Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:17]([OH:18])[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:10]2=O)=[CH:5][CH:4]=1.[N:20]1([C:26]([CH:28]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:10]([CH2:28][C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:27])[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=3[C:17]2=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(N2C(=O)C3=C(CCCC3)C2O)cc1
Reactant: O=C(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)C3=C(CCCC3)C2CC(=O)N2CCCCC2)cc1
Yield: 50.8 %

Procedure:
2-(4-Methoxyphenyl)-3-hydroxy-4,5,6,7-tetrahydroisoindolin-1-one (2.59 g) and piperidinocarbonylmethylenetriphenylphosphorane (4.6 g) were dissolved in 50 ml of dry toluene and the solution was refluxed gently for 20 hours. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography. Fractions eluted with dichloromethaneethyl acetate (5:1) were collected and concentrated to give crude crystals. This product was recrystallized from ether-hexane (1:3) to give 1.87 g of 2-(4-methoxyphenyl)-3-piperidinocarbonylmethyl-4,5,6,7-tetrahydroisoindolin-1-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17](=[CH:23]OCC)[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>C(O)C>[NH2:16][C:15]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[CH:23][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reaction time: 24 h

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (10 g) and ethyl 2-cyano-3-ethoxyacrylate (7.0 g) in absolute ethanol (200 ml) was heated under reflux with stirring for 24 hours. Evaporation of solvent and recrystallisation from diisopropyl ether gave ethyl 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-pyrazole-4-carboxylate, m.p. 131°-134°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:19][C:20]([C:22]1[C:23]2[S:31][CH:30]=[C:29]([CH2:32]Br)[C:24]=2[C:25]([Cl:28])=[N:26][CH:27]=1)=[O:21])[CH3:18]>C1COCC1.CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[C:23]2[S:31][CH:30]=[C:29]([CH2:32][O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:24]=2[C:25]([Cl:28])=[N:26][CH:27]=1)=[O:21])[CH3:18]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc([N+](=O)[O-])c3)csc12
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 3-nitrophenol (457 mg, 3.29 mmol) (Aldrich) and potassium carbonate powder (498 mg, 3.60 mmol) in dry THF (10 mL) and DMF (5 mL) was stirred at 50° C. for 15 minutes before a solution of 3-bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (1.00 g, 2.99 mmol) (from Example 1 supra) in THF (8+2 mL) was added. The reaction was stirred at 50° C. for 3 hours and the resulting mixture was concentrated to remove most of the solvent. The residue was dissolved in EtOAc (200 mL), washed with water (2×25 mL) and brine (25 mL), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (CH2Cl2/MeOH, 98/2 to 90/10) to give 4-chloro-3-(3-nitro-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 911 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31]O)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:54]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:33])(=[N:29][CH2:30][CH2:31][Br:54])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NCCO)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CS(=O)(=NCCBr)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a stirring suspension of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-[2-hydroxy-ethyl]sulfoximide (0.6 g, 0.00118 mol) in DCM (6 mL) was added triphenyl phosphine (460 mg, 0.00177 mol) followed by carbon tetrabromide (589 mg, 0.00177 mol) at 25-30° C. Reaction mixture was stirred at same temperature for 3 hr. Subsequent work up and column purification (100-200 mesh silica gel, 10-50% ethyl acetate in hexane) gave 300 mg of titled product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.I[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)[CH2:10][CH3:11]
Reactant: Oc1ccncc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1ccc(=O)cc1
Temperature: 25 °C

Procedure:
The starting material may be prepared as follows: A solution of 4-hydroxypyridine (950 mg.) and 1-iodopropane (2.34 ml.) in acetone (30 ml.) was stirred under reflux for 2 hours with powdered potassium carbonate (2.76 g.). The reaction mixture was cooled to room temperature and filtered. The solvent was evaporated from the filtrate and the residue was purified by chromoatograph on Kieselgel 60 (100 g.) eluting with methylene chloride/MeOH 100:0 to 80:20 v/v to give 1-n-propyl-4-pyridone (1.05 g.), an oil having n.m.r. in CDCl3 :-0.9(t, 3H); 1.75(m, 2H9; 3.7(t, 2H); 6.23(d, 2H); 7.28(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-n-propylpyridinium toluene-p-sulphonate.
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4]([Br:8])[CH:5]=[CH:6][CH:7]=1.[C:10]1(B(O)O)[C:23]2[C:24]3=[C:25]4[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[C:16]4[CH:15]=[CH:14][C:13]3=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[C:10]1([C:6]2[CH:5]=[C:4]([Br:8])[CH:3]=[C:2]([C:17]3[C:16]4[C:25]5=[C:24]6[C:13](=[CH:14][CH:15]=4)[CH:12]=[CH:11][CH:10]=[C:23]6[CH:22]=[CH:21][C:20]5=[CH:19][CH:18]=3)[CH:7]=2)[C:23]2[C:24]3=[C:25]4[C:20](=[CH:21][CH:22]=2)[CH:19]=[CH:18][CH:17]=[C:16]4[CH:15]=[CH:14][C:13]3=[CH:12][CH:11]=1
Reactant: Brc1cccc(Br)c1Br
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cc(-c2ccc3ccc4cccc5ccc2c3c45)cc(-c2ccc3ccc4cccc5ccc2c3c45)c1
Reaction time: 7 h
Yield: 38.6 %

