Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]2([CH3:56])[NH:22][C:21](=[O:23])[N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]3[C:34](=[O:35])[C:33]([CH3:53])([CH2:36][CH2:37][C:38]4[CH:43]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:41]([OH:48])=[C:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:39]=4)[NH:32][C:31]3=[O:54])[C:19]2=[O:55])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65].Cl>CN(C)C=O.O>[C:44]([C:42]1[CH:43]=[C:38]([CH2:37][CH2:36][C:33]2([CH3:53])[N:32]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:31](=[O:54])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:20]3[C:19](=[O:55])[C:18]([CH3:56])([CH2:17][CH2:16][C:7]4[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=4)[N:22]([CH2:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8])[C:21]3=[O:23])[C:34]2=[O:35])[CH:39]=[C:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41]=1[OH:48])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC1(CCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)NC(=O)N(CCCCCCN2C(=O)NC(C)(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)C1=O
Reactant: CCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN1C(=O)N(CCCCCCN2C(=O)N(CCCCCC)C(C)(CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2=O)C(=O)C1(C)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
7.75 g (0.01 mol) of 3,3'-hexamethylene-bis-[5-(3",5"-di-tert-butyl-4"-hydroxyphenylethyl)-5-methylhydantoin] is added portionwise with stirring to a slurry of 1.92 g (0.04 mol) of a 50% dispersion of sodium hydride in mineral oil in 100 g of dry dimethylformamide. The temperature of the reaction mixture is maintained at 50°-55° C until gas evolution ceases. 3.3 g (0.02 mol) of 1-bromohexane is then added dropwise over a period of 15-30 minutes. The temperature of the mixture is maintained between 60°-80° C until the reaction is complete. The reaction mixture is then poured into water and neutralized with dilute hydrochloric acid. The mixture is then extracted with chloroform. The chloroform phase is dried and completely concentrated under reduced pressure to yield as the residue the desired 3,3'-hexamethylene-bis[5-(3",5"-di-tert-butyl-4"-hydroxyphenylethyl)-5-methyl-1-n-hexylhydantoin].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH:37]([C@@H:39]1[N:44]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:43][CH2:42][N:41]([C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[C:53]([O:58][CH3:59])[CH:52]=2)[CH2:40]1)[CH3:38].Cl.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:55][C:54]3[CH:56]=[CH:57][C:51]([N:41]4[CH2:42][CH2:43][N:44]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[C@@H:39]([CH:37]([CH3:38])[CH3:36])[CH2:40]4)=[CH:52][C:53]=3[O:58][CH3:59])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: CO
Solvent: OCC(F)(F)F
Product: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To 5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.241 g, 0.490 mmol) and 4-{(3S)-3-(1-methylethyl)-4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-2-(methyloxy)aniline (0.174 g, 0.489 mmol) were dissolved in 5 mL of trifluoroethanol with stirring in a pressure vessel. Hydrogen chloride (0.49 mL, 4N in dioxane, 2.0 mmol) was added, and the vessel was sealed. The reaction was heated to 80° C. for 3 days and subsequently cooled to rt. The reaction was poured into 10 mL of 7N NH3 in MeOH and concentrated onto silica gel. The compound was purified by flash chromatography, and the fractions containing the desired compound were concentrated in vacuo. The material was triturated with diethyl ether, filtered, and washed with diethyl ether. The solid was collected to afford the title compound (0.191 g, 0.236 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.33 (br. s., 1H), 8.42 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 8.03-8.09 (m, 1H), 7.70-7.78 (m, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.29-7.43 (m, 3H), 7.25 (d, J=8.8 Hz, 1H), 7.10-7.19 (m, 2H), 6.87-6.95 (m, 1H), 6.61 (s, 1H), 6.43-6.52 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.43-3.51 (m, 1H), 3.30-3.41 (m, 2H), 3.27 (s, 3H), 2.99 (s, 3H), 2.91-2.98 (m, 1H), 2.68-2.85 (m, 2H), 2.51-2.60 (m, 1H), 2.22-2.30 (m, 1H), 2.05-2.16 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.87 (d, J=7.0 Hz, 3H). MS (M+H, ES+) 811.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>O>[N:6]([C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(I)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccc(I)cc1
