Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:11]=[C:10]([CH:12]3[CH2:18][C:17](=[O:19])O[C:14](=[O:15])[CH2:13]3)[CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7].[CH3:20][NH2:21].O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:20][N:21]1[C:17](=[O:19])[CH2:18][CH:12]([C:10]2[CH:9]=[CH:8][C:5]3[C:6]([CH3:7])=[C:2]([CH3:1])[O:3][C:4]=3[CH:11]=2)[CH2:13][C:14]1=[O:15]
Reactant: CN
Reactant: Cc1oc2cc(C3CC(=O)OC(=O)C3)ccc2c1C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1oc2cc(C3CC(=O)N(C)C(=O)C3)ccc2c1C
Temperature: 0 °C

Procedure:
3.87 g (0.015 mol) of 3-(2,3-dimethyl-6-benzofuranyl)-glutaric anhydride [c.f. Example (4a) to (e)] are dissolved in 12.5 ml of toluene and 12.5 ml of glacial acetic acid. 10 ml of a 1.88 molar solution of methylamine in toluene are added to this solution at room temperature and the reaction mixture is heated to the boiling point for 61/2 hours, using a water separator. The cooled reaction mixture is poured onto an ice-water mixture and extracted with ether and the organic phase is washed with sodium bicarbonate and saturated sodium chloride solution until neutral. The organic phase is then dried over sodium sulfate and evaporated in a rotary evaporator. N-Methyl-3-(2,3-dimethyl-6-benzofuranyl)-glutarimide thus obtained as sand-coloured crystals of melting point 182°-185° crystallises spontaneously.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][N:15]=[C:16]([NH:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:28]#[N:29])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([Sn](CCCC)(CCCC)C#CC)[CH2:31][CH2:32]C.CO>C1(C)C=CC=CC=1.ClCCl.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>[O:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][NH:19][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][N:15]=2)[N:12]=[CH:11][C:10]([C:28]#[N:29])=[C:9]3[NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:30]#[C:31][CH3:32])[CH:3]=2)[CH2:23][CH2:24]1
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CC#Cc1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Temperature: 150 °C
Yield: 41.1 %

Procedure:
A mixture of 4-(3-iodophenylamino)-6-(2-morpholinoethylamino)-1,7-naphthyridine-3-carbonitrile (105.6 mg, 0.21 mmol, 1 eq) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.02 mmol, 0.1 eq) was taken up in toluene (2.5 mL) in microwave tube. Tributyl(prop-1-ynyl)stannane (193 uL, 0.63 mmol, 3 eq) was added to the mixture. The tube was sealed and heated 150° C. for 1 hr. Work-up followed by chromatography (1-3% Methyl alcohol in dichloromethane), yielded 35.6 mg product (41% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.04 (s, 3 H) 2.40-2.46 (m, 4 H) 2.55 (t, J=6.69 Hz, 2 H) 3.30-3.40 (m, 2 H) 3.55-3.60 (m, 4 H) 6.64 (t, J=5.68 Hz, 1 H) 7.01 (s, 1 H) 7.23 (s, 1 H) 7.25 (s, 2 H) 7.34-7.40 (m, 1 H) 8.28 (s, 1 H) 8.84 (s, 1 H) 9.61 (s, 1 H).
Reaction SMILES: [CH2:1]([C:8]1[CH:12]=[C:11]([C:13](=[O:16])[CH2:14][CH3:15])[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:17].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH2:24]=O.Cl>O1CCOCC1.C(OCC)C>[ClH:17].[CH2:1]([C:8]1[CH:12]=[C:11]([C:13](=[O:16])[CH:14]([CH3:24])[CH2:15][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)c1cc(Cc2ccccc2)no1
Reactant: C1CCNCC1
Reactant: C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CN1CCCCC1)C(=O)c1cc(Cc2ccccc2)no1
Reaction time: 72 h