Procedure:
Under the atmosphere of argon gas, 6 g of tribromobenzene available as a commercial reagent, 9.4 g of 1-pyrenyl boronic acid and 0.88 g of tetrakis(triphenylphophine)palladium were dissolved in 150 ml of toluene, and then the 57 ml of 2M sodium carbonate aqueous solution was added therein, followed by 7 hours reflux on heating. After standing to cool, the precipitated solid was separated through filtration, and then followed by washing with water and methanol, and drying. The obtained solid was refined through a silica gel chromatography (developing solvent: toluene/hexane=1/3) and then 4.1 g of 3,5-dipyrenylbromobenzene of pale yellow solid was obtained (Yield: 38%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][C:32](=[O:37])[CH:31]=[C:30]2OS(C(F)(F)F)(=O)=O>C(Cl)(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[O:33][C:32](=[O:37])[CH:31]=[C:30]2[NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]=[CH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:4][CH2:3]1
Reactant: O=c1cc(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2o1
Reactant: NC1CCN(CC=Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=c1cc(NC2CCN(CC=Cc3ccccc3)CC2)c2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.5 %

Procedure:
To a solution of 1-(3-Phenyl-allyl)-piperidin-4-ylamine (4) (1.01 g,4.65 mmol) and diisopropylethylamine (1.63 mL, 9.3 mmol) in 10 mL CHCl3 was added a solution of compound 3 (1.1 g, 5.6 mmol) in 10 mL CHCl3. The reaction was stirred at room temperature for about 3 hours. The reaction mixture was then washed with water and brine and dried with MgSO4. The yellow residue was triturated with a small volume of dichloromethane and filtered. The final product was converted to the HCl salt by addition of 4.0N HCl in dioxane to a suspension of the compound in dichloromethane. The solvent was removed by evaporation and the residue triturated with methanol to give the title compound (780 mg, 39%). 1H NMR (300 MHz, MeOD-d4) δ 1.92-2.22 (2H, m), 2.35-2.45 (2H, bd, J=11.8 Hz), 3.15-3.35 (2H, m), 3.65-3.75 (2H, bd, j=12.3), 3.85-4.0 (1H, m), 3.90-4.00 (2H, d, J=6.9 Hz), 5.46 (1H, s), 6.32-6.43 (1H, p, J=7.7 Hz), 6.92-6.98 (1H, d, J=16.2 Hz), 7.31-7.41 (4H, m), 7.52-7.54 (2H, m), 7.58-7.62 (1H, dd, J=2.0, 8.8 Hz), 8.148 (1H, s).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:47])[NH:21][C@@H:22]([C:34]1[N:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[N:36][N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([NH:21][C@@H:22]([C:34]1[N:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[N:36][N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:47]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](Cc1ccc2ccccc2c1)C(=O)N[C@H](Cc1ccc2ccccc2c1)c1nnnn1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
((1R)-2-(2-Naphthyl)-1-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethylcarbamoyl)ethyl)carbamic acid tert-butyl ester (215 mg; 0.34 mmol) was dissolved in a mixture of methylene chloride (4 ml) and trifluoroacetic acid (2 ml) and stirred at room temperature for 30 min. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and aqueous sodium hydrogencarbonate (10%; 10 ml). The phases were separated, the organic phase was dried (Magnesium sulfate) and the solvent removed in vacuo. The residue was chromatographed on silica (3×20 cm) using ethyl acetate as eluent to afford 152 mg of (2R)-2-amino-3-(2-naphthyl)-N-((1R)-2-(2-naphthyl)-1-(1-phenethyl-1H-tetrazol-5-yl)ethyl)propionamide.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:30])=[N:25][CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:30][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[C:27]([CH3:29])[N:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cnc(N)c(-c2ccc(OC3CCCCC3)nc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=CN2CCS(=O)(=O)N=C2C(c2ccc(OC3CCCCC3)nc2)=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 238 mg) in THF (dry) (10 ml) was added 2-chloroethanesulfonyl chloride (0.375 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-[6-(cyclohexyloxy)pyridin-3-yl]-5-methylpyrazin-2-amine (338 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (84.5 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:28][S:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][C:30]([S:29][CH3:28])=[CH:31][CH:32]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: CSc1ccc(CBr)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(SC)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methylsulfanyl-benzyl bromide following a procedure analogous to that described for Intermediate 7. LC (method 4): tR=1.12 min; Mass spectrum (ESI+): m/z=508 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9]([C:18]3[N:23]=[C:22]([CH2:24][C:25]#[N:26])[CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1
Reactant: N#CCc1cccc(Br)n1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cccc(CC#N)n3)cc21

