Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:7][CH:6]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:18][CH:17]=2)=[O:14])=[O:9])[C:5]([CH3:43])([CH3:42])[CH2:4][O:3]1.C(O)(=O)C>O>[OH:7][CH:6]([C:5]([CH3:42])([CH3:43])[CH2:4][OH:3])[C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:18][CH:17]=1)=[O:14])=[O:9]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(OC(=O)CCNC(=O)C2OC(C)(C)OCC2(C)C)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(OC(=O)CCNC(=O)C(O)C(C)(C)CO)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.5 %

Procedure:
A solution of 500 mg of 4-(Oleoylamino)phenyl 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionate in a mixed solvent composed of 20 ml of acetic acid and 10 ml of water was stirred at room temperature for 15 hours. 20 ml of water was then added to the reaction mixture, which was then extracted with methylene chloride. The methylene chloride layer was washed with water, and dried over anhydrous sodium sulfate. After removal of the solvent under vacuum evaporation, the residue obtained was subjected to silica gel column chromatography to obtain 395 mg of the title compound (yield: 85%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)[S:26][C:19]=34)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[CH:24]=[C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])=[CH:29][CH:28]=5)[S:26][C:19]=34)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCOCCO
Product: OCCOCCNCc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-(2-amino-ethoxy)-ethanol and 4-[7-(1H-indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 459 (MH+); HPLC RT: 3.48 minutes.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(O)(=O)C.Br>O>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)=[CH:16][N:17]=2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2ncc(-c3ccc(OC)cc3)s2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)s2)cc1
Reaction time: 16 h
Yield: 74.9 %

Procedure:
Then, in a 300 ml-three-necked flask, 13.9 g (39.3 mM) of 2-(4-hexylphenyl)-5-(4-methoxyphenyl)tiazole, 76.5 ml of acetic acid and 69.5 ml of 47%-hydrobromic acid were placed, followed by heat-stirring for 16 hours at 100°-110° C. After the reaction, the reaction mixture was poured into cool water, followed by extraction with ethyl acetate. The organic layer was successively washed with water, 5 %-sodium hydrogenecarbonate aqueous solution and water, followed by distilling-off of the solvent under reduced pressure. The residue was dissolved in a mixture solvent of ethanol/chloroform=1/1, followed by decolorization with activated carbon and distilling-off of the solvent under reduced pressure. The resultant residue was recrystallized two times from toluene to obtain 10.0 g of 2-(4-hexylphenyl)-5-(4-hydroxyphenyl)thiazole (Yield: 75.8%). ##STR37##
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:19]1([C:25]([CH:27]=[O:28])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(=S)=S>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:27]([OH:28])[C:25](=[O:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCCCCCc1ccc(C(O)C(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
57.0 g (0.30 mole) of n-octylbenzene are dissolved in 800 ml of carbon disulfide, the solution is cooled to 0° C., 66.5 g (0.50 mole) of aluminum chloride are added, and a solution of 40.0 g (0.30 mole) of phenylglyoxal and 50 ml of carbon disulfide are added dropwise at from 5° to 10° C., while stirring vigorously. The yellow to orange reaction mixture is stirred for a further 15 hours without being cooled, after which it is poured carefully onto 1 l of semiconcentrated ice-cold hydrochloric acid, and the mixture is stirred thoroughly. The phases are separated, the organic phase is extracted by shaking with 300 ml of water, the aqueous phases are extracted with 300 ml of methylene chloride, and the combined organic phases are dried over sodium sulfate. The solution is filtered and the solvent is distilled off to give 75.0 g (=77% of theory) of crude product which has a melting range of 85°-89° C. and is 95% pure according to gas chromatography. Recrystallization from methanol gives analytically pure 4'-n-octylbenzoin.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([N+:15]([O-])=O)[C:13]=2[NH2:14])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH2:14])=[C:12]([NH2:15])[CH:11]=[N:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cncc(N)c2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) (382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (CXVIII) as purple solid (330 mg, 1.59 mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz): δ 2.18 (s, 3H), 2.34-2.36 (m, 4H), 3.13-3.16 (m, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found C10H17N5 m/z 208 (M+H).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3([CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21]3)[N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(OCC)(=O)C>C(Cl)Cl>[CH2:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:11]3[CH:25]=[CH:24][C:23](=[O:26])[CH:22]=[CH:21][C:12]3=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(C2=NC3(C=CC(=O)C=C3)C(c3ccccc3)=C2)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCN1CCN(c2cc(-c3ccccc3)c3ccc(=O)ccn23)CC1
Temperature: 20 °C
Yield: 70 %

