Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]([F:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24].CO.[C:27](=O)([O-:29])[O-:28].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:27]([OH:29])=[O:28])[N:8]([CH2:11][C:12]([F:15])([CH3:14])[CH3:13])[N:7]=[CH:6]2
Reactant: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(Br)cc21
Reactant: O=C([O-])[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reaction time: 17 h
Yield: 74.5 %

Procedure:
A solution of 6-Bromo-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole (15.9 g, 39.8 mmol) in 9:1 methanol:water (300 mL) was degassed for 10 min with an ultrasonic bath. Carbon monoxide gas was then bubbled through the solution for 2 min. To the resulting solution was added, successively, potassium carbonate (16.5 g, 119 mmol), 1,3-bis(diphenylphosphino)propane (0.82 g, 1.99 mmol), and palladium(II) acetate (0.45 g, 1.99 mmol). A balloon of CO with a purge valve was attached to the reaction flask, and the flask was evacuated and recharged five times with CO, and kept under balloon pressure of CO. The flask was heated in an oil bath set to 60° C. and stirred for 17 hr. The mixture was then cooled in an ice bath and acidified with 6M HCl to an apparent pH of <2. The resulting mixture was transferred to a separatory funnel and diluted with ether (500 mL) and water (250 mL). After shaking, the organic layer was stirred with activated charcoal (6 g) at ambient temperature for 15 min, then filtered through a glass microfiber filter to remove the charcoal and palladium residues. The filtrate was extracted with 1M NaOH (300 mL). The aqueous layer was stirred and acidified to pH<2 with conc. HCl. After stirring for a few minutes, a precipitate formed, which was collected by filtration, washed with water, and dried under vacuum to afford the title compound as a light tan powder (10.8 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][NH2:22])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=O)[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:19]([NH:21][N:22]1[C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]2[C:27]1=[O:32])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@@H](C(=O)NN)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)c2ccccc2C1=O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Yield: 44.2 %

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide and 0.41 g of phthalic anhydride in 50 ml of toluene was heated at reflux for 2 hours. The mixture was cooled and the solvent was evaporated and replaced with ethyl acetate. The ethyl acetate solution was washed with 2M aqueous hydrochloric acid, 5% aqueous sodium hydrogen carbonate and then with brine. The ethyl acetate phase was dried over anhydrous magnesium sulphate and the solvent was evaporated. The residue was trituated with diethyl ether to give 0.60 g of (E)-2(R)-[1(S)-(tertbutoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-N-phthalimidovaleramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])[CH:9]=[C:8]([C:23]([OH:25])=[O:24])[C:7]2=[O:26].[CH3:29][NH2:30]>>[CH3:9][NH2:10].[Cl:1][C:2]1[C:3]([NH:30][CH3:29])=[C:4]([F:27])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([F:19])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])[CH:9]=[C:8]([C:23]([OH:25])=[O:24])[C:7]2=[O:26]
Reactant: O=C(O)c1cn(-c2cc(O)c(F)cc2[N+](=O)[O-])c2c(Cl)c(F)c(F)cc2c1=O
Agent: CN
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(O)c(F)cc3[N+](=O)[O-])c2c1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 145.3 %

Procedure:
8-Chloro-6,7-difluoro-1-(4-fluoro-5-hydroxy-2-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg) was added to an aqueous solution (about 40%; 750 mg) of methylamine, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted 3 times repeatedly. Isopropyl alcohol (1.5 ml) was added to the resultant residue. Deposits were collected by filtration and washed with isopropyl alcohol and diisopropyl ether in that order to obtain the title compound (120 mg) as a yellow powder.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[N:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:8]=1)[CH3:5])([OH:3])=O.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>>[CH:22]1([NH:25][C:1]([CH:4]([O:6][C:7]2[N:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:8]=2)[CH3:5])=[O:3])[CH2:24][CH2:23]1
