Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][C:6]([CH:7]=O)=[C:5]([OH:13])[CH:4]=1.[OH-].[K+].[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21](=[O:24])[CH2:22]Br>C(O)C.O>[CH3:16][O:17][C:18](=[O:25])[CH2:19][CH2:20][C:21]([C:22]1[O:13][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:10]([O:11][CH3:12])=[CH:9][C:6]=2[CH:7]=1)=[O:24]
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: COC(=O)CCC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)CCC(=O)c1cc2cc(OC)c(OC)cc2o1
Reaction time: 0.33 h
Yield: 32.1 %

Procedure:
To a stirred suspension of 4,5-dimethoxy-2-hydroxy-benzaldehyde (9.3 g) in dry ethanol (90 ml) under nitrogen was added slowly a solution of potassium hydroxide (3.14 g) in dry ethanol (60 ml). The resulting solution was stirred for 20 minutes, then 5-bromo-4-oxo-pentanoic acid methyl ester (10.65 g) was added slowly. The mixture was stirred for 24 hours, then diluted slowly with water (900 ml). The precipitated solid was filtered off, washed with water, dried under vacuum and crystallized from acetone-ether to give 4-(5,6-dimethoxy-benzo[b]furan-2-yl)-4-oxo-butanoic acid methyl ester (4.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][NH:21]2)[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:31])CC.S(=O)(=O)(O)O>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:25](=[O:26])[NH:24][C:23](=[O:27])[CH2:22][N:21]2[CH:28]=[O:31])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3NCC(=O)NC3=O)cc2Cl)cc1
Reactant: CCC(=O)Cl
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: CS(=O)(=O)c1ccc(Oc2c(Cl)cc(N3C(=O)NC(=O)CN3C=O)cc2Cl)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
1 g of 2-[3,5-dichloro-4-(4-methylsulfonylphenoxy)phenyl]hexahydro-1,2,4-triazine-3,5-dione was suspended in 10 ml of formic acid. 5 ml of propionyl chloride and 1 ml of concentrated sulfuric acid were successively added dropwise, and the mixture was stirred at 80° C. for 5 hours. After it had been cooled, a further 10 ml of propionyl chloride were added to complete the reaction, and the mixture was again heated at 80° C. for 5 hours with stirring. It was then poured onto ice-water, and the precipitate was filtered off with suction and extracted by boiling with a little toluene. The residue was recrystallized from isopropanol/diisopropyl ether, melting point 212° C., decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11](=[C:13]1[CH2:18][CH2:17][C@H:16]2[C@H:19]3[C@H:29]([CH2:30][CH2:31][C@:14]12[CH3:15])[C@:27]1([CH3:28])[C:22]([CH2:23][C@@H:24](O)[CH2:25][CH2:26]1)=[CH:21][CH2:20]3)[OH:12].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C@H:24]2[CH2:25][CH2:26][C@@:27]3([CH3:28])[C:22](=[CH:21][CH2:20][C@@H:19]4[C@@H:29]3[CH2:30][CH2:31][C@@:14]3([CH3:15])[C@H:16]4[CH2:17][CH2:18][C:13]3=[N:11][OH:12])[CH2:23]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Reactant: Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)c3ccc(N)cc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=NO)CC[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.4 %

Procedure:
p-Aminobenzoic acid (0.22 g, 1.6 mmol) was added to the stirred solution of 17-oximino-5-androsten-3β-ol (9) (0.5 g, 1.6 mmol) and dicyclohexylcarbodiimide (DCC) (0.34 g, 1.6 mmol) in anhydrous dichloromethane (30.0 ml). The reaction mixture was stirred for 48 hr at room temperature (20-25°) and completion of the reaction was monitored by TLC. The precipitated dicyclohexylurea (DCU) was filtered, solvent removed under vacuum and the residue was crystallized from ethyl acetate:petroleum ether (60:80) to obtain 17-oximino-5-androsten-3β-yl 4-aminobenzoate (14) (0.28 g, 56.0%) mp 165-168° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O)C.[H-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:14][C@@:11]1([CH2:13][N:18]2[CH2:19][CH2:20][N:15]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]3)[CH2:16][CH2:17]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCN(C[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)CC2)CC1
Temperature: 50 °C
Reaction time: 9 h
Yield: 65.7 %