Procedure:
2-(4-Allyl-1-piperazinyl)-4-phenyl-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (40 g) is heated for 10 minutes to a temperature of about 220° C. After being cooled to a temperature of about 20° C., the residue is dissolved in methylene chloride (500 cc) and poured into silica (1 kg) contained in a column 6.5 cm in diameter. Successive elutions are performed with pure methylene chloride (1 liter), a mixture of methylene chloride and ethyl acetate (90:10 by volume) (1 liter) and a mixture of methylene chloride and ethyl acetate (80:20 by volume) (1 liter); the corresponding eluates are discarded. Elution is then performed with a mixture of methylene chloride and ethyl acetate (70:30 by volume) (3 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (200 cc), 3-(4-allyl-1-piperazinyl)-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (28 g), m.p. 125° C., is obtained.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[O:13][N:12]=[C:11]([NH2:14])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C(OCC)(=O)C>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:19]=1[C:20]([NH:22][C:23]([NH:14][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[O:13][N:12]=1)=[O:24])=[O:21]
Reactant: Nc1cc(-c2cccc(C(F)(F)F)c2)on1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2cccc(C(F)(F)F)c2)on1

Procedure:
5-(3-(Trifluoromethyl)phenyl)-3-aminoisoxazole (300 mg.) and excess 2,6-dichlorobenzoyl isocyanate were mixed in 50 ml. of ethyl acetate under nitrogen, and stirred for several hours at room temperature. The product was separated by filtration, m.p., 233° C. (dec)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2O[C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:35]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[NH:35][C:12](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:13][N:14]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C/c2nnc(C(C)c3ccc(F)cc3)o2)ccc1-n1cnc(C)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2nnc(C(C)c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
A solution of 2-[1-(4-fluorophenyl)ethyl]-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (23 mg) and ammonium acetate (88 mg) in acetic acid (1 mL) was stirred at 150° C. for 10 hours. The reaction solution was left to cool to room temperature and concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.C([O:14][CH:15]1[CH2:23][CH2:22][CH:21]2[CH:17]([CH2:18][N:19]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20]2)[C:16]1=[O:31])(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[CH2:24]([N:19]1[CH2:18][CH:17]2[CH:21]([CH2:22][CH2:23][CH:15]([OH:14])[C:16]2([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[OH:31])[CH2:20]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccccc1[Mg]Br
Reactant: CC(=O)OC1CCC2CN(Cc3ccccc3)CC2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1C1(O)C(O)CCC2CN(Cc3ccccc3)CC21
Temperature: 0 °C
Yield: 26.8 %

