Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])#[CH:2].Cl[C:16]([O:18][CH3:19])=[O:17].[H-].[Na+].Cl>O1CCCC1>[CH3:19][O:18][C:16]([NH:9][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[CH:2])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=1)=[O:17]
Reactant: C#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Reactant: COC(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)NC(=O)OC)cc1[N+](=O)[O-]
Temperature: -10 °C
Yield: 40.8 %

Procedure:
3 g (0.016 mol) 4-Ethynyl-3-nitrobenzamide (Compound I-1), 45 ml tetrahydrofuran and 6 ml methyl chloroformate were added into a 100 ml four-neck reactor flask, stirred to dissolve and cooled to −10° C., and 7.5 g sodium hydride was added and maintained at about 0° C. for 30 minutes. After the completion of the reaction, the reaction mixture was poured into crushed ice and the pH was adjusted to acidic with hydrochloric acid, and then extracted with 200 ml ethyl acetate. The organic layer was washed with water for three times, and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain about 3.5 g crude product, which was separated by column chromatography to obtain N-methoxycarbonyl-4-ethynyl-3-nitrobenzoateamide (Compound I-2), 1.6 g (0.0065 mol), yield 40.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:33]([F:36])([F:35])[F:34])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[C:19]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CO.[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:33]([F:35])([F:34])[F:36])[O:16][N:15]=[C:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH2:28][C:29]([F:31])([F:32])[F:30])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1CC(F)(F)F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 50-mL pressure tank reactor (10 atm), was placed ethyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoate (300 mg, 0.55 mmol, 1.00 equiv), methanol (5 mL), sodium hydroxide (600 mg, 15.00 mmol, 13.69 equiv), water (5 mL). The resulting solution was stirred overnight at 70° C. The pH value of the solution was adjusted to 5 with hydrogen chloride (3 mol/L). The resulting solution was extracted with 3×10 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. This resulted in 200 mg (crude) of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(2,2,2-trifluoroethyl)benzoic acid as yellow oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]2([CH3:24])[CH3:23]>C(Cl)Cl>[CH3:9][O:10][C:11]1[C:20]([C:5](=[O:7])[CH3:6])=[CH:19][C:18]2[C:17]([CH3:22])([CH3:21])[CH2:16][CH2:15][C:14]([CH3:24])([CH3:23])[C:13]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a suspension of AlCl3 (6.6 g, 49.6 mmol) in CH2Cl2 (225 mL) at 0° C. was added acetyl chloride (3.5 mL, 49.6 mmol) dropwise via syringe. To the resulting homogeneous light brown solution was added 6-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 2, 9.0 g, 41.3 mmol) in CH2Cl2 (25 mL) via cannula. The mixture was then stirred at ambient temperature for 1 h, poured onto ice and extracted with Et2O (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a white solid (10.7 g, 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9]O)[CH:2]=1.[BrH:11]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][CH2:9][Br:11])[CH:2]=1
Reactant: OCCCc1cccnc1
Reactant: Br
Product: BrCCCc1cccnc1

Procedure:
To 17.0 g (124 moles) of 3-(3-pyridyl)-1-propanol was added 240 mL of 48% hydrobromic acid. The mixture was heated under reflux for 4 hours, and then evaporated to dryness to afford the hydrobromide salt of 3-(3-pyridyl)-1-bromopropane as an oil in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:32])[C:30]#[CH:31].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH:30]([C:29]#[CH:32])[CH3:31])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: C#CC(C)Br
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(C)Oc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
First, 100 mg of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-61) was dissolved in 0.60 ml of N,N-dimethylformamide, to which 64 mg of potassium carbonate and 45 mg of 3-bromo-1-butyne were added, and the mixture was stirred at 70° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 96 mg (yield, 83%) of 3-{4-chloro-2-fluoro-5-(3-butyn-2-yloxy)phenyl}-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-157).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[CH3:19][C:20]1[CH:21]=[C:22]2[C:27](=O)[O:26][C:24](=[O:25])[C:23]2=[CH:29][CH:30]=1>CC#N>[NH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([N:1]3[C:27](=[O:26])[C:22]4[C:23](=[CH:29][CH:30]=[C:20]([CH3:19])[CH:21]=4)[C:24]3=[O:25])[CH2:3][CH2:4]2)=[CH:11]1
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Solvent: CC#N
Product: Cc1ccc2c(c1)C(=O)N(C1CCN(CCc3c[nH]c4ccccc34)CC1)C2=O
Yield: 27.4 %

