Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].[NH2:13]C(N)=O.S1(CCCC1)(=O)=O.C(=O)=O>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([NH:13][C:8](=[O:7])[C:3]=12)=[O:6]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: NC(N)=O
Agent: O=C=O
Solvent: O=S1(=O)CCCC1
Product: O=C1NC(=O)c2c(F)cccc21
Reaction time: 0.25 h

Procedure:
A mixture of 49.8 parts (0.3 mole) of 3-fluorophthalic anhydride and 9.9 parts (0.165 mole) of urea in 126 parts of sulfolane is heated at 125°-130° C., while stirring. The mixture is stirred for 30 minutes, when the evolution of carbon dioxide is complete, after which stirring is continued for a further 15 minutes at 168° C. The solvent is distilled off (98 parts) at a bath temperature of 130°-160° C. under 0.3 mbar. A gas chromatogram shows that it contains 2.75 parts of 3-fluorophthalimide. The distillation residue is triturated with water, and the product is filtered off under suction, washed and dried, 44.5 parts of 3-fluorophthalimide of melting point 179°-182° C. being obtained. The total yield is 47.25 parts (95.3% of theory) of 3-fluorophthalimide.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[C:1]([C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][CH:22]=[C:20]([CH2:19][Cl:18])[N:15]=2)=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(C(=O)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1ccc(-c2nc(CCl)co2)cc1
Yield: 46 %

Procedure:
In substantially the same manner as in Reference Example 47, 4-benzoylbenzamide was allowed to react with 1,3-dichloroacetone to give 2-(4-benzoylphenyl)-4-chloromethyloxazole. The yield was 46%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 138-139° C.
Reaction SMILES: [OH-].[Li+].[Al+3].[OH-].[OH-].[OH-].[C:7]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([OH:20])([CH2:13]3)[CH2:11]1)[CH2:17]2)(O)=[O:8]>O1CCCC1>[OH:8][CH2:7][C:10]12[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][C:12]([OH:20])([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: [Al+3]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCC12CC3CC(CC(O)(C3)C1)C2
Yield: 95 %

Procedure:
15 mmol of aluminiumlitium hydroxide was suspended in 15 ml of tetrahydrofuran (THF) in a nitrogen atmosphere. To the solution was slowly added 10 mmol of the 1-carboxy-3-adamantanol obtained in Preparation Example 5 while the temperature of the solution was maintained at less than 10° C. or below by ice water bath. After the temperature of the mixture was raised to room temperatures, the mixture was refluxed for 16 hours. And, as the result, the 1-carboxy-3-adamantanol was converted into a 1-hydroxymethyl-3-adamantanol (yield: 95%) with a conversion of 99%.
Reaction SMILES: Br.[C:2]([O:6][C:7]([CH2:9][N:10]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17][N:16]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:15][CH2:14][N:13]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:12][CH2:11]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41]>C(#N)C>[C:2]([O:6][C:7]([CH2:9][N:10]1[CH2:21][CH2:20][N:19]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:18][CH2:17][N:16]([CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:15][CH2:14][N:13]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:12][CH2:11]1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CN1CCNCCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Agent: Br
Solvent: CC#N
Product: COC(=O)CN1CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
1,4,7-Tri-tertbutoxycarbonylmethyl-1,4,7,10-tetraazacyclododecane hydrobromide (25.0 g, 42 mmol) was slurried in acetonitrile and treated with TMG (70 mL). Methyl bromoacetate (6.5 g, 42 mmol) was added in one portion, and the mixture was refluxed for 3 hours. After stirring at ambient temperature for an additional 18 hours, the solvent and excess TMG were removed by rotary evaporation. The residue was dissolved in CHCl3, washed with water, and dried (Na2SO4). Evaporation of the solvent afforded the title product as a pale oil (23 g, 95%). 1H NMR (CDCl3): 1.4 (s, 27 H) , 2.8 (s, 16 H), 3.2 (s, 6 H), 3.4 (s 2 H), 3.6 (s, 3 H).
