Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2[N:15]([CH3:36])[C:16](=[O:35])[C:17]([CH3:34])=[C:18]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]4)=[O:27])[CH:21]=3)[C:13]=2[C:12](=[O:37])[N:11]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:10]1=[O:47].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:14]1[N:15]([CH3:36])[C:16](=[O:35])[C:17]([CH3:34])=[C:18]2[C:13]=1[C:12](=[O:37])[N:11]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[C:10](=[O:47])[N:19]2[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:28]2[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]2)=[O:27])[CH:21]=1
Reactant: COc1ccc(Cn2c(=O)c3c(Nc4cccc(C(=O)N5CCC(O)C5)c4)c(C)c(=O)n(C)c3n(-c3ccc(I)cc3F)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c3n(-c3cccc(C(=O)N4CCC(O)C4)c3)c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
To a stirred solution of 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (550 mg, 0.732 mmol) in THF (2 ml) and Methanol (1 ml), was added K2CO3 (202 mg, 1.464 mmol) at RT. The reaction mixture was stirred at room temperature for 3 h under N2 atm. The solvents were evaporated in vacuo and the residue was suspended in dilute HCl (10 ml). The suspension was extracted several times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to afford crude 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (2d) (500 mg) which was carried forward for the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)C1C=CC=CC=1.CON(C)[C:14](=[O:38])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C[Li]>>[CH2:31]([O:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14](=[O:38])[CH3:3])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CON(C)C(=O)CCCCCCCCCCCCCCCOCc1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li]C
Agent: [Na+]
Product: CC(=O)CCCCCCCCCCCCCCCOCc1ccccc1

Procedure:
More specifically, compound (I) where R1, R3, R4, R5 are methyl groups, R2 is a hydroxyl group, m=1 and n=13 can be prepared in the following manner: Oxacycloheptadecan-2-one reacts with dimethylhydroxylamine in the presence of trimethylaluminium at 0° C. and at atmospheric pressure to yield N-methoxy-N-methyl-16-hydroxyhexadecanamide. The hydroxy function of this compound is then protected in the presence of sodium hydride and benzyl bromide at −78° C. and atmospheric pressure. The resulting N-methoxy-N-methyl-16-benzyloxyhexadecanamide is subsequently treated with methyllithium at −78° C. and at atmospheric pressure to yield 17-benzyloxyheptadecan-2-one. This reacts with the vinylmagnesium to afford 18-benzyloxy-3-methyloctadec-1-en-3-ol that in the presence of trimethylhydroquinone, zinc chloride and concentrated hydrochloric acid yields 2-(15-benzyloxypentadecyl)-2,5,7,8-tetramethylchroman-6-ol. Catalytic hydrogenation of this compound in the presence of palladium on charcoal affords 2-(15-hydroxypentadecyl)-2,5,7,8-tetramethylchroman-6-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C@H:12]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH3:13])[CH2:11][O:10]1.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([C@H:12]([O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH3:13])[CH2:11][N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (1.7 g) and imidazole (0.49 g) in N,N-dimethylformamide (17 ml) was added 60% oily sodium hydride in mineral oil (0.29 g) by portions at 20° C. with constant stirring. After 5 minutes, the mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled, then poured into water (50 ml) and extracted with ethyl acetate (20 ml×3). The ethyl acetate layers were combined, washed with saturated aqueous sodium chloride solution (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (3 cm×15 cm) using methanol-ethyl acetate (5:95) as the eluent. The desired fraction was concentrated under reduced pressure to give (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-2-butanol (1.8 g) as a colorless syrup.
Reaction SMILES: [CH2:1]=[O:2].[OH-:3].[Na+].[P:5]([OH:9])([OH:8])([OH:7])=[O:6].[NH2:10][C:11]([NH2:13])=[NH:12]>CO>[C:1](=[O:6])([OH:3])[OH:2].[NH2:12][C:11]([NH2:13])=[NH:10].[P:5](=[O:6])([OH:9])([OH:8])[OH:7]
Reactant: [OH-]
Reactant: C=O
Agent: N=C(N)N
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: O=C(O)O