Procedure:
In 2 ml of dioxane, 1.5 g (7 mmol) of 3-benzyl-5-propionylisoxazole prepared above in the procedure (2), 0.93 g (7.7 mmol) of piperidine hydrochloride, 0.25 g (8.3 mmol) of paraformaldehyde and two droplets of 12N-hydrochloric acid were heated under reflux for 60 minutes. When left over in a cool place for 3 days after completion of the reaction, the reaction mixture became a solid. Diethyl ether was added to the solid. A solid was collected by filtration and then dried, whereby 3-benzyl-5-(2-methyl-3-piperidinopropionyl)isoxazole hydrochloride was obtained as colorless crystals. Analytical results of the crystals obtained: Yield: 1.6 g (73.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].CCCC[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-:41].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:35]4[CH2:39][CH2:38][CH:37]([OH:41])[CH2:36]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: CCCCN1CCCC1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCC(O)C1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 85 μL (1.02 mmol) of R-(+)-3-pyrrolidinol in 5.0 ml dimethylformamide was stirred at room temperature for 4 hr and at 60° C. for 1 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, and purified by preparative TLC. Yield 84.2 mg (33%) yellow solid: mp 215-220° C.
Reaction SMILES: [N:1]1([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25](=S)[NH:26][CH2:27][CH2:28][CH3:29])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:34]C(C)C)(C)C>C(O)(=O)C>[N:1]1([CH2:8][CH:9]([N:11]2[C:24]3[CH:23]=[C:22]([C:25]([NH:26][CH2:27][CH2:28][CH3:29])=[O:34])[CH:21]=[CH:20][C:19]=3[S:18][C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)OC(C)C
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCCCC1)c1ccccc1S2
Solvent: CC(=O)O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCCCC1)c1ccccc1S2
Temperature: 20 °C
Reaction time: 0.75 h

Procedure:
Mercuric aoetate (I.8I g) dissolved in glacial acetic acid (35 cc) is added in the course of 20 minutes to a solution of 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-N-propyl-2-phenothiazinecarbothioamide (2.5 g) in acetic acid (25 cc), and the mixture is stirred for 45 minutes at a temperature in the region of 20° C. The black suspension obtained is filtered on sintered glass plugged with celite, and the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl acetate (250 cc) and distilled water (50 cc). The organic phase is washed successively with normal sodium hydroxide (2×100 cc) and distilled water (3×100 cc) and with saturated aqueous sodium chloride solution (100 cc) and dried over magnesium sulphate. After filtration, the yellow filtrate is concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and a crude yellow oil (2.1 g) is thereby obtained This residue is taken up with boiling isopropyl ether (80 cc). The small amount of insoluble matter is removed by filtration and crystallization is primed in the filtrate by cooling maintained with stirring. The crystals are filtered off on sintered glass to give 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-N-propyl-2-phenothiazinecarboxamide (1.29 g) in the form of an offwhite solid, m.p. 113° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:33]([C:40](NO)=[O:41])C1C=CC=CC=1>C1COCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([C:24]([CH3:32])([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:12][CH2:13][N:14]([C:40]([OH:41])=[O:33])[CH2:15][CH2:16]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCNCC2)c(C)c1
Solvent: C1CCOC1
Product: Cc1cnc(CN(Cc2ncccc2C(C)(C)c2ccccc2)C2CCN(C(=O)O)CC2)c(C)c1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
A stirred solution of (3,5-dimethyl-pyridin-2-ylmethyl)-[3-(1-methyl-1-phenyl-ethyl)-pyridin-2-ylmethyl]-piperidin-4-yl-amine (1.20 g, 2.8 mmol) and N-(phenoxycarbonyl)-hydroxylamine (515 mg, 3.4 mmol) in THF (28 mL) was heated at reflux for 16 hours. The mixture was cooled to room temperature, concentrated, and purified on a silica gel column (40 g, eluted with 5% NH4OH/10% MeOH/CH3CN) to afford COMPOUND 350 (1.12 g, 82%), as a white solid. 1H NMR (CDCl3) δ 1.10-1.26 (m, 2H), 1.51 (d, 2H, J=11.5 Hz), 1.62 (s, 6H), 2.23 (s, 3H), 2.25 (s, 3H), 2.48 (t, 3H, J=11.5), 3.41 (s, 2H), 3.60 (s, 2H), 3.86 (d, 2H, J=12.0 Hz), 7.03 (d, 2H, J=7.5 Hz), 7.12-7.25 (m, 5H), 7.87 (d, 1H, J=8.0 Hz), 8.10 (s, 1H), 8.50 (d, 1H, J=3.5 Hz); 13C NMR (CDCl3) δ 18.31, 18.76, 27.73(2), 31.23 (2), 42.86, 43.94(2), 54.18, 54.78, 58.20, 121.96, 126.15(2), 126.42, 128.93(2), 131.98, 133.14, 134.44, 139.45, 143.75, 146.51, 146.89, 149.75, 161.05; ES-MS m/z 488 (M+H). Anal. Calcd. For C29H37N5O2.0.6H2O: C, 69.88; H, 7.72; N, 14.05. Found: C, 69.51; H, 7.55; N, 14.12.
Reaction SMILES: [CH3:1][CH:2]([C:11](=[O:21])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[F:22][C:23]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:24]=1[NH2:25]>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:11](=[O:21])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:25]([C:24]2[C:26]([F:33])=[C:27]([F:32])[C:28]([F:31])=[C:29]([F:30])[C:23]=2[F:22])[C:3]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C(=O)CC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: Nc1c(F)c(F)c(F)c(F)c1F
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2c(F)c(F)c(F)c(F)c2F)c(-c2ccccc2)cc1=O
Yield: 27.7 %