Reaction SMILES: ClCCl.CO[C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][C:11](C)=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1.B(Br)(Br)Br.[CH3:39][OH:40]>>[OH:40][CH2:39][C:6]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:9]2=[N:10][CH:11]=[CH:12][C:13]([CH3:14])=[C:8]2[N:7]=1
Reactant: CO
Reactant: COc1nc2c(C)cc(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccnc2c1nc(CO)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
30 ml of a dichloromethane solution of 410 mg (1 mmol) of 2-methoxy-methyl-7-methyl-3[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl)-methyl]-3H-imidazo[4.5-b]pyridine was stirred, cooled with ice. During this step, 10 ml (10 mmol) of dichloromethane solution of 1M boron tribromide was added little by little thereto dropwise. The mixture was further agitated at a room temperature for 12 hours. The reaction product mixture was cooled, while stirred. During this step, methanol was added little by little. The solvent was distilled out at a reduced pressure. The residue was mixed with water, neutralized with sodium bicarbonate, adjusted to a weak acidity with acetic acid and decanted to remove the water. The residue was mixed with methanol. The solvent was distilled out at a reduced pressure. The residue was treated with isopropylether for re-crystallization to obtain 330 mg of the intended compound.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Reactant: [Li]C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1cc([N+](=O)[O-])ccc1C(C)O
Yield: 89.8 %

Procedure:
Following the General Procedure of Description 8, MeTiCl3 was freshly prepared prior to use from commercial titanium tetrachloride (TiCl4) (4.73 mL, 8.17 g, 43.1 mmol) and methyl lithium (MeLi) (1.6 M in Et2O, 26.9 mL, 43.0 mmol) in anhydrous diethyl ether (Et2O) (230 mL). A solution of 2-methyl-4-nitro-benzaldehyde (7b) (7.11 g, 43.0 mmol) in anhydrous Et2O (200 mL) was added. Aqueous work-up afforded 7.0 g (90% yield) of the target compound (7c) as a yellow solid. The material was of sufficient purity to be used directly in the next step without further isolation and purification procedures. Rf: ˜0.24 (EtOAc/Hxn=1:2 v/v). 1H NMR (300 MHz, CDCl3): δ 8.07 (dd, J=8.7, 2.7 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.72 (d, J=9.0 Hz, 1H), 5.18 (q, J=6.6 Hz, 1H), 2.42, (s, 3H), 1.92-1.88 (br. m, 1H), 1.47 (d, J=6.3 Hz, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=O.O.[NH2:21][NH2:22]>C(O)COCCO>[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:3]=1[C:4](=[N:21][NH2:22])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1
Reactant: NN
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1cccc(Cl)c1
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1cccc(Cl)c1)c1cc([N+](=O)[O-])ccc1N

Procedure:
In the manner given in Preparation 1, 2-amino-3'-chloro-5-nitrobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-amino-3'-chloro-5-nitrobenzophenone hydrazone.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:16])[CH2:14][OH:15])[C@H:9]([CH3:17])[CH2:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:23]1[C:28]([N+:29]([O-:31])=[O:30])=[CH:27][C:26]([Cl:32])=[CH:25][N:24]=1>C1(C)C=CC=CC=1>[Cl:32][C:26]1[CH:27]=[C:28]([N+:29]([O-:31])=[O:30])[C:23]([O:15][CH2:14][C:13]([N:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=3)[CH2:8][C@H:9]2[CH3:17])=[O:16])=[N:24][CH:25]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of 1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-2-hydroxy-ethanone (0.77 g, 2.9 mmol) in dry toluene (30 mL) at 0° C. was added sodium hydride (0.13 g, 3.2 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes at 0° C. followed by addition of 2,5-dichloro-3-nitro-pyridine (0.60 g, 3.18 mmol) as a solution in toluene (5 mL). The reaction was stirred at ambient temperature overnight. The, reaction was concentrated and chromatographed on silica gel to give the title compound (0.96 