglycine (19 mg, 0.18 mmol), EDCl (36 mg, 0.19 mmol), HOBt (26 mg, 0.19 mmol), and N,N-diisopropylethylamine (90 μL, 0.52 mmol) in DMF (1.5 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 20 mg (20%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1 H), 8.37 (s, 1 H), 8.09 (s, 1 H), 7.82 (d, 1 H), 7.67 (s, 1 H), 7.26-7.39 (m, 5H), 7.16-7.23 (m, 2 H), 5.66 (s, 2 H), 4.40 (d, 1 H), 4.10 (d, 1 H), 3.01-3.23 (m, 3 H), 2.75 (t, 1 H), 2.18 (s, 6H), 2.06-2.15 (m, 3 H), 1.70 (q, 1 H), 1.53 (q, 1 H); ES-MS m/z 592.16 HPLC RT (min) 2.39.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH3:16])=[C:10]([C:12](=[O:15])[CH2:13]Br)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH2:13][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH3:16])=[O:15])[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(=O)CBr
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1[nH]c(-c2ccccc2)nc1C(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
10 Grams (0.036 mol) of 2-phenyl-4-(2-bromoethanoyl)-5-methyl-1H-imidazole and 8.5 grams (0.034 mol) of N-(diphenylmethyl)piperazine and 5 grams (0.036 mol) of potassium carbonate were added to 300 ml of ethanol. The mixture was refluxed under stirring overnight. After cooling, the salts were removed by filtration and the solvent was removed under reduced pressure. The residue was extracted by dichloromethane and washed twice with water. The organic layer was dried over sodium sulfate and evaporated. Trituration of the residue with ethanol gave a white precipitate, 1-diphenylmethyl-4-[2-(2-phenyl-5-methyl-1H-imidazol-4-yl)-2-oxoethyl]piperazine, which was used in the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]([N:19]1[C:23]2[N:24]=[C:25](F)[N:26]=[C:27]([O:28][C:29]3[C:34]([CH3:35])=[CH:33][C:32]([CH3:36])=[CH:31][C:30]=3[CH3:37])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]2[N:24]=[C:25]([NH:1][C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)[N:26]=[C:27]([O:28][C:29]3[C:30]([CH3:37])=[CH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])[C:22]=2[CH:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Oc2nc(F)nc3c2ccn3Cc2ccccc2)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3c2ccn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-aminobenzonitrile (101 mg, 0.86 mmol) in 1-methyl-2-pyrridone (1 mL) was added NaH (34 mg, 0.86 mmol). The reaction mixture was stirred at room temperature for 15 min and a solution of 7-benzyl-2-fluoro-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine (62 mg, 0.17 mmol) in 1-methyl-2-pyrridone (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h, poured into ice water, and extracted with EtOAc (2×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=75:25) yielded 64 mg (82%) of 4-[7-benzyl-4-(2,4,6-trimethyl-phenoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-benzonitrile.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH2:14](I)[CH2:15][CH3:16].[H-].[Na+].O>CN(C=O)C>[CH2:14]([O:1][CH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3])[CH2:15][CH3:16]
Reactant: CCCI
Reactant: COC(=O)c1ccc(C(C)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC(C)c1ccc(C(=O)O)cc1
Reaction time: 1 h

Procedure:
Methyl 4-(1-hydroxyethyl)benzoate (2.0 g) dissolved in DMF (30 ml) was mixed with propyl iodide (3.8 g), and then sodium hydride (50% in oil, 0.53 g) was added. After the end of the exothermic reaction, the mixture was stirred for 1 hour and then water was cautiously added. It was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was hydrolyzed by method P-a. This resulted in the product with the molecular weight of 208.26 (C12H16O3); MS (ESI): 209 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].[I-:14].[Na+].[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1>CC(=O)CC>[I-:14].[CH2:2]([N+:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([CH3:23])[CH:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cc1ccncc1C
Reactant: CCCCC#CCCCCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCC#CCCCCCC[n+]1ccc(C)c(C)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
12-Chloro-dodec-5-yne (1 mmol) was mixed with Sodium iodide (3 mmol) and 3,4-lutidine (3 mmol) in butanone. The mixture was refluxed for 3 days and cooled to room temperature, filtrated. The butanone was removed in vacuum, and the resulting residue was partitioned between water and ethyl ether. The aqueous layer was washed extensively with ether until no 3,4-lutidine was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (72%). 1HNMR, (300 MHz, CDCl3, ppm, ppm), 9.22 (s, 1H), 9.04 (d, 1H), 7.80 (d, 1H), 4.84 (t, 3H), 2.52 (s, 3H), 2.50 (s, 3H), 1.92-2.14 (m, 6H), 1.28-1.45 (m, 10H), 0.84 (t, 3H). 13CNMR, 157.84, 143.39, 141.81, 138.53, 128.72, 80.80, 79.90, 61.23, 32.03, 31.54, 29.08, 28.48, 25.91, 22.30, 20.78, 18.96, 18.79, 17.44, 14.02.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[CH2:35]([NH:37][C:38]([NH:40][C:41]1[CH:46]=[C:45]([C:47]2[S:48][CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[N:51]=2)[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1)=[O:39])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.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>[CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:44]3[CH:43]=[N:42][C:41]([NH:40][C:38](=[O:39])[NH:37][CH2:35][CH3:36])=[CH:46][C:45]=3[C:47]3[S:48][CH:49]=[C:50]([C:52]([F:55])([F:53])[F:54])[N:51]=3)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate (Intermediate 79, 400 mg, 0.68 mmol) in dimethylformamide (15 mL) was purged argon gas, then tetrakis(triphenylphosphine)palladium (69.25 mg, 0.06 mmol) followed by 1-ethyl-3-{5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}urea (Intermediate 17, 360 mg, 0.82 mmol) was added. The mixture was stirred at room temperature and sodium carbonate (217 mg, 2.05 mmol) which was dissolved in minimum amount of water was added and the reaction mixture was heated to 95° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was poured into water (200 mL) and stirred for 30 min. The obtained solid was filtered and dried to give the crude compound. The crude was purified by column chromatography eluting with a gradient of 30% ethyl acetate/petroleum ether to 60% ethyl acetate/petroleum ether to afford 260 mg (49%) of tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:17])([CH3:16])[CH:14]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]\[C:13]([CH3:17])([CH3:16])[CH3:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)C=O
Solvent: C1CCNC1
Solvent: CO
Product: CC(C)(C)/C=C1/C(=O)Nc2cc(Cl)ccc21