Reactant: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)O
Reactant: NC1CC1
Product: CC(Oc1ncn(-c2ccc(C(F)(F)F)cc2)n1)C(=O)NC1CC1

Procedure:
Three g of the product of Example 65 was reacted with 1.1 g of cyclopropylamine, substantially as shown in Example 60, to obtain 2.6 g of the desired product, m.p. 175°-177°.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[S:20][C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][CH:28]=3)=[C:22]([CH3:25])[C:23]=2[CH3:24])[O:7][C@@H:6]1[CH2:35][O:36]C(=O)C)(=O)C.C[O-].[Na+].CC(O)=O>CO>[CH2:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:21]2[S:20][C:19]([C@H:8]3[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:35][OH:36])[O:7]3)=[C:23]([CH3:24])[C:22]=2[CH3:25])=[CH:28][CH:29]=1)[CH3:34]
Reactant: CCc1ccc(Cc2sc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(C)c2C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(Cc2sc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(C)c2C)cc1
Yield: 28.3 %

Procedure:
To a solution of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-3,4-dimethylthiophen-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (57) (125 mg, 0.223 mmole) in MeOH (5 mL) was added NaOMe (25 wt % in MeOH, 310 μL, 1.34 mmole). The reaction mixture was stirred at ambient temperature for 2 h before AcOH (2 mL) was added. Purification by reverse phase preparative HPLC provided the title compound 60 (24.8 mg, 0.0632 mmole, 28%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@H:7]([OH:9])[CH2:6]1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C@H:5]1[CH2:8][C@H:7]([O:9][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1
Reactant: COC(=O)C[C@H]1C[C@H](O)C1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution trans-(3-hydroxy-cyclobutyl)-acetic acid methyl ester (168 mg, 1.17 mmol) in DMF (1.5 mL) is added, NaH (60% in oil, 70 mg, 1.75 mmol) at 0° C. After stirring at 0° C. for 15 minutes, benzyl bromide (167 uL, 1.40 mmol) is added at 0° C. The mixture is stirred at room temperature for 2 hours and quenched with H2O. The mixture is extracted with dichloromethane, and the organic layer is concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography to give trans-(3-benzyloxy-cyclobutyl)-acetic acid methyl ester (110 mg, 40%); ESI-MS m/z 235 [M+1]+, retention time 1.97 min (condition A).
Reaction SMILES: ClC([SiH3])(Cl)Cl.BrC(Br)C.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:23]1[CH:41]=[CH:40][C:26]([CH2:27][C@@H:28]2[C:33]([CH3:35])([CH3:34])[O:32][C:31]([O:36][CH3:37])=[N:30][S:29]2(=[O:39])=[O:38])=[C:25]([F:42])[CH:24]=1>CC(N(C)C)=O.[Zn].[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:13]([O:12][C:10]([N:17]1[CH2:20][CH:19]([C:23]2[CH:41]=[CH:40][C:26]([CH2:27][C@@H:28]3[C:33]([CH3:35])([CH3:34])[O:32][C:31]([O:36][CH3:37])=[N:30][S:29]3(=[O:39])=[O:38])=[C:25]([F:42])[CH:24]=2)[CH2:18]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC1=NS(=O)(=O)[C@H](Cc2ccc(Br)cc2F)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CC(=O)N(C)C
Product: COC1=NS(=O)(=O)[C@H](Cc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2F)C(C)(C)O1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Zinc dust (252 mg) was suspended in DMA (0.5 ml) and heated to 65° C. Subsequently, trichloromethylsilane (27 mg) and dibromoethane (34 mg) were added and the mixture was stirred at 65° C. for 30 min. Then 1-BOC-3-iodoazetidine (465 mg) in 0.5 ml of DMA was added dropwise and the mixture was stirred for a further 30 min. (R)-5-(4-bromo-2-fluorobenzyl)-2-methoxy-6,6-dimethyl-5,6-dihydro-[1,4,3]oxathiazine 4,4-dioxide (250 mg) was dissolved in 1 ml and added dropwise to the warm solution, and the mixture was stirred at 65° C. for a further 30 min. Copper(I) iodide (25 mg) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride (53 mg) were added and the suspension was heated to 85° C. for 1 hour. After cooling, the mixture was filtered through a membrane. The solution was purified by means of preparative HPLC. This gave the product (91 mg) with a molecular weight of 456.5 g/mol (C21H29FN2O6S), MS (ESI): (M-butene+H+) 401.5 g/mol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.C1(N(CCC(OCC)=O)C(C2C=CC3N(C)C(CNC4C=CC(C(=N)N)=CC=4)=NC=3C=2)=O)C=CC=CC=1.Cl.