Procedure:
A mixture of (R)-2-chloro-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (3 g, 13.79 mmol), tert-butyl 4-piperazin-1-yl-piperidine-1-carboxylate (3.9 g, 14.48 mmol), and ethanol (30 ml) was stirred at 50° C. for 9 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1) to obtain a yellow amorphous form. The amorphous form was dissolved in N,N-dimethylformamide (18 ml), sodium hydride (651 mg, 16.28 mmol) was added while cooling on ice, and the resultant solution was stirred at the same temperature for 1 hour. To the reaction mixture, ethyl acetate (6 ml) and water (42 ml) were added in this order, and the precipitated crystals were filtered off and washed with water. The filtrate was recrystallized from 2-propanol (20 ml)/water (60 ml) to obtain tert-butyl (S)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]piperidine-1-carboxylate (4.08 g, 66%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7](=[O:9])[C:6]2[CH:13]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH2:11])=[CH:17][CH:16]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: Nc1ccc(Br)cc1
Product: Nc1ccc(Cl)cc1C(=O)Nc1ccc(Br)cc1

Procedure:
A similar procedure starting from 5-chloroisatoic anhydride and 4-bromoaniline gave N-(4-bromophenyl)-2-amino-5-chlorobenzamide which gave the expected NMR, MS, and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26](F)[CH:25]=2)=[CH:4][CH:3]=1.[CH3:31][O-:32].[Na+].O>CN1CCCC1=O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([O:32][CH3:31])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnc(F)c4)n3n2)CC1
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: O
Product: COc1cc(-c2c(-c3ccc(F)cc3)nc3ccc(N4CCN(C)CC4)nn23)ccn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution under argon of 0.10 g (0.25 mmol) of 2-(4-fluorophenyl)-3-(2-fluoropyrid-4-yl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in N-methylpyrrolidone is added 0.65 mL (3.4 mmol) of sodium methoxide at 30% by weight in methanol. After stirring for 4 days at room temperature, the medium is poured into 200 mL of water and the product is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure to give a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([O:16]CC)=[O:15])=[C:12]([CH3:19])[O:11][N:10]=1.[OH-].[Na+].CCOCC.Cl>CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:19])[O:11][N:10]=1
Reactant: CCOC(=O)c1c(-c2ccccc2OC)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1-c1noc(C)c1C(=O)O
Temperature: 65 °C
Reaction time: 20 h

Procedure:
The reaction mixture of ethyl 3-(2-methoxyphenyl)-5-methylisoxazole-4-carboxylate (12.85 g, 49.2 mmol) and sodium hydroxide (9.84 g, 246 mmol) in MeOH (100 mL) and Water (10 mL) in a 500-mL round bottom flask was stirred at 65° C. for 20 hours. The MeOH was removed in vacuo, then the concentrated reaction mixture was transferred to a 500-mL separatory funnel with 150 mL of water and 100 mL of ether. The organic layer was discarded. The aqueous layer was acidified by adding concentrated HCl (26 mL). The product precipitated and was separated by filtration and dried under high vacuum to give 10.63 g (93%, theoretical yield 11.47 g). 1H NMR (400 MHz, CD3OD) δ 2.69 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 7.00-7.07 (m, 2H, aryl), 7.32-7.34 (m, 1H, aryl), 7.43-7.48 (m, 1H, aryl).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([CH2:16][N:17]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:23][CH:22]=3)[C:18](=[O:20])[CH3:19])=[CH:13]2)=[CH:8][CH:7]=1)(=[NH:5])[NH2:4].Cl.[C:35](=[NH:40])(OCC)[CH3:36].C(N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:35]([N:31]1[CH2:30][CH2:29][CH:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([N:17]([CH2:16][C:12]3[CH:11]=[CH:10][C:9]4[C:14](=[CH:15][C:6]([C:3](=[NH:4])[NH2:5])=[CH:7][CH:8]=4)[CH:13]=3)[C:18](=[O:20])[CH3:19])=[CH:22][CH:23]=2)[CH2:33][CH2:32]1)(=[NH:40])[CH3:36]
Reactant: CC(=O)N(Cc1ccc2ccc(C(=N)N)cc2c1)c1ccc(OC2CCNCC2)cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=N)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 197.7 %