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (1.22 g, 5 mmol) was dissolved in warm methyl cyanide (50 cm3) and a solution of 4-methylphthalic anhydride (0.81 g, 5 mmol) in methyl cyanide (10 cm3) was added dropwise with stirring to precipitate a white solid. The suspension was stirred overnight then the solid collected and heated in acetic anhydride (40 cm3) for 2 hours on a steam bath. The acetic anhydride was evaporated. The residue was dissolved in very dilute aqueous acetic acid and the solution basified by addition of conc. ammonia to give a gum. The mother liquor was decanted and the gum recrystallised from ethanol to give crystals of the title compound (0.53 g, 27.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Cl-].[Al+3].[Cl-].[Cl-].[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C(Cl)Cl>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([S:11]([NH2:12])(=[O:14])=[O:13])[CH:4]=1)(=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)c2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.9 %

Procedure:
To a well stirred solution of 4-chloro-3-sulfamoyl-benzoyl chloride (0.5 g, 1.97 mmol) in 5 mL methylene chloride is added aluminum chloride (0.485 g, 1.85 mmol). After 30 min, benzene (1 mL, 5.72 mmol) is added and the reaction is stirred for 2 h at room temperature. The reaction mixture is then poured over ice, acidified with 6 N HCl and extracted three times with diethyl ether. The organic layers were combined, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography to yield 40 mg (69%) of the title compound as a tan solid. MS (m/z): 294 (M-1). Analytics calculated for C13H10ClNO3S: C, 52.8; H, 3.41; N, 4.74. Found: C, 52.62; H, 3.21; N, 4.72.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][C:13]([NH2:15])=[O:14]>CN(C)C=O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][C:13]([NH2:15])=[O:14])[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc[nH]n1
Reactant: NC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc([N+](=O)[O-])n1
Yield: 47.3 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 150 mg, 1.33 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (58 mg, 1.46 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, bromoacetamide (201 mg, 1.46 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 2-(3-nitro-pyrazol-1-yl)-acetamide (107 mg, 48%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]=1[CH3:18])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]2[O:13][C:15]([CH2:17][OH:27])([CH3:16])[CH2:14][C:7]=2[C:6]=1[CH3:18])(=[O:3])[CH3:2]
Reactant: C=C(C)Cc1c(C)c(OC(C)=O)c(C)c(C)c1O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(C)(CO)O2
Reaction time: 1 h
Yield: 87.3 %

Procedure:
In methylene chloride (100 ml) was dissolved 4-acetoxy-2-(2-methyl-2-propenyl)-3,5,6-trimethylphenol [30 g (40.3 mmol)]. To the solution was added at 0° C., in limited amounts, m-chloroperbenzoic acid [16.7 g (67.8 mmol)]. The reaction mixture was stirred for one hour, and there was added triethylamine (30 ml), followed by stirring for further one hour. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate, and then dried, followed by distilling off the solvent. The residue was crystallized from isopropyl ether-hexane to obtain the desired 5-acetoxy-2-hydroxymethyl-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran [9.3 g (yield 87.4%, m.p. 98°-99° C.)].
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.CN(C=O)C.Br[CH2:16][CH2:17][CH2:18][C:19]#[N:20]>CCCCC>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:16][CH2:17][CH2:18][C:19]#[N:20])[CH:5]=1
Reactant: Oc1cccnc1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: N#CCCCOc1cccnc1
Yield: 56 %

Procedure:
Sodium hydride (13.3 g., 0.32 mol, 57% oil dispersion) was washed with pentane to remove the oil and 26.1 g. (0.275 mol) of 3-hydroxypyridine in 300 ml. of anhydrous DMF was added with cooling in a cold water bath. The mixture was then stirred and heated at 60° for 1 hour. After cooling to 25°, 40.7 g. (0.275 mol) of 4-bromobutyronitrile in 40 ml. of anhydrous DMF was added dropwise over 1 hour with cooling to keep the reaction temperature below 30°. The reaction mixture was then stirred at 25° for 17 hours and the solvent was removed in vacuo. The residue was treated with 100 ml. of water and the product was extracted with CH2Cl2. After washing the extract with 1N NaOH and then with H2O, it was dried (MgSO4) and concentrated in vacuo to an oil which was distilled to yield 25.1 g., b.p. 133°-135°/0.4 mm, (56% yield), of 4-(3-pyridinyloxy)butyronitrile.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([CH2:14][S:15]C(=O)C)[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=1)C>Cl>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][CH:5]([CH2:14][SH:15])[C:4]([OH:19])=[O:3])[CH:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)C(CSC(C)=O)Cc1ccnc(N)c1
Agent: Cl
Product: Nc1cc(CC(CS)C(=O)O)ccn1