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:21][O:22][CH2:23][CH2:24][N:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[N:27]=[C:26]1S(C)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:26]4[N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=4)=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Cn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(-c3nn(C)c4cc(F)cnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of 4-(6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (37 mg) in DMF (4 mL) was added NaH (60% in oil, 4.02 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (28.0 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccc(F)c2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2cccc(F)c2)nc1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added 2-(3-fluorophenyl)-5-nitropyridine (3.8 g, 17 mmol), Pd/C (0.5 g) and methanol (100 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give 6-(3-fluorophenyl)pyridin-3-amine 219-1 as brown solid. MS m/z 189.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C@@H:11]([CH3:16])[C:12]([O:14]C)=[O:13].C1COCC1.O[Li].O>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][C@@H:11]([CH3:16])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)[C@H](C)CSc1ccccc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1SC[C@@H](C)C(=O)O
Temperature: 50 °C
Reaction time: 12 h

Procedure:
In a round-bottom flask, 7.11 g (29.6 mmoles) of methyl (2S)-3-[(2-methoxyphenyl)sulfanyl]-2-methylpropanoate (7a-1) and 35.5 mL of THF are introduced. 6.21 g (0.148 mole) of LiOH.H2O dissolved in 35.5 mL of water is added. The mixture is stirred at 50° C. for 12 hours then concentrated under reduced pressure. The residue is taken up with water and the extract is taken up with toluene. The aqueous phase is acidified (pH=2) by adding 36% hydrochloric acid and then extracted with ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The title compound is obtained in the form of a white solid, (5 g, 22.1 mmoles) that can be recrystallized in isopropyl ether if desired.
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.[F:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:35])=[C:20]([CH:34]=1)[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[C:26]([Cl:33])[CH:25]=1)=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[N:1]1[N:10]2[C:4]([CH2:5][N:6]([C:28]([C:27]3[CH:31]=[CH:32][C:24]([NH:23][C:21](=[O:22])[C:20]4[CH:34]=[C:16]([F:15])[CH:17]=[CH:18][C:19]=4[CH3:35])=[CH:25][C:26]=3[Cl:33])=[O:29])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.185 g of 5,10-dihydro-4H-pyrazolo[5,1-c][1,4]benzodiazepine, 0.391 g of 4-[(5-fluoro-2-methylbenzoyl)amino]-2-chlorobenzoyl chloride and 0.158 g of diisopropylethylamine in 10 ml of dichloromethane is stirred at room temperature overnight. The mixture is washed with H2 O, 1N HCl, H2O, 1M NaHCO3, brine and dried (Na2SO4). The solution is passed through a thin pad of hydrous magnesium silicate and the filter cake washed with dichloromethane. The filtrate is again passed through a thin pad of hydrous magnesium silicate. The filtrate is concentrated and the solid crystallized from ethyl acetate to give crystals, m.p. 137°-140° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].[CH2:14](Br)[CH:15]=[CH2:16]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=C(CCCl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A solution of 3-chloro-1-phenylpropan-1-one (100 g, 0.595 mol) in THF (280 ml) was added dropwise to a well-stirred mixture of zinc powder (need not be activated) (40 g, 1.231 mol, satd aq NH4Cl solution (1500 ml) and THF (400 ml). Allyl bromide (143 g, 1.19 mol) was dissolved in THF (200 ml) was slowly added to the reaction mixture. The reaction was mildly exothermic, and the mixture began to reflux spontaneously. After refluxing had ceased, the mixture was stirred for 1 h. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to give 1-chloro-3-phenylhex-5-en-3-ol (122 g, 97%). 1H NMR: (400 MHz, CDCl3): δ=2.24 (s, 1H), 2.34 (m, 2H), 2.53 (m, 1H), 2.75 (m, 1H), 3.20 (m, 1H), 3.58 (m, 1H), 5.18 (t, 1H), 5.51 (m, 1H), 7.26 (m, 1H), 7.26-7.39 (m, 3H).