[C:46]([C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:56][C:57]2[N:61]([CH3:62])[C:60]3[CH:63]=[CH:64][C:65]([C:67]([N:69]([CH2:76][CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79])[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=4)=[O:68])=[CH:66][C:59]=3[N:58]=2)=[CH:51][CH:50]=1)(=[NH:48])[NH2:47].[Cl:83][C:84]([O:86][CH2:87][CH2:88][CH2:89][CH2:90][CH2:91][CH3:92])=[O:85]>CC(C)=O.O>[CH3:92][CH2:91][CH2:90][CH2:89][CH2:88][CH2:87][O:86][C:84](/[N:48]=[C:46](\[NH2:47])/[C:49]1[CH:50]=[CH:51][C:52]([NH:55][CH2:56][C:57]2[N:61]([CH3:62])[C:60]3[CH:63]=[CH:64][C:65]([C:67]([N:69]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=4)[CH2:76][CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:68])=[CH:66][C:59]=3[N:58]=2)=[CH:53][CH:54]=1)=[O:85].[ClH:83].[C:46]([C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:56][C:57]2[N:61]([CH3:62])[C:60]3[CH:63]=[CH:64][C:65]([C:67]([N:69]([CH2:76][CH2:77][C:78]([O:80][CH2:81][CH3:82])=[O:79])[C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=4)=[O:68])=[CH:66][C:59]=3[N:58]=2)=[CH:51][CH:50]=1)(=[NH:47])[NH2:48]
Reactant: CCCCCCOC(=O)Cl
Agent: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCOC(=O)/N=C(\N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
350 mL acetone, 250 mL water and 32.2 g potassium carbonate were stirred in round bottom flask at 25° C. The reaction mixture was cooled to 10° C. and 100 g of 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxy carbonylethyl)amide hydrochloride of Formula (E) was added. 15 mL acetone and 16.8 mL n-hexyl chloroformate were added to the reaction mixture and stirred for 1 hour. The precipitated product was filtered and washed with mixture of acetone and water. The wet-cake was dissolved in acetone and stirred for 30 min. The product was obtained by addition of water followed by filtration. The wet-cake thus obtained was washed with acetone and dried to obtain dabigatran etexilate of Formula (E). 50 g dabigatran etexilate and 500 mL ethyl acetate were stirred at 25° C. The reaction mixture was charcoalized and filtered. The filtrate was heated 75° C. to 80° C. and stirred for 30 minutes and cooled to 25° C. to 35° C. The reaction mixture was filtered and washed with ethyl acetate to obtain pure dabigatran etexilate of Formula (F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)=[O:10].[CH3:29][Mg]Br.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[N:15]([CH2:16][CH2:17][CH2:18][OH:19])[C:14]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:13]=2[N:12]=1)([OH:10])[CH3:29]
Reactant: CCN(CC)c1cccc2nc(C(=O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(C(C)(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67 %

Procedure:
To a stirred solution of (2,4-dichlorophenyl)[7-(diethylamino)-1-(3-hydroxypropyl)-1H-benzimidazol-2-yl]methanone (300 mg, 0.714 mmol) in tetrahydrofuran (7 mL) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 714 μL, 2.14 mmol) at 0° C. After being stirred for 6.5 h at room temperature, the reaction mixture was quenched with aqueous ammonium chloride at 0° C., diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo. The resulting solid was washed with diethyl ether to afford the desired product as a yellow solid (210 mg, 0.481 mmol, 67%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]([NH:11][CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[C:22]([F:24])[C:21](F)=[C:20]([F:26])[CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9].CO>CN(C=O)C.O.C(Cl)Cl>[F:26][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][CH:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[O:17][N:16]=2)[CH:23]=[C:22]([F:24])[C:21]=1[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)NCC1CC(c2cc(F)c(F)c(F)c2)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NCC1CC(c2cc(F)c(-n3ccnc3)c(F)c2)=NO1