Procedure:
2-Acetylsulfanylmethyl-3-(2-amino-pyridin4-yl)-propionic acid ethyl ester (52 mg, 0.13 mmol) was dissolved in conc. HCl (2 mL) under argon. The solution was heated to reflux for 1 h. Concentration under reduced pressure gave the title compound as the hydrochloride salt (32 mg, 100%).
Reaction SMILES: [H-].[Na+].[CH:3]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][C:35](=[O:38])[NH:36][CH:37]=4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:27]=[CH:28][C:29]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH:3]5[CH2:7][CH2:6][CH2:5][CH2:4]5)=[N:36][CH:37]=4)=[CH:30][N:31]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: BrC1CCCC1
Reactant: O=c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC2CCCC2)ncc1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
60% sodium hydride (21 mg) and cyclopentyl bromide were added to a DMF solution (4 ml) of 2-(1-cyclopentylpiperidin-4-yloxy)-5-(1H-pyridin-2-on-5-yl)pyrimidine (120 mg), and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:24][CH:23]=[CH:22][C:21]=3[F:25])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:28])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1c(F)cccc1F
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3c(F)cccc3F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2,6-difluoro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 11.12(s, 1H), 8.71 (m, 1H), 8.26 (m, 2H), 8.13 (d, 1H), 7.98 (d, 1H), 7.75 (m, 2H), 7.62 (m, 1H), 7.31 (t, 2H), 4.01 (d, 1H), 3.60 (d, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.15 (t, 2H), 1.45 (m, 2H), 1.43 (q, 2H), 1.17 (m, 2H), 0.81 (t, 3H); LC/MS m/z 514 (M−H)−, 516 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[NH2:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21]#[N:22].C(N(CC)CC)C>CC(O)C>[CH3:16][C:15]1[NH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[C:20]([C:21]#[N:22])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1

Procedure:
A suspension of 5.4 g (24.0 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 13.05 g (95.9 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] in 2-propanol (27 ml) and triethylamine (0.33 ml) was stirred at reflux temperature for 15 h. After cooling, the precipitate was collected by filtration, washed twice with cold 2-propanol and dried under high vacuum to yield 5.98 g (72% of th.) of the racemic title compound as a tan solid.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([N:11]1[CH2:15][CH:14]([N:16]2C(=O)[C:19]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]3[C:17]2=[O:26])[CH2:13][N:12]1[CH2:27][CH3:28])[CH3:10].Cl.[F:30]C1C=CC(C(Cl)=O)=CC=1>>[F:30][C:23]1[CH:22]=[CH:19][C:18]([C:17]([NH:16][CH:14]2[CH2:15][N:11]([CH2:9][CH3:10])[N:12]([CH2:27][CH3:28])[CH2:13]2)=[O:26])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CC(N2C(=O)c3ccccc3C2=O)CN1CC
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Product: CCN1CC(NC(=O)c2ccc(F)cc2)CN1CC

Procedure:
A solution of 10 g. (0.026 mole) of 1,2-diethyl-4-phthalimidopyrazolidine maleate in 25 ml. of 6 N hydrochloric acid was refluxed two hours, the resulting mixture was cooled and filtered. The filter cake was washed with water which was combined with the acidic solution. The acidic solution was made basic with dilute sodium hydroxide and cooled with ice. To the resulting solution was added 8.2 g. (0.052 mole) of p-fluorobenzoyl chloride and the mixture shaken for 10 minutes. The resulting mixture was extracted with chloroform, the chloroform diluted with an equal volume of isopropyl ether and the resulting solution extracted with dilute hydrochloric acid. The acid layer was made basic with dilute sodium hydroxide and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized from isooctaneisopropyl ether and recrystallized from isooctaneisopropyl ether containing a few drops of ethyl acetate and clarified by charcoal treatment. The product (2.0 g; 29%) melted at 114°-116° C.
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]4)=[CH:17][CH:16]=3)=[O:13])[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:34].C(OCC)C>O1CCOCC1>[ClH:34].[NH:23]1[CH2:24][CH2:25][O:26][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]([C:10]3[CH:9]=[N:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)=[O:13])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3cnn(-c4ccccc4)n3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc([C@H]2CNCCO2)cc1)c1cnn(-c2ccccc2)n1
Temperature: 60 °C
Reaction time: 48 h
Yield: 93.2 %