Procedure:
[6-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)pyridin-2-yl]acetonitrile was prepared, according to the procedure of Example 5 using (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and (6-bromo-2-pyridyl)acetonitrile (J. Org. Chem. 1988, 53, 786-790), as an off-white solid: mp 210-212.5° C.; 1H NMR (DMSO-d6) δ1.68 (s, 6H), 4.27 (s, 2H), 7.00 (d, 1H, J=8.3 Hz), 7.34 (d, 1H, J=7.1 Hz), 7.89-7.96 (m, 2H), 8.00-8.05 (m, 2H), 10.42 (s, 1H); MS (ESI) [M−H]−=292; Anal. Calcd. For C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C, 68.49; H, 5.19; N, 13.74.
Reaction SMILES: C([Li])CCC.Br[C:7]1[O:8][CH:9]=[CH:10][C:11]=1[Br:12].[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Br:12][C:11]1[CH:10]=[CH:9][O:8][C:7]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: Brc1ccoc1Br
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2occc2Br)C(=O)N1
Temperature: -20 °C

Procedure:
n-Butyl lithium is reacted with 2,3-dibromofuran in ether at -70° C. according to the procedure of Zaluski et al. [Bull. soc. chim. Fr., p. 1843 (1970)] and Sornay et al. [loc. cit., p. 990 (1971)]. The reaction mixture is warmed to -20° C. and an equivalent of anhydrous alloxan in tetrahydrofuran is added dropwise. Reaction is allowed to proceed to completion by warming to room temperature for 2 hours. The product, 5-(3-bromo-2-furyl)-2,4,6(1H,3H,5H)pyrimidinetrione is isolated according to the method of Example 5.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([NH:18]C(=O)OC(C)(C)C)[CH2:3]1.Cl.O1CCOCC1>CO>[F:26][C:2]1([F:1])[CH2:8][N:7]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:6][CH2:5][CH:4]([NH2:18])[CH2:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(NC(=O)OC(C)(C)C)CC(F)(F)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (0.96 g, 2.56 mmol) in MeOH (3 mL) was added HCl in 1,4-dioxane (4 M, 12.8 mL, 51.2 mmol) and the solution was stirred at room temperature for 16 hr. The solvents were removed under reduced pressure and the residue was dissolved in DCM (30 mL). The organic layer was washed with saturated aqueous NaHCO3 solution (30 mL), dried over Na2SO4 and the solvent removed under reduced pressure to give 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine. This amine was dissolved in MeOH/THF (1:1, 50 mL) and treated with formaldehyde (38% in water, 0.45 mL, 6.21 mmol). After 5 min, sodium cyanoborohydride (0.39 g, 6.21 mmol) was added portionwise and the resulting mixture stirred for 5 hr. Additional formaldehyde (38% in water, 0.45 mL, 6.21 mmol) and sodium cyanoborohydride (0.39 g, 6.21 mmol) were added and the resulting mixture was stirred for 60 hr. The solvents were removed under reduced pressure and the crude was purified via silica gel column chromatography (0-10% MeOH/DCM) to give 6,6-difluoro-N,N-dimethyl-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-amine as a yellow oil (0.64 g, 82% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.07-8.03 (m, 1H), 3.82 (s, 3H), 3.70-3.57 (m, 2H), 3.42-3.29 (m, 1H), 3.24-3.05 (m, 1H), 3.04-2.98 (m, 1H), 2.51-2.40 (m, 1H), 2.35-2.29 (m, 6H), 2.20-2.01 (m, 2H), 1.97-1.82 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].I[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29].O>CS(C)=O>[CH2:3]([C:11]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: FC(F)(F)C(F)(F)CCCCI
Reactant: C=CCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
Sodium hydride (60%, 326 mg, 8.14 mmol) was added to dimethyl sulfoxide (5 ml) under argon atmosphere and cooled to 0° C. To this mixture, diethyl 2-(7-octeny)malonate (2 g, 7.40 mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added, followed by stirring for 1 hour. After cooling to 0° C., 1-iodo-5,5,6,6,6-pentafluorohexane (2.68 g, 8.88 mmol) dissolved in dimethyl sulfoxide (5 ml) was slowly added to the reaction mixture, followed by stirring for 2 hours at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/20) to give diethyl 2-(7-octenyl)-2-(5,5,6,6,6-pentafluorohexyl)malonate (2.3 g, Yield 70%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([O:14]C)=O)[CH:11]=1)[NH:8][CH:7]=[CH:6][C:5]2=[O:16].[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH2:22])[CH3:18].C(N(CCNC(C1C=NC2C(=CC=C(I)C=2)N=1)=O)CCOC1C(F)=NC=CC=1)C>>[CH2:17]([N:19]([CH2:23][CH3:24])[CH2:20][CH2:21][NH:22][C:12]([C:10]1[CH:11]=[C:2]([I:1])[CH:3]=[C:4]2[C:9]=1[NH:8][CH:7]=[CH:6][C:5]2=[O:16])=[O:14])[CH3:18]
Reactant: CCN(CC)CCN
Reactant: COC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Agent: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Product: CCN(CC)CCNC(=O)c1cc(I)cc2c(=O)cc[nH]c12
Yield: 86.3 %