Procedure:
In a manner similar to the method described in example 1a, 6-chlorooxindole (0.88 g, 5 mmol) was reacted with 2,2-dimethyl-propionaldehyde (0.43 g, 5 mmol) (Aldrich), pyrrolidine (0.36 g, 5 mmol) in methanol to give a mixture of E- and Z-6-Chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one. Purification by chromatography (EtOAc:hexanes=1:2) led to E-6-chloro-3-(2,2-dimethyl-propylidene)-1,3-dihydro-indol-2-one as an off-white foam (Yield 0.82 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:43][C:44]#[N:45]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:43][C:44]#[N:45])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:30])[C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:17]1=[O:31])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: N#CCBr
Reactant: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](N(CC#N)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: -78 °C
Reaction time: 16 h
Yield: 27.7 %

Procedure:
A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide [Example 1] (0.01 g) in THF (2 ml) was cooled to −78° C. under nitrogen, and treated with lithium bis(trimethylsilyl)amide (1.0M solution in THF; 0.026 ml), followed by bromoacetonitrile (0.013 g). The resultant solution was allowed to reach room temperature and stirred for a further 16 h. The mixture was then cooled to −78° C. and further lithium bis(trimethylsilyl)amide (0.026 l) added. After reaching room temperature, the reaction mixture was stirred for a further 18 h and then quenched by the addition of methanol (1 ml). The resultant solution was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.003 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])=[S:18]
Reactant: Cc1ncoc1CSCCN
Reactant: CN(C)CCN=C=S
Product: Cc1ncoc1CSCCNC(=S)NCCN(C)C

Procedure:
5-[(2-Aminoethyl)thiomethyl]-4-methyloxazole is reacted with 2-dimethylaminoethyl isothiocyanate by the procedure of Example 1 to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH3:34])[C:16]=1[C:17]1[NH:18][C:19]2[CH:25]=[C:24]([C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:23]=[CH:22][C:20]=2[N:21]=1.[OH-].[Na+]>O>[CH:8]([C:14]1[NH:13][C:12]([CH3:11])=[C:16]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[C:15]=1[CH3:34])=[O:9]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1[nH]c(C=O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
Phosphoryl chloride (2.43 g) was slowly added dropwise to N,N-dimethylformamide (15.9 g) at room temperature, and stirred at room temperature for 30 minutes. To this mixture, an N,N-dimethylformamide solution of the 2-(2,4-dimethyl-pyrrol-3-yl)-5-benzoylbenzimidazole (2.5 g) obtained in Example 7 was slowly added dropwise. After stirring for 2 hours, 50 ml of a 1 N sodium hydroxide aqueous solution was added, heated to 80° C., and stirred for 2 hours. After the starting material was disappeared, reaction mixture was slowly added to water, and precipitate was collected by filtration. The solid was dried in vacuo to afford 2-(2-formyl-3,5-dimethyl-pyrrol-4-yl)-5-benzoylbenzimidazole (1.63 g, 60%) as a brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[CH3:2]
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)cc1CC1CCCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1CC1CCCCC1

Procedure:
A solution of (4-benzyloxy-2-cyclohexylmethylphenoxy)acetic acid ethyl ester (1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.II.[I:15](O)(=O)(=O)=O>CO>[CH3:12][O:11][C:1]([C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]=1[I:15])=[O:10]
Reactant: COC(=O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Solvent: CO
Product: COC(=O)c1[nH]c(=O)[nH]c(=O)c1I
Temperature: 25 °C
Yield: 546.9 %

Procedure:
Methyl orotate (20.0 g, 118 mmol) was combined with iodine (12.8 g, 50 mmol) and periodic acid (4.8 g, 21 mmol) in methanol (250 mL) and heated at reflux for 20 h. After cooling to ambient temperature, the volatiles were removed by rotary evaporation. The solid residue was slurried in water, collected by filtration, washed well with water and dried under vacuum at 70° C. to provide the title compound (34 g, 97% yield) as a solid. It was used without further purification. MS: m/z=296.