Procedure:
To a suspension of 27.6 g of 2-methoxyphenylmagnesium bromide in 60 cm' of tetrahydrofuran are added dropwise, at room temperature and with stirring, a solution of 4.7 g of (3aRS,5RS,7aSR)-5-acetoxy-2-benzyl-4-perhydroisoindolone in 90 cm3 of tetrahydrofuran. The reaction mixture is stirred at room temperature for 3 hours, treated with 200 cm3 of saturated aqueous ammonium chloride solution and taken up in 200 cm3 of ethyl ether and 100 g of ice. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 80 cm3 of petroleum ether and then chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 1 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (95/5 by volume) and collecting 25 cm3 fractions. Fractions 14 to 21 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 1.55 g of (3aRS,4RS,5RS,7aSR)-2-benzyl-4-(2-methoxyphenyl)-4,5-perhydroisoindolediol are obtained, melting at 140° C.
Reaction SMILES: Br[CH2:2][C@@H:3]([NH:5][C:6]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])[CH3:4].[Na+].[C:29]1([S:35]([O-])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(OCC)(=O)C>[C:26]([C:23]1[CH:24]=[CH:25][C:6]([NH:5][C@@H:3]([CH3:4])[CH2:2][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])=[C:7]([CH:22]=1)[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[O:9])#[N:27]
Reactant: O=S(=O)([O-])c1ccccc1
Reactant: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CBr)cc1OC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2cc(C#N)ccc2N[C@@H](C)CS(=O)(=O)c2ccccc2)cc1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (S)-2-(2-bromo-1-methylethylamino)-5-cyano-N-(3,4-dimethoxybenzyl)benzamide (147 mg) in dimethylsulfoxide (2 mL) was added benzenesulfonic acid sodium salt (81.6 mg), and the mixture was stirred for 3 hours at 90° C. The resulting mixture was diluted with ethyl acetate and washed successively with water and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and ethyl acetate (9:1) to give (S)-5-cyano-N-(3,4-dimethoxybenzyl)-2-(2-phenylsulfonyl-1-methylethylamino)benzamide (94 mg) as a solid substance.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[F-].[Cs+].[CH:15]1([CH:21]=[CH:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>CS(C)=O>[CH:15]1([CH:21]([CH2:3][C:4]([C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[O:5])[CH2:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(C=CC1CCCCC1)c1cccc(O)c1
Reactant: C=C(O[Si](C)(C)C)c1ccco1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccco1)C1CCCCC1)c1cccc(O)c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(furan-2-yl)ethylene (1.66 g, 9.1 mmol; prepared according to J. Chem. Soc.,Perkin Trans. I 1989, 1585) and CsF (0.41 g, 2.7 mmol) were added to a suspension of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin (2.6 g, 1.82 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% ACOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 2.7 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:24]=[CH:23][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:25]1[CH2:27][C@H:26]1[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1>>[OH:25][C@@H:26]([CH2:27][NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[S:18][CH:19]=[CH:20][C:21]=3[CH3:22])=[O:16])[CH2:13][CH2:14]2)=[CH:23][CH:24]=1)[CH2:28][O:29][C:30]1[C:38]2[NH:37][C:36](=[O:39])[NH:35][C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=c1[nH]c2cccc(OC[C@@H]3CO3)c2[nH]1
Reactant: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Product: Cc1ccsc1C(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)cc2)CC1
Yield: 14.4 %

Procedure:
{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}(3-methyl-2-thienyl)methanone (0.174, 0.507 mmol) was reacted with 4-[(2S)oxiranylmethoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.108 g, 524 mmol) according to Procedure G to give the title compound (0.04 g, 0.073 mmol).
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:68][C:69]1[CH:83]=[C:82]2[C:72]([NH:73][CH:74]=[C:75]2[CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:71][CH:70]=1>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:78][CH:77]([CH2:76][C:75]4[C:82]5[C:72](=[CH:71][CH:70]=[C:69]([OH:68])[CH:83]=5)[NH:73][CH:74]=4)[C:79]([OH:81])=[O:80])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 205 (100 mg, 0.22 mmol) was activated in 2 mL of DMF with 92 mg (0.24 mmol) of HBTU and 85 μL of DIEA for 10 minutes at room temperature. 5-hydroxy-L-tryptophane (56 mg) dissolved in 1 mL DMF was added, followed by 44 μL of DIEA. The mixture was stirred at room temperature for 1 h, then was evaporated to dryness. The oil was purified using RP-HPLC column to give the pure Compound 236.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][CH2:5][C:6]#[C:7][C:8]([O:10][CH3:11])=[O:9].[CH3:13][Cu]>>[CH3:13]/[C:6](/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:12])[CH3:1])=[CH:7]/[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C#CCCC=C(C)C
Reactant: C[Cu]
Product: COC(=O)/C=C(/C)CCC=C(C)C