Procedure:
189 grams of paraformaldehyde (6 moles) were dissolved in the heat in 450 grams of methanol under the addition of 1 gram of sodium hydroxide. After addition of 390 grams of a hot guanidine phosphate solution, which had been previously produced from 180 grams of guanidine carbonate (1 mole) and 254 grams of 85% phosphoric acid (2.2 moles), the mixture was boiled at reflux for about one hour until a clear solution was obtained. Then there were added a further 250 grams of methanol as well as a further 434 grams of the above mentioned guanidine phosphate solution after which the mixture was heated at reflux for a further 41/2 hours. The solution formed contained 51.1% solids, 42.2% methanol and 6.7% water.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-ethyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[C:9]([Cl:27])=[N:10][C:11]2[C:16]([C:17]=1[NH:18][CH2:19][C:20]1([OH:26])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)=[CH:15][CH:14]=[CH:13][CH:12]=2.C(N(CC)CC)C>ClCCl.C(=O)(O)[O-].[Na+]>[Cl:27][C:9]1[C:8]([NH:7][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:17]([NH:18][CH2:19][C:20]2([OH:26])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Reactant: CCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere butyryl chloride (322 μL, 3.11 mmol) was added dropwise was added to a suspension of 4-{[(3-amino-2-chloroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-ol (0.92 g, 2.83 mmol) in dichloromethane (28 mL). After 2 hours triethylamine (0.79 mL, 5.66 mol) was added and the reaction mixture was stirred for 2 hours. More butyryl chloride (0.2 mL) and triethylamine (0.30 mL) were added. The reaction mixture was stirred for an additional hour and then diluted with saturated aqueous sodium bicarbonate (50 mL) and extracted with dichloromethane (3×60 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (40 mL) and brine (30 mL), dried over sodium sulfate, filtered, and then concentrated under reduced pressure to provide N-(2-chloro-4-{[(4-hydroxytetrahydro-2Hthiopyran-4-yl)methyl]amino}quinolin-3-yl)butanamide as an off-white solid.
Reaction SMILES: [C:1]([O:4][C:5]([C:9](=[O:11])[CH3:10])=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.C1(C)C=CC=CC=1>[C:1]([O:4][C:5]([C:9](=[O:11])[CH2:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:6][O:7][CH3:8])(=[O:3])[CH3:2]
Reactant: COC=C(OC(C)=O)C(C)=O
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC=C(OC(C)=O)C(=O)CC(=O)c1ccccc1
Temperature: -78 °C