Reaction time: 1 h

Procedure:
6 g of p-iodoaniline was dispersed in a solution comprising 25 cc of water and 7.5 cc of 36% hydrochloric acid and cooled with ice. 2.1 g of sodium nitrite was dissolved in 13 ml of water and the resulting solution was added dropwise slowly to the dispersion to effect the diazotization reaction. A solution of 2.5 g of sodium azide in 18 ml of water was added dropwise thereto and, after stirring for one hour, the mixture was subjected to extraction with benzene. After the dehydration with sodium sulfate, benzene was evaporated to obtain p-azidoiodobenzene.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.ClCCl>C(N(CC)CC)C>[CH3:1][CH:2]([S:4]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Reactant: CC(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Propanesulphonyl chloride (1.74 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3 a-f, triethylamine (4.35 ml) and dry dichloromethane (180 ml) and the mixture stirred at ambient temperature for 24 hours. Further quantities of 2-propanesulphonyl chloride (1.75 ml then 1 ml) and triethylamine (4.35 ml then 2.5 ml) were added after stirring for 24 hours and 48 hours respectively. After stirring for a further 24 hours, the mixture was filtered and the filter bed was washed with dichloromethane (30 ml). The combined filtrate and washing were washed with water (200 ml), saturated aqueous sodium bicarbonate (2×200 ml), then water (200 ml) and then dried over magnesium sulphate. The dichloromethane was removed by distillation to give a residue which was purified by flash chromatography on a silica gel column eluted with dichloromethane: industrial methylated spirit (19:1) followed by crystallisation from 2-propanol (25 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl 2-propanesulphonate, m.p. 130°-133°.
Reaction SMILES: CCN(C(C)C)C(C)C.[I:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([I:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(I)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(I)ccc2oc1=O
Temperature: 25 °C
Yield: 33.8 %

Procedure:
DIEA (30.3 μL, 0.17 mmol) was added to 6-iodo-3-carboxy-coumarin (50.0 mg, 0.16 mmol) and HATU (66.2 g, 0.17 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (33.1 mg, 0.16 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 27.4 mg of product in 34% yield: LCMS (ESI) m/z 508 (MH+).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1)[CH:32]=[CH:33][C:34](O)=[O:35]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:30]=[C:29]([O:28][CH3:27])[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: COc1cc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc(OC)c1
Yield: 66 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3,5-dimethoxycinnamic acid under the conditions described in example 86 to yield 66% of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1)[CH:5]=[O:6].[CH3:20][Mg]Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:20])[C:7]([C:10]#[C:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][N:9]=1
Reactant: C[Mg]Cl
Reactant: Cc1ccc(F)cc1C#Cc1cnc(Cl)cc1C=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)ncc1C#Cc1cc(F)ccc1C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of 2-chloro-5-((5-fluoro-2-methylphenyl)ethynyl)isonicotinaldehyde (705 mg, 2.6 mmol) in tetrahydrofuran (11 mL) cooled at −15° C. was added a solution of 3.0M methylmagnesium chloride in tetrahydrofuran (1 mL, 3.1 mmol) dropwise over 1 minute. The reaction mixture was stirred at this temperature for 15 minutes and then quenched with a few drops of saturated aqueous ammonium chloride solution, tetrahydrofuran was evaporated in vacuo, and the resulting residue was redissolved in dichloromethane (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a colorless oil that was redissolved in dichloromethane (10 mL) and treated with Dess-Martin periodinane (1.4 g, 3.