Procedure:
contacting the isolated product of step c with lithium dimethyl cuprate and methyl copper to produce methyl (Z)-3,7-dimethylocta-2,6-dienoate; and
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:21]([O:23][CH3:24])=[O:22]>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:31]2[CH2:30][CH2:29][N:28]([C:27]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=3[CH3:17])[CH2:33][CH2:32]2)=[O:13])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: COC(=O)c1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 77.6 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (1.08 g) described in Preparation Example 16 and methyl 3-methyl-4-(piperazin-1-yl)benzoate (1.05 g) described in Preparation Example 97 and by the reaction and treatment in the same manner as in Example 87, the title compound (1.59 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)[C:11]#N)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O=[CH:25][C:26](=C)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=3)[CH:25]=[C:26]([CH3:27])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1Cl
Reactant: C=C(C)C=O
Product: COc1ccc(-c2cc(C)cn2-c2ccc(S(N)(=O)=O)cc2)cc1Cl

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3-chloro-4-methoxyphenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 37%), melting at 160-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.C=O.O.[C:27]([O:30][CH2:31]C)(=O)[CH3:28]>C(O)C>[CH2:27]([O:30][CH2:31][NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1)[CH3:28]
Reactant: CCOC(C)=O
Reactant: Nc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Agent: C=O
Solvent: O
Solvent: CCO
Product: CCOCNc1ccc(C(=O)NCc2ccc(Oc3ccccc3)s2)cn1
Yield: 66.1 %

Procedure:
To a solution of 6-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-138 (600 mg, 1.8 mmol) in ethanol (40 mL) were added 5,5-dimethylimidazo phospho-2,4-dione (260 mg, 2.0 mmol) and 37% formaldehyde aqueous solution (3 mL), and the solution was stirred under reflux for 30 minutes. Water and ethyl acetate were added to the reaction solution, which was then partitioned, and the organic layer was washed with water twice. NH silica gel was added to the organic layer, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (ethyl acetate), and the title compound (457 mg, 1.19 mmol, 66.1%) was obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=O)[O:28]CC)[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:33][NH:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(N(CC)CC)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:28])[N:34]([CH:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[CH3:33])[CH:21]=3)[C:12]2=[O:32])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC1CCCC1
Reactant: CCOC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1)C1CCCC1
Temperature: 130 °C

Procedure:
To a solution of 0.16 g of ethyl (4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-carbamate obtained in stage a) below in 2 mL of tetrahydrofuran are added successively 0.368 mL of N-methylcyclopentylamine and 0.512 mL of triethylamine. The reaction mixture is heated by microwave at 130° C. for 3 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica, eluting with a mixture of ethyl acetate and cyclohexane (60/40 by volume) to give 0.048 g of 3-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-1-cyclopentyl-1-methylurea, the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:9][C:4]1[CH:5]=[C:6]([O:8][CH3:10])[CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)cc(O)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)cc(O)c1
Yield: 80 %

Procedure:
1 mmol of 3,5-Dihydroxy-toluene was taken in 3 mL of acetone, and then 3 mmol of K2CO3 was added and stirred for several minutes. Then, a solution of CH3I (3 mmol) in 10 ml of acetone was added from a pressure-equalizing dropping funnel, and the reaction was monitored by TLC. Upon completion, the reaction mixture was filtered to remove K2CO3, and evaporated by a rotatory evaporator to remove acetone. The mixture was then purified by column chromatography to give 5-methyl-3-methoxy-phenol (80%).