Temperature: 40 °C
Reaction time: 0.05 h
Yield: 56.7 %

Procedure:
A solution of imidazole (42 mg) in dry DMF (5 mL) is treated with 60% sodium hydride dispersion in mineral oil (25 mg), stirred for 3 minutes and treated with (-)-5-(acetamidomethyl)-3-(3,4,5-trifluorophenyl)isoxazoline (see Example 25) (150 mg). After 18 hours, the mixture is heated to 40° C. for 2 hours. TLC analysis (5% CH3OH--CH2Cl2) indicated the reaction to be virtually complete. The mixture is diluted with water (50 mL) and extracted with EtOAc (6×20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a white solid. Chromatography over silica (radial chromatography, 2 mm plate) eluting with CH2Cl2, 2% and 5% CH3OH--CH2Cl2 gives 100 mg of the title compound as a white solid, mp 168-169° C., [α]25D -80° (c 0.61, DMSO).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21]([OH:23])=O)=[CH:8][C:7]2=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.ON1C2C=CC=CC=2N=N1.[N:57]1([C:63]2[CH:69]=[CH:68][C:66]([NH2:67])=[CH:65][CH:64]=2)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C)C1C=CN=CC=1.CN(C)C=O.C(N(CC)CC)C>[N:57]1([C:63]2[CH:64]=[CH:65][C:66]([NH:67][C:21]([C:9]3[O:10][C:11]4[C:6]([C:7](=[O:24])[CH:8]=3)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=4[N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)=[O:23])=[CH:68][CH:69]=2)[CH2:58][CH2:59][O:60][CH2:61][CH2:62]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
6-Methoxy-8-(4-Methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) (3.0 g, 8.5 mmol), TBTU (5.5 g, 17 mmol), 1-hydroxybenztriazole (2.6 g, 17 mmol), 4-dimethylaminopyridine (0.05 g, catalytic) and commercially available 4-morpholin-4-yl-aniline (1.66 g, 9.3 mmol) were dissolved in dimethylformamide (100 mL). Triethylamine (3.5 mL, 25 mmol was added and this mixture stirred at room temperature for 17 hours. The reaction mixture was concentrated under vacuum and the residue was partitioned between chloroform (400 mL) and saturated aqueous sodium bicarbonate (50 mL). The organic′layer was separated, dried (Na2SO4), vacuum-filtered and concentrated under vacuum. The residue was purified by chromatography on silica eluted with 2-5% methanol in chloroform and then triturated with ether to yield a yellow powder. (1.6 g=39%) LCMS-m/z=479.5 mp=234-236° C.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[CH2:2]1.[NH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1>CO>[OH:1][CH:3]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:2][NH:14][CH2:15][CH2:16][NH:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:21][CH:20]=1
Reactant: NCCNC(=O)c1ccc(-n2ccnc2)cc1
Reactant: COc1ccc(OCC2CO2)cc1
Solvent: CO
Product: COc1ccc(OCC(O)CNCCNC(=O)c2ccc(-n3ccnc3)cc2)cc1
Reaction time: 24 h

Procedure:
To a solution of 2.39 g (13.2 mmol) 1,2-epoxy-3-(4-methoxyphenoxy)propane in 25 mL methanol is added 3.05 g (13.2 g) N-(2-aminoethyl)-4-(1H-imidazol-1-yl)benzamide. The reaction mixture is stirred under a nitrogen atmosphere for 24 h. After this time, the precipitate is collected and recrystallized from ethanol to provide the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][CH3:22].[ClH:23].O1CCOCC1>CCO.O.CN(C=O)C>[ClH:23].[CH3:22][O:21][CH2:20][CH2:19][CH2:18][O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: COCCCOC1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (1.0 g) was mixed with DMF (15 ml), and sodium hydride (55% suspended in oil) (300 mg) was added thereto, followed by stirring at room temperature for 10 minutes. To the reaction mixture was added 1-bromo-3-methoxypropane (1.0 g), followed by stirring at room temperature overnight. Water was added to the reaction mixture, and the reaction mixture was concentrated under reduced pressure. EtOAc and water were added to the obtained residue, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (10 ml), and a 4 M hydrogen chloride/dioxane (10 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure to obtain 4-(3-methoxypropoxy)piperidine hydrochloride (302 mg).