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then diluted with dichloromethane (100 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 40 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow solid (700 mg, 90%), which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)[CH2:4][CH3:5].[CH2:23]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(P([Pd-4](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)C=CC=CC=1>[CH2:23]([NH:25][C:26](=[O:27])[NH:28][C:29]1[N:30]=[CH:31][C:32]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:6]([CH:3]([CH2:4][CH3:5])[CH2:2][OH:1])[CH:7]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]3=[O:17])=[C:33]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:34]=1)[CH3:24]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOC(=O)c1cn(C(CC)CO)c2ccc(I)cc2c1=O
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C(CC)CO)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a suspension of ethyl 1-(1-hydroxybutan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 64, 282 mg, 0.78 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (Intermediate 17, 350 mg, 0.84 mmol) in 1,4-dioxane (3 mL) was added a solution of cesium carbonate (467 mg, 1.43 mmol) in water (1 mL) followed by tetrakis(triphenylphosphino)palladium(0) (48.7 mg, 0.04 mmol). The reaction mixture was stirred at 100° C. for 2 h, cooled to room temperature, and diluted with water (2 mL). The precipitate that formed was collected by filtration, washed with water and hexanes. Purification via column chromatography (silica, 95:5 methylene chloride/methanol) provided ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxybutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellow/orange solid (136 mg, 27%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].C([CH:14]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:30][CH:29]=2)[C:17]2=[N:18][C:19](=S(=O)=O)[CH:20]=[C:21]([CH3:22])[C:16]2=[N:15]1)C.Cl>O.CN(C=O)C>[CH2:1]([O:5][C:14]1[N:26]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:44][N:43]=[N:42][N:41]=3)=[CH:32][CH:33]=2)[C:17]2=[N:18][CH:19]=[CH:20][C:21]([CH3:22])=[C:16]2[N:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: CCC1N=C2C(C)=CC(=S(=O)=O)N=C2N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1nc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 0.08 h
Yield: 49 %

Procedure:
A mixture of 100 mg (1.3 mmol) of n-butanol, 400 mg (3.6 mmol) of potassium tert. butoxide and DMF was heated at 80 degree C. for 5 minutes. 300 mg (0.65 mmol) of 2-ethyl-sulfonyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-3H-imidazo[4.5-b]pyridine was added to the mixture. The resultant was heated for 2 hours. The reaction product mixture was mixed with water, neutralized with 2n HCl and extracted with dichloromethane. The dichloromethane phase was washed with a saturated saline and dried with anhydrous magnesium sulfate. The solvent was distilled out at a reduced pressure and the residue was treated with ether hexane-dichloromethane or re-crystallization to obtained 140 mg of the intended compound.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]1=[O:25])=O)(C)(C)C.Cl.[OH-].[Na+]>C(OCC)C.O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]1=[O:25]
Reactant: CC(C)(C)OC(=O)NCCCCCCn1c(=O)ccc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-[6-(N-tert-Butoxycarbonylamino)-1-hexyl]-1,2-dihydroquinoline-2-one (480 mg) was treated with a large excess of hydrogen chloride in dietyl ether with stirring for 1 hour at room temperature. The crystalline product was isolated by filtration and redissolved in water whereafter the solution was made strongly alkaline with sodium hydroxide and extracted twice with chloroform. The organic phase was dried over potassium carbonate, filtered and evaporated to yield the title compound as a colourless oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:37](=[O:41])[CH:38]([F:40])[F:39].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:37](=[O:41])[CH:38]([F:40])[F:39])[N:23]([CH2:25][O:26][CH2:27][CH3:28])[CH:24]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reactant: CON(C)C(=O)C(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOCn1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1C(=O)C(F)F