Procedure:
To a solution of 545 mg (3.5 mmol) of 1-methoxy-3-oxobut-1-en-2-yl acetate in THF (14.2 mL) at −78° C. was added LHMDS (3.45 mL of a 1 M solution in toluene) dropwise. After stirring for min at −78° C., the reaction mixture was treated with 0.4 mL (3.5 mmol) of benzoyl chloride dropwise, then removed from the cold bath and allowed to warm to room temperature and continue stirring for 18 h. The reaction was quenched with 10 mL 10% aq HCl and extracted with diethyl ether (3×10 mL). The organic fractions were combined, washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate which was used the subsequent step without further purification. To a solution of crude 1-methoxy-3,5-dioxo-5-phenylpent-1-en-2-yl acetate (3.5 mmol) in toluene (35 mL) was added pyridinium p-toluenesulfonate (130 mg, 0.5 mmol). The reaction mixture was heated at reflux under a nitrogen atmosphere for 1 h before being cooled and concentrated under reduced pressure and purified by flash chromatography (80 g SiO2, 0-100% ethyl acetate/hexanes gradient elution) to provide 4-oxo-6-phenyl-4H-pyran-3-yl acetate. LC/MS (M+H)+ 231.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:39][CH2:38][N:37]([C:35](=[O:36])[CH2:34][O:33][CH3:32])[CH2:42][CH2:41]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COCC(=O)N1CCNCC1
Product: COCC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[4-(2-methoxy-acetyl)-piperazin-1-yl]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-methoxy-1-piperazin-1-yl-ethanone following General Procedure C.
Reaction SMILES: COC1C=CC(CN=[N+]=[N-])=CC=1.COC1C=C(C(=O)C#CC(OCC)=O)C=CC=1OC.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:58]=[CH:59][C:60]=1[O:61][CH3:62])[C:37]([C:39]1[N:43](CC2C=CC(OC)=CC=2)[N:42]=[N:41][C:40]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[O:38].COC1C=C(C=CC=1OC)C(C1N(CC2C=CC(OC)=CC=2)NNC=1C(OCC)=O)=O>C1(C)C=CC=CC=1>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:58]=[CH:59][C:60]=1[O:61][CH3:62])[C:37]([C:39]1[NH:43][N:42]=[N:41][C:40]=1[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[O:38]
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1ccc(OC)c(OC)c1
Agent: CCOC(=O)C#CC(=O)c1ccc(OC)c(OC)c1
Agent: CCOC(=O)C1=C(C(=O)c2ccc(OC)c(OC)c2)N(Cc2ccc(OC)cc2)NN1
Agent: COc1ccc(CN=[N+]=[N-])cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn[nH]c1C(=O)c1ccc(OC)c(OC)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In the same manner as in Intermediate 4, a solution of 4-methoxybenzyl azide (1.8 g) in toluene (10 ml) was added to a solution of ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate (intermediate 2) (2.4 g, 9.2 mmol) in toluene (80 ml). The mixture was stirred at 100° C. for 18 hr. The reaction solution was concentrated under reduced pressure to give a mixture of ethyl 5-(3,4-dimethoxybenzoyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and ethyl 4-(3,4-dimethoxybenzoyl)-3-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate as an oil. The oil was used in the next reaction without purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:38]C1C=CC(B(O)O)=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([CH3:38])=[CH:3][CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-methylphenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=511, obsd.=511).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])=[O:26])=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)NCC(=O)c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 2-amino-4′-bromoacetophenone hydrochloride (5.0 g), 4-heptyloxybenzoic acid (4.72 g) and 1-hydroxybenzotriazole (2.7 g) in dichloromethane (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSCD) (3.65 ml) and the mixture was stirred for 3 hours at ambient temperature. The reaction mixture was diluted with dichloromethane (200 ml), and washed with water, 1N hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in ethyl acetate and collected by filtration to give 2-(4-heptyloxybenzoylamino)-4′-bromoacetophenone (6.73 g).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[C:27]([O:31][C:32]([C:34]1[C:57]([OH:58])=[C:56]([C:59]([F:62])([F:61])[F:60])[CH:55]=[CH:54][C:35]=1[CH2:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([CH2:50][C:51](O)=[O:52])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>C(#N)C.C(N(CC)CC)C>[CH3:2][N:3]([CH3:4])[C:51](=[O:52])[CH2:50][C:47]1[CH:48]=[CH:49][C:44]([C:41]2[CH:42]=[CH:43][C:38]([O:37][CH2:36][C:35]3[C:34]([C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:33])=[C:57]([OH:58])[C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=3)=[CH:39][CH:40]=2)=[CH:45][CH:46]=1
Reactant: CNC
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3)cc2)ccc(C(F)(F)F)c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 10 h
Yield: 171.3 %

Procedure:
Dimethylamine hydrochloride (41 mg, 0.502 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (96 mg, 0.50 mmol), hydroxybenzotriazole (77 mg, 0.50 mmol) and triethylamine (0.10 ml) were added to a solution of (4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetic acid (168 mg, 0.334 mmol) obtained in Example (7) in acetonitrile (10 ml). After the mixture was stirred for 10 hours, a saturated aqueous ammonium chloride solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=3/1-methylene chloride/methanol=15/1) to give the title compound as a pale yellow crystal (303 mg, yield: 34%).
Reaction SMILES: [CH:1]1([CH:4]2[CH2:9][NH:8][CH2:7][CH2:6][NH:5]2)[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH:1]1([CH:4]2[CH2:9][N:8]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH2:6][N:5]2[CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1CNC(C2CC2)CN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)C(C3CC3)C2)cc1
Temperature: 60 °C