Procedure:
In 110 ml of xylene were dissolved 3.1 g (0.011 mole) of 2-methyl-1,5-diphenyl-1,3,5-pentanetrione, 20.0 g (0.11 mole) of 2,3,4,5,6-pentafluoroaniline, 3.1 g (0.016 mole) of paratoluenesulfonic acid and 22.0 g of Molecular Sieves 5A, followed by reflux for 1 hours. After cooling the reaction mixture, solid matter was removed by filtration and the filtrate was then concentrated. After 200 ml of chloroform was added, the resultant solution in chloroform was washed first with 50 ml of 10% hydrochloric acid and then with 50 ml of a 10% aqueous solution of sodium hydroxide. After washing the solution in chloroform further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to column chromatography (eluent: 50.1 mixed solvent of chloroform and methanol). The resulting crystals were recrystallized from a 1:1 mixed solvent of acetone and hexane, thereby affording 1.3 g of 3-methyl-1-(2,3,4,5,6-pentafluorophenyl)-2,6-diphenyl-4(1H)-pyridinone having a melting point of 192°-194° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:48]=[C:17]2[N:18]([CH:41]3[CH2:46][CH2:45][CH:44]([CH3:47])[O:43][CH2:42]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:48]=[C:17]2[N:18]([CH:41]3[CH2:46][CH2:45][CH:44]([CH3:47])[O:43][CH2:42]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:30][CH:31]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(C)OC2)c2nc(C)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(C)OC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogen carbonate (0.64 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-methyl-4-(6-methyltetrahydro-2H-pyran-3-yl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.18 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-Carbonyldiimidazole (0.073 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.062 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.097 g, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(O[C:40](=[O:46])OC(Cl)(Cl)Cl)Cl.[CH2:48]([NH:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:49].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][O:35][C:40](=[O:46])[N:50]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:48][CH3:49])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Reactant: CCNCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)OC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CN(C(=O)c1ccc(OC)c(OCCCOC)c1)C(C)C
Reaction time: 8 h