Procedure:
N-[(7-Amidino-2-naphthyl)methyl]-N-[4-[(4-piperidyl)oxy]phenyl]acetamide dihydrochloride (56 mg) was dissolved in 2 ml of ethanol, 28 mg of ethyl acetoimidate hydrochloride and 36 mg of triethylamine were added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was evaporated, and the resulting residue was purified by an ODS (YMC-GEL ODS-A 120-230/70) column chromatography using methanol:water (2:98) as the eluent, followed by addition of a small amount of 1N hydrochloric acid and freeze-drying to give 60 mg of N-[4-[(1-acetoimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]acetamide dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[C:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:10]=3[C:9]=2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3=CCCCC3)c2s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A solution (0.11 M) of methyl 5-(4-chlorophenyl)-6-cyclohex-1-en-1-yl-4H-thieno[3,2-b]pyrrole-2-carboxylate in TFA at 0° C. was treated with triethylsilane (1.5 eq.). The reaction mixture was stirred at 0° C. for 2 h then solvent was evaporated to give the title compound (99%) as a solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[C:16](\[CH3:19])/[CH:17]=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]1([CH2:26][CH2:27][CH2:28][Mg]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(CCCC(O)CCCC2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:10][CH2:11][C@H:12](/[CH:15]=[C:16](\[CH3:19])/[CH:17]([OH:18])[CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Br[Mg]CCCc1ccccc1
Reactant: C/C(C=O)=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: OC(CCCc1ccccc1)CCCc1ccccc1
Solvent: C1CCOC1
Product: C/C(=C\[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1)C(O)CCCc1ccccc1

Procedure:
The alcohol 137 was prepared from the crude aldehyde 136. and 1.5 mL (0.75 mmol) of 120 in 2.0 mL of THF as described above for the synthesis of alcohol 121 in Example 1 to give 220 mg of the crude diastereomeric alcohol 137. Flash chromatography (elution with 20% ethyl acetate in hexane) afforded 146 mg of the alcohol 137 as an oil. 1H NMR consistent with structure.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([OH:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Na+].C(=O)([O-])O.[Na+].Cl[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CC1(C)N([O])C(C)(C)CCC1.O.C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11](=[O:14])[CH2:12][Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC(O)CCl)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCl)COC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
To the mixture consisting of 30 mmol (6.44 g) of 1-benzoyloxy-3-chloro-2-propanol, 1.5 mmol (234 mg) of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 33 mmol (3.4 g) of sodium bromide, 90 mmol (7.50 g) of sodium hydrogencarbonate, 75 ml of ethyl acetate and 35 ml of water was added dropwise 45 mmol (30 g) of sodium hypochlorite aqueous solution (1.5 mmol/g) under cooling with ice. Temperature of the reaction system was about 4° C. and pH was about 8.5. After the dropping was completed, stirring was further continued for 30 minute. Thereto was added 20 ml of a 5% sodium thiosulfate aqueous solution and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered off and concentrated under reduced pressure to obtain a crude product. It was purified with silica gel column to obtain 5.56 g of 1-benzoyloxy-3-chloro-2-propanon. The yield was 87%.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:8][C:9]1[C:10]([F:35])=[C:11]([CH:32]=[CH:33][CH:34]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:30][CH3:31])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CCl)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Chloroacetyl chloride (135 mg) was added to a solution of 4-(3-chloro-2-fluoroanilino)-6-(piperidin-4-yloxy)-7-methoxyquinazoline di-hydrochloride (500 mg) (Starting material for Example 16) and diisopropylethylamine (368 mg) in methylene chloride (15 ml) that was cooled at 0° C. and the mixture was stirred for 2 hours and allowed to warm to room temperature. The reaction mixture was adsorbed onto silica and the residue purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 94/6). The fractions containing the expected product were combined and were re-purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 96/4). The fractions containing the expected product were combined and evaporated under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[1-(chloroacetyl)piperidin-4-yloxy]-7-methoxyquinazoline as a crystalline solid (0.33 g); 1H NMR Spectrum: (DMSO d6) 1.60-1.83 (m, 2H), 1.94-2.10 (m, 2H), 3.36-3.46 (m, 2H), 3.67-3.86 (m, 2H), 3.94 (s, 3H), 4.40 (s, 2H), 4.77 (m, 1H), 7.22 (s, 1H), 7.27 (t, 1H), 7.46-7.55 (m, 2H), 7.89 (s, 1H), 8.38 (s, 1H), 9.60 (s, 1H); Mass Spectrum: (M+H)+ 479.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21]OS(C)(=O)=O)[N:9]=1.[N:30]1[CH:35]=[CH:34][C:33]([C:36]2[NH:37][C:38]([SH:41])=[N:39][N:40]=2)=[CH:32][CH:31]=1.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:11]=[C:10]([CH2:20][CH2:21][S:41][C:38]2[NH:37][C:36]([C:33]3[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=3)=[N:40][N:39]=2)[N:9]=1
Reactant: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCOS(C)(=O)=O)n2)c1
Reactant: Sc1nnc(-c2ccncc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)nc(CCSc3nnc(-c4ccncc4)[nH]3)n2)c1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
Compound 95, methanesulfonic acid 2-{4-[N′-(3-methyl-benzylidene)-hydrazino]-6-morpholin-4-yl-pyrimidin-2-yl}-ethyl ester (50 mg., 0.12 mmol) was dissolved in tetrahydrofuran (2 mL). To the reaction mixture was added 5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (124 mg., 0.66 mmol) and sodium hydride (12 mg., 0.5 mmol) and the vessel was stirred at room temperature for sixteen hours. The solvent was removed under reduced pressure and the crude oil was purified by column chromatography to give Compound 25, N-(3-methyl-benzylidene)-N′-{6-morpholin-4-yl-2-[2-(5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-pyrimidin-4-yl}-hydrazine (34 mg.).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:19]4[C:24]([CH:25]=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[CH3:27][Mg]Br.O>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([O:18][C:19]4[C:24]([CH:25]([OH:26])[CH3:27])=[CH:23][CH:22]=[CH:21][N:20]=4)=[C:13]([C:14]([F:16])([F:15])[F:17])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cccnc1Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-{[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]oxy}pyridine-3-carbaldehyde (417, 20 mg, 0.055 mmol, 1 equiv.) was dissolved in tetrahydrofuran (2 mL), cooled to 0° C. and treated with methylmagnesium bromide (28 μL, 0.083 mmol, 1.5 equiv). After stirring for 30 minutes, the mixture was poured into water (10 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC (gradient 80:20 to 5:95; water containing 0.05% trifluoroacetic acid:acetonitrile containing 0.05% trifluoroacetic acid) to provide the titled compound 418. High resolution mass spectrometry (ES+) m/z=379.1374, [(M+H)+ calculated for C18H18F3N4O2: 379.1376].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[N:36]1([C:2]2[C:7]([C:8]#[N:9])=[C:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=3)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[S:27][CH:28]=3)[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: C1CNC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 100 mg (0.19 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.015 ml (0.22 mmol) of azetidine were stirred in 2.5 ml of THF overnight. Another 0.025 ml (0.36 mmol) of azetidine was then added, and the mixture was once more stirred at RT overnight. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 85 mg (82% of theory) of the desired target compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14].[CH3:15][O:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][O:16][C:17](=[O:33])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CCc1ccccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c1OCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCOc2ccccc2CCC(=O)OC)ccc2c1OCC2=O
Reaction time: 3 h
Yield: 68.1 %