Procedure:
To a solution of (S)-tert-butyl 2-(4-(2-phenyl-2H-1,2,3-triazole-4-carboxamido)phenyl)morpholine-4-carboxylate (30 mg, 66.7 μmol, Eq: 1.00) in dioxane (2 ml) was added 4 M HCl in dioxane (250 μl, 1.00 mmol, Eq: 15). The reaction mixture was stirred at 60° C. for 48 hours. To the mixture was added 2 ml of diethyl ether and stirred for 15 min at room temperature. The mixture was filtered and concentrated in high vacuum to give the expected HCl salt as a light-yellow solid (24 mg, 93.2%). MS (ISP): 350.3 ([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[F:15][C:12]1[CH:13]=[CH:14][C:9]2[N:8]=[N:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:27]3[CH2:26][CH2:25][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=4)[CH2:29][CH2:28]3)[C:10]=2[CH:11]=1
Reactant: Fc1ccc2nnn(CCCCCl)c2c1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Fc1ccc2nnn(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c2c1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
1-(4-chlorobutyl)-6-fluoro-1H-benzotriazole (8.2 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.3 g compound (I-32) with a yield of 65.7%. ESI-MS [M+H]+: m/z 422.2.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C:7]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[N:9]=1
Reactant: Cc1ccc(-c2cc(C#N)c(Cl)nc2-c2ccc(Cl)cc2Cl)cc1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C#N)c(N3CCCCC3)nc2-c2ccc(Cl)cc2Cl)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To an oven-dried round bottom flask fitted with a rubber septa was added toluene (1 mL), the product of Step D of Example 114 (0.050 g; 0.134 mmol) and piperidine (0.070 mL; 0.670 mmol). The sealed reaction mixture was heated at 100° C. and stirred for 16 hours. The reaction mixture was allowed to cool to room temperature, then it was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic portion was separated and washed with more saturated NaHCO3 solution (2×), brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification was done by MPLC (silica gel; 0-10% ethyl acetate:hexane) to afford the desired product: m/e=422 (M+1) Rt=5.10 min on LCMS.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([CH2:12]Cl)=[N:7]2.[N:23]1[C:31]([NH2:32])=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[N:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:32][C:31]1[N:23]=[CH:24][N:25]=[C:26]2[C:30]=1[N:29]=[CH:28][N:27]2[CH2:12][C:6]1[N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[C:4](=[O:22])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[Cl:1])[N:7]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1-n1c(Cn2cnc3c(N)ncnc32)nc2cccc(Cl)c2c1=O
Yield: 38.3 %

Procedure:
Prepared according to Procedure C using 2l (250 mg, 0.746 mmol), adenine (111 mg, 0.821 mmol), K2CO3 (113 mg, 0.821 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 and recrystallized from EtOH to provide 124 mg of a brown solid (38%), mp 257.0-257.1° C. 1H NMR (DMSO-d6) δ: 8.06 (s, 1H); 8.01 (s, 1H); 7.71 (t, J=8.0 Hz, 1H); 7.57 (dd, J=0.9, 7.9 Hz, 1H); 7.52-7.59 (m, 1H); 7.50 (dd, J=1.6, 7.8 Hz, 1H); 7.38 (dd, J=1.1, 8.2 Hz, 1H); 7.27 (dd, J=0.6, 8.3 Hz, 1H); 7.24 (br s, 2H); 7.17 (dt, J=0.9, 7.6 Hz, 1H); 5.07 (d, J=17 Hz, 1H); 4.97 (d, J=17 Hz, 1H); 3.79 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.8, 156.2, 154.7, 153.2, 152.8, 150.1, 149.3, 142.0, 135.1, 133.2, 131.8, 130.1, 130.1, 127.2, 123.8, 121.6, 118.4, 117.9, 113.1, 56.2, 44.8. MS (ES): m/z 434.0 (M+). Anal. calcd. for C21H16ClN7O2.0.5H2O.0.04KCl: C, 56.57; H, 3.84; Cl, 8.27; N, 21.99. Found: C, 56.29; H, 3.75; Cl, 8.21; N, 21.61.