Procedure:
To a stirred solution of (3S,4R)-3-hydroxymethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (250 mg, 0.505 mmol) in CH2Cl2 (10 mL) is added triphosgen (56 mg, 0.187 mmol) and DMAP (197 mg, 1.62 mmol). The resulting solution is stirred 30 min before the addition of commercially available N-ethylbenzylamine (113 μL, 0.758 mmol). The mixture is further stirred overnight, then diluted with CH2Cl2 and poured into an aqueous saturated solution of NaHCO3. The layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH 100:0 to 98:2). TLC, Rf (CH2Cl2/MeOH 95:5)=0.2. MS (LC-MS): 655.9 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 6.36 min.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:17])=[C:7]([C:11]([I:16])=[C:12]([NH2:15])[C:13]=1[I:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].[C:18]1(=[O:25])[O:24][C:22](=O)[CH2:21][CH2:20][CH2:19]1.S(=O)(=O)(O)O>O>[C:22]1(=[O:24])[N:15]([C:12]2[C:11]([I:16])=[C:7]([C:6]([I:17])=[C:5]([N:4]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:2][C:1]3=[O:3])[C:13]=2[I:14])[C:8]([OH:10])=[O:9])[C:18](=[O:25])[CH2:19][CH2:20][CH2:21]1
Reactant: CC(=O)Nc1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=C1CCCC(=O)O1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(I)c(N2C(=O)CCCC2=O)c(I)c(N2C(=O)CCCC2=O)c1I

Procedure:
From 3-acetamido-5-amino-2,4,6-triiodobenzoic acid. A mixture of 11.4 g. of 3-acetamido-5-amino-2,4,6-triiodobenzoic acid, 23 g. of glutaric anhydride and 1 ml. of concentrated sulfuric acid was heated on a steam bath for 21/2 hours. The reaction mixture was stirred with water and the product (14.4 g.) collected by filtration. The product was recrystallized twice from acetone to give 3,5-bis(glutarimido)-2,4,6-triiodobenzoic acid. The same compound is obtained if the 3-acetamido-5-amino-2,4,6-triiodobenzoic acid is replaced by 3,5-diacetamido-2,4,6-triiodobenzoic acid.
Reaction SMILES: Br[CH:2]([CH2:19][CH3:20])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].N[C:22]1[CH:27]=[CH:26][CH:25]=CC=1.[CH3:28][N:29](C)[CH:30]=O>>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:29]([CH3:30])[CH3:28])[C:19]2[CH:20]=[CH:25][CH:26]=[CH:27][CH:22]=2)=[N:10][CH:9]=1
Reactant: Nc1ccccc1
Reactant: CCC(Br)C(=O)Nc1ncc(Cc2ccccc2Cl)s1
Reactant: CN(C)C=O
Product: CN(C)C(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-butyramide (37 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing aniline (186 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (24 mg, 0.062, 62%). ESI-MS m/z calc. 385.1. found 386.1 (M+1)+ Retention time 3.48 minutes.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17](OS(C)(=O)=O)[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=1.[C:27]1([SH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[CH3:6][O:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH:17]([S:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:15]=1
Reactant: Sc1ccccc1
Reactant: COCOc1ccc(CC(OS(C)(=O)=O)C(=O)OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(CC(Sc2ccccc2)C(=O)OC)cc1