Procedure:
This compound was prepared, starting from compound 99 (2.00 g, 6.08 mmol) and N,N-diethylethylenediamine (1.21 mL, 8.56 mmol), according to the procedure developed for compound 10. Reaction time under reflux: 14 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 96/4, v/v) to give compound 100 (2.17 g, 5.25 mmol) as a beige solid. Yield 86%; Rf (Al2O3, CH2Cl2/EtOH, 96/4, v/v) 0.51; mp 141-143° C.; IR (KBr) ν 1392, 1491, 1560, 1617, 1641, 2800-3000, 3293 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.07 (t, 6H, J=7.1 Hz), 2.62 (q, 4H, J=7.1 Hz), 2.71 (t, 2H, J=6.3 Hz), 3.50 (m, 2H), 6.30 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.07 (d, 1H, J=1.9 Hz), 8.79 (d, 1H, J=1.9 Hz); ESI-MS m/z 413.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:6][C:5]2[C:7]([CH3:21])=[C:8]([CH:13]3[CH2:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:23](O)(=[O:27])[CH2:24][CH2:25][CH3:26]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:23]([C:16]1[C:17](=[O:19])[CH2:18][CH:13]([C:8]2[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]3[O:3][C:2]([CH3:22])([CH3:1])[CH2:6][C:5]=3[C:7]=2[CH3:21])[CH2:14][C:15]=1[OH:20])(=[O:27])[CH2:24][CH2:25][CH3:26]
Reactant: CCCC(=O)O
Reactant: Cc1c(C)c(C2CC(=O)CC(=O)C2)c(C)c2c1OC(C)(C)C2
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCCC(=O)C1=C(O)CC(c2c(C)c(C)c3c(c2C)CC(C)(C)O3)CC1=O
Temperature: 25 °C

Procedure:
To a solution of 3.18 g of the 5-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)cyclohexane-1,3-dione in 50 ml of absolute toluene was added 6.93 ml of anhydrous butyric acid and refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford an oily residue. To the solution of the residue in 50 ml of absolute toluene was added 0.26 g of 4-dimethylaminopyridine. After refluxing 8 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 3.8 g of 2-butyryl-5-(2,3-dihydro-2,2,4,6,7-pentamethylbenzofuran-5-yl)-3-hydroxycyclohex-2-en-1-one as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][O:12][CH3:13]>>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: COCCCCl
Reactant: O=C1CCNCC1
Product: COCCCN1CCC(=O)CC1

Procedure:
1-(3-Methoxypropyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-3-methoxypropane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[CH2:6][CH2:5][CH2:4][C:3]=1[CH:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]1=[O:17].Br>C(Cl)(Cl)Cl.C(O)(=O)C>[OH:8][C:7]1[CH:2]=[C:3]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH3:16])[C:10]2=[O:17])[CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCCCC(C2=C(Cl)C(=O)CCC2)C1=O
Agent: Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCCCC(c2cccc(O)c2)C1=O

Procedure:
Using chloroform as solvent. A solution of 3-(2-chloro-3-oxocyclohex-1-enyl)-hexahydro-1-methylazepin-2-one (5.12 g) in chloroform (50 ml) was treated with 48% HBr in acetic acid (2 ml). After 12 hours the organic solvent was removed under reduced pressure and the residue triturated with aqueous ammonia to yield the title compound m.p. 192°-3° C. (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[Cl:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1Cl
Yield: 85.5 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-chlorobenzoic acid (1.02 g, 5.94 mmole) (ACROS, 32525-5000), DMF (50 ml) and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (1.16 g, 6.99 mmole), 2.04 g (85.5% yield) of 2-chloro-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino) benzoic acid was obtained as a pale brown solid.