Reaction SMILES: C([O:5][NH:6][C:7](=[N:59]S(C1C(C)=C(C)C2OC(C)(C)CC=2C=1C)(=O)=O)[NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:41]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[C:13](=[O:40])[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[CH:27][C:26]([C:36]([F:39])([F:38])[F:37])=[N:25]2)=[CH:20][CH:19]=1)(=[O:17])=[O:16])(C)(C)C.N1CCCCC1>CN(C)C=O>[NH2:41][C@@H:12]([CH2:11][CH2:10][CH2:9][NH:8][C:7]([NH2:59])=[N:6][OH:5])[C:13]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:28]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[CH:27][C:26]([C:36]([F:39])([F:38])[F:37])=[N:25]2)=[CH:22][CH:23]=1)(=[O:16])=[O:17])=[O:40]
Reactant: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)[C@H](CCCNC(=NS(=O)(=O)c3c(C)c(C)c4c(c3C)CC(C)(C)O4)NOC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: Cc1ccc(-c2cc(C(F)(F)F)nn2-c2ccc(S(=O)(=O)NC(=O)[C@@H](N)CCCNC(N)=NO)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound (15a) is treated with 20-50% piperidine in N,N-dimethylformamide (0.1 M) to remove the Fmoc protecting group. The residue is purified by reverse phase chromatography (acetonitrile/water with 0.05% trifluoroacetic acid) and then dissolved in 95% trifluoroacetic acid-methylene chloride (0.1 M). The mixture is stirred at 25° C. for 6 h and then concentrated under reduced pressure. The residue is purified by reverse phase chromatography (acetonitrile/water with 0.05% trifluoroacetic acid) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([NH2:25])[CH:19]=3)([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:26])[CH:5]=[CH:6][CH:7]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([N:8]2[C:9](=[O:26])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2([C:18]2[CH:23]=[CH:22][C:21]3[NH:24][C:28](=[O:29])[NH:25][C:20]=3[CH:19]=2)[OH:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2(O)c3ccccc3C(=O)N2c2cccc(Cl)c2F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(O)(c2ccc3[nH]c(=O)[nH]c3c2)N1c1cccc(Cl)c1F
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a solution of 2-(3-chloro-2-fluorophenyl)-3-(3,4-diaminophenyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (100 mg, 0.26 mmol) in tetrahydrofuran (3 mL) was added 1,1′-carbonyldiimidazole (63 mg, 0.39 mmol) at room temperature. The reaction mixture was stirred for 2 h, at which time the solvent was evaporated. The residue was purified by reverse phase HPLC to afford 5-[2-(3-chloro-2-fluorophenyl)-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1,3-dihydro-2H-benzimidazol-2-one (34 mg). 1H NMR (400 MHz, d6-DMSO): 10.63 (s, 1H), 10.52 (s, 1H), 7.84 (d, 1H), 7.72 (d, 1H), 7.68-7.58 (m, 2H), 7.50 (dt, 1H), 7.31-7.29 (m, 2H), 7.19 (t, 1H), 6.84-6.77 (m, 3H); MS (EI) for C21H13ClFN3O3: 408 (MH−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:14]([C:15](=[O:17])[CH3:16])=[CH:13][CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C.[Si:27](OS(C(F)(F)F)(=O)=O)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>C(Cl)Cl>[Si:27]([O:17][C:15]([C:14]1[C:9]([C:8]#[C:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH2:16])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(=O)c1cccnc1C#Cc1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccnc1C#Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
455 mg 1-(2-(pyridin-2-ylethynyl)pyridin-3-yl)ethanone was dissolved in 10 mL DCM, 1.069 mL of DIPEA was added, the solution was cooled 0° C. and 1.42 mL of tert-butyldimethylsilyltrifluormethansulfonate added slowly. The mixture was stirred 30 min at 0° C., warmed to 25° C. and filtrated over a plug of silica (cyclohexane/ethylacetate 1:1+small amount of TEA) to yield 1.025 g 3-(1-(tert-butyldimethylsilyloxy)vinyl)-2-(pyridin-2-ylethynyl)pyridine as oil. Analysis: HPLC-MS: Rt=1.59 min (method E) m+H=337.