Procedure:
A mixture of 2-cyclopropyl piperazine (50 mg, 0.40 mmol), 1-(2-bromoethyl)-4-nitrobenzene (360 mg, 1.6 mmol), tetrabutylammonium iodide (15 mg, 0.16 mmol), and K2CO3 (220 mg, 1.6 mmol) in DMF (2 mL) was heated to 60° C. for 16 hours. LC showed formation of the desired product, which was separated by mass-directed HPLC. LC-MS (IE, m/z): 425 [M+1]+. (0.86 μm)
Reaction SMILES: [NH2:1][C:2]1[N:19]=[CH:18][C:17](Br)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[OH:21][C:22]1[CH:23]=[C:24]([C:28]#[CH:29])[CH:25]=[CH:26][CH:27]=1.C(N(CC)CC)C>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[N:19]=[CH:18][C:17]([C:29]#[C:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([OH:21])[CH:23]=2)=[CH:16][C:3]=1[C:4]([N:6]=[S@@:7]([CH3:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C#Cc1cccc(O)c1
Reactant: C[S@@](=O)(=NC(=O)c1cc(Br)cnc1N)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[S@@](=O)(=NC(=O)c1cc(C#Cc2cccc(O)c2)cnc1N)c1ccccc1
Temperature: 70 °C
Reaction time: 3.3 h
Yield: 4.3 %

Procedure:
To a degassed solution containing (S)-2-amino-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (106 mg, 0.3 mmol) and 3-hydroxyphenylacetylene (50 mg, 0.42 mmol) in 2.0 mL EtOAc at room temperature was added triethylamine (0.13 mL, 0.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (21 mg, 0.03 mmol), and copper(I) iodide (6 mg, 0.03 mmol). The reaction was stirred at 70° C. for 3.3 hours. Additional 3-hydroxyphenylacetylene was added (50 mg, 0.42 mmol) and then again at 5.3 hours (75 mg, 0.63 mmol). The reaction was cooled to room temperature, and after 23 hours additional dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.03 mmol) was added. The reaction was heated to 60° C. and 3-hydroxyphenylacetylene (120 mg, 1.0 mmol) in 0.7 mL EtOAc (degassed) added dropwise over 7 minutes. The heat was removed after 1 hour and the reaction stirred an additional 22 hours at room temperature. The reaction was dissolved in EtOAc and washed with H2O. The EtOAc layer was extracted with 2% aqueous HCl. The combined acidic aqueous layers were washed with 30% EtOAc/hexane and then made basic with Na2CO3. The basic aqueous layer was extracted with EtOAc. Then the combined organic layers washed with brine, dried with anhydrous Na2SO4 and concentrated. The yellow oil was purified by chromatography (silica gel, CHCl3/EtOAc) to give the title compound as a white solid (5 mg, 4%).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3]1.[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=O.N1CCCCC1.Cl>C(O)C>[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[O:27])=[C:24]([CH3:35])[NH:23][C:22]=1[CH:36]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:19]=2)[C:16]([OH:18])=[O:17])[NH:3][C:2]1=[O:1]
Reactant: O=C1Cc2c(cccc2-c2cncc(C(=O)O)c2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Agent: Cl
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cncc(C(=O)O)c4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 60 °C

Procedure:
A mixture of 5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-nicotinic acid (381 mg, 1.5 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (374 mg, 1.5 mmol) and piperidine (1 mL) in ethanol (5 mL) was heated in a sealed cube at 60° C. for 5 hours. The reaction was acidified with 1N HCl and the resulted precipitate was collected by vacuum filtration, washed with water and dried to give the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([C:29]1[CH:34]=[CH:33][C:32](/[C:35](/[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][CH3:47])[N:40]=2)=[CH:36]\CO)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].O>O1CCCC1>[Br:24][CH2:20]/[CH:36]=[C:35](/[C:39]1[N:40]=[C:41]([O:46][CH3:47])[C:42]([Cl:45])=[CH:43][CH:44]=1)\[C:32]1[CH:31]=[CH:30][C:29]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:34][CH:33]=1
Reactant: BrC(Br)(Br)Br
Reactant: COc1nc(/C(=C/CO)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Yield: 118 %

Procedure:
Triphenylphosphine (1.10 g) and carbon tetrabromide (1.81 g) were sequentially added to a solution of (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-en-1-ol (912 mg) in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound as a black powder (1.28 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.Cl[C:21]1[CH:31]=[C:25]2[N:26]([CH3:30])[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=1>>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][N:24]2[C:23](=[O:32])[N:22]=[C:21]([O:14][CH2:13][C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:18])([F:19])[F:1])[CH:4]=4)=[CH:12][CH:11]=3)[CH:31]=[C:25]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Product: CN1CCCn2c1cc(OCc1ccc(Oc3cccc(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (4-(3-(trifluoromethyl)phenoxy)phenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.