Procedure:
A mixture of 0.154 g (0.8 mmol) of 6-hydroxy-7-propyl-2H-benzofuran-3-one, 0.27 g (0.82 mmol) of 2-[(5-bromopentyl)oxy]benzenepropanoic acid methyl ester, 0.382 g (2.77 mmol) of anhydrous granular potassium carbonate, and 6 mL of anhydrous N,N-dimethylformamide was stirred at 60°-65° C. for 3 hr. The resulting slurry was cooled and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 7:3 and 6:4 hexane-ethyl acetate. There was obtained 0.24 g (68%) of 2-[5-[(2,3-dihydro-3-oxo-7-propylbenzofuran-6-yl)oxy]pentyloxy]benzenepropanoic acid methyl ester as a pale-yellow oil. A 0.1 g (0.227 mmol) sample of this material was dissolved in 10 mL of tetrahydrofuran and 1 mL of 3N aqueous HCl was added. The mixture was stirred at room temperature for 2.5 hr then heated at 60°-65° C. for 28 hr. After being stirred overnight at room temperature, the solution was diluted with water and worked-up with dichloromethane in the usual manner giving a viscous oil. Flash chromatography on silica gel, eluting with ethyl acetate and 9:1 ethyl acetate-methanol gave 0.04 g (41.5%) of 2-[ 5-[(2,3-dihydro-3-oxo-7-propylbenzofuran-6-yl)oxy]pentyloxy]benzenepropanoic acid as a pale-yellow gum which crystallized. Trituration of a sample with ether-hexane gave a pale-yellow solid, mp 101°-102.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:18][C:19]1[C:24]([NH:25][C:26](OC(C)(C)C)=[O:27])=[CH:23][CH:22]=[C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:20]=1)C(OCC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:27]=[C:26]1[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:20]=2)[NH:25]1
Reactant: CCOC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1Cc2nc(-c3ccccc3)ccc2NC1=O)OCc1ccccc1
Yield: 102.6 %

Procedure:
A solution of 1L (145 mg, 0.287 mmol) in TFA (1 mL) and CH2Cl2 (1 mL) was stirred at RT for 1 h. After this time, no starting material was detected by LC-MS. The reaction was concentrated under reduced pressure. The resulting residue was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (20 mL). The aqueous layer was extracted with EtOAc (20 mL×2). The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to give the title compound as a white solid (110 mg, 100%). LC/MS (method A): retention time=3.09 min, (M+H)+=374.