Temperature: -78 °C
Reaction time: 17 h
Yield: 72.6 %

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-1-ethoxymethyl-1H-imidazole (2.00 g) was dissolved in THF (10 mL), and was cooled to −78° C. while stirring under an argon atmosphere. To the present solution was added dropwise n-butyl lithium (2.69 M hexane solution, 3.18 mL) slowly using a syringe, followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methyl difluoroacetamide (1.41 g) was added using a syringe, and stirring was continued for 17 hours while the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=0%→20%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (1.74 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-(trifluoromethyl)phenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, chloroform-d) δ ppm 1.21 (t, J=7.1 Hz, 3H) 2.71 (s, 6H) 4.14 (q, J=7.2 Hz, 2H) 7.31 (d, J=7.8 Hz, 2H) 7.53 (d, J=7.8 Hz, 2H) 7.61 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]3[O:27][CH2:26]3)[CH:18]=2)[CH:14]=1)=[O:7].[CH3:34][N:35]([CH3:41])[CH2:36][CH2:37][CH2:38][NH:39][CH3:40]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:29])=[C:13]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][N:39]([CH2:38][CH2:37][CH2:36][N:35]([CH3:41])[CH3:34])[CH3:40])[CH:18]=2)[CH:14]=1)=[O:7]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC2CO2)c1
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(O)CN(C)CCCN(C)C)c1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 31, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-(2,3-epoxypropoxy)benzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 45% yield; NMR Spectrum: (DMSOd6) 1.8 (m, 2H), 2.18 (s, 3H), 2.33 (s, 3H), 2.58 (s, 6H), 2.6 (m, 2H), 2.92 (t, 2H). 2.96 (s, 6H), 4.03 (m, 5H), 6.9 (m, 1H). 7.15 (m, 1H), 7.2 (m, 3H), 7.28 (t, 1H), 7.48 (t, 1H), 7.56 (m, 2H), 7.8 (d, 1H), 9.95 (s, 1H), 10.13 (s, 1H); Mass Spectrum: M+H+ 562.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[CH3:17][N:18]1[C:22]([CH2:23][NH:24][C:25]2[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=2[CH3:31])=[CH:21][C:20]([CH3:33])=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:17][N:18]1[C:22]([CH2:23][NH:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=2[CH3:31])[O:32][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[N:10]=3)[N:7]=2)=[CH:21][C:20]([CH3:33])=[N:19]1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1cc(CNc2cc(O)ccc2C)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CNc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)n(C)n1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 72.4 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (210 mg, 0.64 mmol), 3-{[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]amino}-4-methylphenol (220 mg, 0.96 mmol), potassium carbonate (220 mg, 1.6 mmol) and N,N-dimethylformamide (1.5 mL) was stirred under microwave irradiation at 150° C. for 40 min. The solvent was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (200 mg, 72%) as a brown solid.
Reaction SMILES: [CH2:1]([N:5]1[C:6](=[O:40])[NH:7][C:8](=[O:39])/[C:9]/1=[CH:10]/[C:11]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].I[CH2:48][CH2:49][CH2:50][CH3:51]>CN(C=O)C.CCOCC>[CH2:1]([N:5]1[C:6](=[O:40])[N:7]([CH2:48][CH2:49][CH2:50][CH3:51])[C:8](=[O:39])/[C:9]/1=[CH:10]/[C:11]1[N:15]=[C:14]([CH2:16][CH2:17][CH2:18][CH3:19])[N:13]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCI
Reactant: CCCCc1nc(/C=C2/C(=O)NC(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1nc(/C=C2/C(=O)N(CCCC)C(=O)N2CCCC)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of Z-1-butyl-5-[[2-butyl-3-(triphenylmethyl)-3H-imidazol-5-yl]methylene]-2,4 imidazolidinedione (1.20 g, 2.26 mmol) in DMF (5 mL) was added K2CO3 (1.56 g, 11.3 retool) and then 1-iodobutane (0.344 mL, 3.02 mmol). The mixture was stirred for 16 hours and then diluted with ether and washed with water and brine. After drying over MgSO4 the product was isolated by chromatography on silica eluting with 80 % petroleum ether 20 % ethyl acetate. MS (CI) 588