Reaction SMILES: C(OC(=O)[C:5](=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[C-:19]#[N:20].[K+].C(O)C>O>[CH2:9]([O:8][C:6](=[O:7])[CH2:5][CH:11]([C:19]#[N:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:10]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
120 g of benzalmalonic acid diethyl ester, 33.6 g of potassium cyanide, 1600 cc of ethanol and 160 cc of water are stirred at a bath temperature of 60° for 12 to 14 hours. The reaction mixture is then cooled with ice water, the potassium bicarbonate which crystallizes is filtered off, the filtrate is made neutral with about 15 cc of 1 N hydrochloric acid, air is passed through the solution with a water jet vacuum pump for 1 hour, the solvent is distilled off on a rotary evaporator, 100 cc of water are added to the oily residue, and extraction is effected 6 times with 250 cc amounts of ether. The 3-cyano-3-phenyl-propionic acid ethyl ester, obtained after distilling off the ether, is purified by vacuum distillation. B.P. 125°-130°/0.15 mm Hg.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:12]1[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=1)[N:6]2[CH3:11].[CH:18]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)(C)C>[CH:18]1([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:2]4[N:10]=[CH:9][N:8]=[C:7]5[C:3]=4[N:4]=[C:5]([C:12]4[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=4)[N:6]5[CH3:11])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)[CH2:19][CH2:20]1
Reactant: c1cc(N2CCNCC2)ccc1OCC1CC1
Reactant: Cn1cc(-c2nc3c(Cl)ncnc3n2C)cn1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2nc3c(N4CCN(c5ccc(OCC6CC6)cc5)CC4)ncnc3n2C)cn1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
A stirred solution of 6-chloro-9-methyl-8-(1-methyl-1H-pyrazol-4-yl)-9H-purine (30 mg, 0.12 mmol), 1-(4-(cyclopropylmethoxy)phenyl)piperazine (34.8 mg, 0.15 mmol), and triethylamine (84.0 uL, 0.60 mmol) in isopropyl alcohol (2.0 mL) were heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by preparatory HPLC (reverse-phase, acetonitrile/water with 0.1% formic acid) to give 16.1 mg (30% yield) of the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N+:17]([O-:19])=[O:18])([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[CH2:26]([O:10][C:9]([CH2:8][CH2:7][C:6]([CH2:5][CH2:4][C:1]([O:3][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:2])([N+:17]([O-:19])=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:15])=[O:11])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)CCC(CCC(=O)O)(CCC(=O)O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CCC(CCC(=O)OCc1ccccc1)(CCC(=O)OCc1ccccc1)[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
To a mixture of [3-(2-carboxyethyl)]-3-nitropentane-1,5-dicarboxylic acid (2.8 g, 0.01 mole) (prepared as described by James K. Young et al., Macromolecules, 1994, 27, 3464-34-71) and cesium carbonate (3.25 g, 0.025 mol) in acetonitrile (20.0 mL) was added benzylbromide (8.55 g, 6.0 mL, 0.05 mole) and the mixture stirred at RT for 24 h. Inorganic salts were filtered and the salts washed with acetonitrile. The filtrate and the washings were combined and evaporated to obtain an oil. Purification by chromatography over silica gel (hexane:ethyl acetate, 7:3) afforded the benzyl ester (40) as colorless viscous oil (4.5 g, yield: 82%). Mass Spectrum (M+H)+ =548.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:18][N:19](C)C=O>CN1C(=O)N(C)CCC1>[C:18]([C:2]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:3]=1[O:4][C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:19]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(C)(C)Oc1cc(C)ccc1Cl
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)C(C)(C)Oc1cc(C)ccc1C#N
Temperature: 200 °C
Yield: 38 %

Procedure:
In a similar manner to Example 48(ii), but starting from ethyl 2-(2-chloro-5-methylphenoxy)-2-methylpropionate instead of ethyl 2-(2-bromo-4-methylphenoxy)-2-methylpropionate and using DMPU as solvent in place of dimethylformamide and heating for 18 hours at 200° C. there was obtained, after evaporation of the dichloromethane extracts a liquid. This was dissolved in ether (200 ml) and the solution washed with water (3×50 ml) to removed the DMPU, then dried (MgSO4) and evaporated. The residue was purified by MPLC, eluting with 10% v/v ethyl acetate in hexane to give ethyl 2-(2-cyano-5-methylphenoxy)-2-methylpropionate (38%) as a colourless oil; NMR (250 MHz, CDCl3): 1.24(3H,t J=7 Hz), 1.67(6H,s), 2.33(3H,s), 4.24(2H, q J=7 Hz), 6.60(1H,s), 6.84(1H,dm, J=8 Hz), 7.44(1H,d J=8 Hz); m/e 265 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].N1C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>ClCCl>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[C:27]([CH:31]=1)[C:28]([NH:15][C:12]1[CH:11]=[N:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)=[CH:14][N:13]=1)=[O:29]
Reactant: Cc1ccc(-c2cnc(N)cn2)cc1C
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])cn2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 5-(3,4-dimethylphenyl)pyrazin-2-amine (2 g, 10.04 mmol, 1.00 equiv) in dichloromethane (70 mL), pyridine (2.4 g, 30.34 mmol, 3.00 equiv), and a solution of 5-chloro-2-nitrobenzoyl chloride (2.21 g, 10.05 mmol, 1.00 equiv) in dichloromethane (20 mL). The resulting solution was stirred overnight at 25° C. in an oil bath, then diluted with 150 mL of dichloromethane and washed with 2×100 mL of diluted hydrochloric acid, 2×200 mL of brine and 2×100 mL of sodium carbonate (sat.), and then 2×200 mL of brine. The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with 40 mL of ethyl acetate/n-hexane (1:1). This resulted in 3.66 g (95%) of 5-chloro-N-(5-(3,4-dimethylphenyl)pyrazin-2-yl)-2-nitrobenzamide as an off-white solid.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N+](CCCC)(CCCC)CCCC)CCC.[C:24](=[O:32])([S:29][CH2:30][CH3:31])[O:25][CH:26](Cl)[CH3:27]>O1CCCC1>[C:24](=[O:32])([S:29][CH2:30][CH3:31])[O:25][CH:26]([O:5][C:1](=[O:6])[CH:2]([CH3:4])[CH3:3])[CH3:27]
Reactant: CCSC(=O)OC(C)Cl
Reactant: CC(C)C(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCSC(=O)OC(C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of tetrabutylammonium isobutyrate (5) (382 mmol) in tetrahydrofuran (500 mL) was added compound (2) (49 g, 288 mmol). The mixture was stirred at ambient temperature for 16 h then the solvent removed in vacuo. The residue was dissolved in diethyl ether (600 mL), washed with water (3×300 mL) and the organic phase was separated, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation (60° C./240 mTorr) to afford the product (7) as a colorless liquid (40 g, 63%). 1H NMR (CDCl3, 400 MHz): δ 1.2 (d, 6H), 1.35 (t, 3H), 1.5 (d, 3H), 1.55 (m, 1H), 2.85 (dq, 2H), 6.95 (q, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O.C[N:24](C=O)C>>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH2:24])=[O:15])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN(C)C=O
Reactant: CC1(COc2ccc(C(=O)O)cc2)CCCCC1
Solvent: O=S(Cl)Cl
Product: CC1(COc2ccc(C(N)=O)cc2)CCCCC1
Reaction time: 1.5 h
Yield: 94 %

Procedure:
Add a drop of anhydrous DMF to a mixture of 4-(1-methyl-cyclohexylmethoxy)-benzoic acid (prepared by following the procedure described in Chem. Pharm. Bull. 1982, 30, 3601-3616) (1 g, 4.03 mmol) and thionyl chloride (3.5 mL) at room temperature. Stir the mixture for 1.5 h and then remove the excess of thionyl chloride in vacuo. Take-up the crude acid chloride in anhydrous THF (10 mL) and add the resulting solution to cold concentrated NH4OH (50 mL). Stir for 2.5 h at room temperature and concentrate in vacuo. Collect the solid formed via filtration and dry in vacuo to obtain the desired intermediate (0.94 g, 94%). MS (ES+) m/z: 248 (M+H)+.