Procedure:
A solution of 15 ml of N,N-dimethylformamide containing 745 mg of methyl 3-(4-methoxymethoxyphenyl)-2-methanesulfonyloxypropionate, 310 mg of thiophenol and 390 mg of potassium carbonate was stirred at 50° C. for 0.5 hours, and ethyl acetate and water were added to the reaction mixture. Then, the ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The ethyl acetate layer was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 698 mg of the desired compound as a syrup.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.CO>C(Cl)Cl>[OH:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(CNCCc2ccccc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CNCCc2ccccc2O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At 0° C., 176.8 ml (176.8 mmol) of a 1N boron tribromide solution in methylene chloride are added dropwise to 16.03 g (53.561 mmol) of methyl 4-{[(2-methoxyphenethyl)amino]methyl}benzoate from Example. I.1 in 100 ml of methylene chloride. After one hour of stirring at 0° C., 150 ml of methanol are added and the solution is heated at reflux for 4 hours. The solvent is distilled off under reduced pressure and the residue is taken up in a mixture of 190 ml of ethyl acetate and 10 ml of methanol. Using 10% strength sodium carbonate solution, the mixture is made alkaline and extracted with ethyl acetate/methanol 9/1. The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent is distilled off under reduced pressure. The crude product is purified by chromatography over silica gel (0.04-0.063 nm) using the mobile phase methylene chloride/methanol 100/2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2[O:12][C:11](C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:44]=[CH:43][CH:42]=[CH:41][C:26]=1[CH2:27][S:28]([N:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:38](=[O:40])[CH3:39])[CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[CH:11]([OH:12])=[O:29].[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:44]=[CH:43][CH:42]=[CH:41][C:26]=3[CH2:27][S:28]([N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:38](=[O:40])[CH3:39])[CH2:35][CH2:36]3)(=[O:29])=[O:30])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2Br)CC1
Product: CC(=O)NC1CCN(S(=O)(=O)Cc2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1
Product: O=CO

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(1-((2-bromobenzyl)sulfonyl)piperidin-4-yl)acetamide. MS (ESI): mass calcd. for C24H26FN5O3S, 483.17; m/z found, 484.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (d, J=1.3, 1H), 7.95 (m, 1H), 7.81 (d, J=7.3, 1H), 7.64-7.55 (m, 1H), 7.50-7.31 (m, 5H), 6.73 (s, 2H), 4.35 (s, 2H), 3.71-3.56 (m, 1H), 3.39 (d, J=11.6, 2H), 2.79 (t, J=10.8, 2H), 1.82-1.67 (m, 5H), 1.41-1.24 (m, 3H).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1.Cl.Cl.[CH3:35][N:36]([CH3:49])[CH2:37][CH2:38][CH2:39][S:40](N1CCNCC1)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>CS(C)=O.O>[F:32][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([S:40]([CH2:39][CH2:38][CH2:37][N:36]([CH3:49])[CH3:35])(=[O:42])=[O:41])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:5]=2[N:4]=1
Reactant: CN(C)CCCS(=O)(=O)N1CCNCC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCNCC2)nc(N2CCOCC2)n1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCN(S(=O)(=O)CCCN(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
A mixture of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 2) (150 mg, 0.378 mmol), N,N-dimethyl-3-(1-piperazinylsulfonyl)-1-propanamine dihydrochloride (WO 2006/046040) (151 mg, 0.491 mmol), and DIPEA (0.40 mL, 2.27 mmol) in DMSO was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water; and the resulting precipitate was collected by filtration, washed with water, and dissolved in CH2Cl2. The solution was dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (95:5), followed by additional chromatography on silica eluting with CH2Cl2/MeOH (96:4) gave N-[3-({4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinyl}sulfonyl)propyl]-N,N-dimethylamine (91 mg, 40%). Treatment with 1.25 M HCl solution in MeOH and recrystallization from MeOH/EtOAc gave the hydrochloride salt: mp 209-211° C.; 1H NMR (DMSO-d6) δ10.16 (br s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 1H), 3.98 (s, 3H), 3.94 (m, 4H), 3.82 (m, 4H), 3.70 (br s, 4H), 3.33 (m, 4H), 3.23 (dd, J=9.3, 5.8 Hz, 2H), 3.12 (m, 2H), 2.75 (s, 6H), 2.08 (td, J=15.4, 7.8 Hz, 2H); Anal. Calcd. for C25H36ClF2N9O4S.0.5H2O: C, 46.8; H, 5.8; N, 19.7. Found: C, 46.9; H, 5.8; N, 19.4%.