Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[N:10]=1)[C:5]([N:19]([O:20][CH3:21])[CH3:18])=[O:6]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2,6-dichloroisonicotinic acid (20.0 g, 0.10 mol) and oxalylchloride (11.2 ml, 0.13 mol) in methylenechloride (100 ml) is stirred at room temperature in the presence of a katalytic amount of dimethylformamide for 2 hours to give a clear solution. The solvent is evaporated under reduced pressure and the residue is added to a well stirred solution of N,O-dimethylhydroxylamine (12.0 g, 0.2 mol) and triethylamine (10.2 g, 0.1 mol) at 0–5° C. After stirring for 2 hours at room temperature the reaction mixture is washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 2,6-dichloro-N-methoxy-N-methyl-isonicotinamide in form of colorless crystals, m.p. 69–70° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([O:20]CC)=[O:19])[C@H:16]3[CH2:23][C@@H:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:17]([C:18]([OH:20])=[O:19])[C@H:16]3[CH2:23][C@@H:13]2[CH2:14][CH2:15]3)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2[C@H]3CC[C@H](C3)[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (965 mg, 2.84 mmol) in tetrahydrofuran (40 ml)-methanol (10 ml) was added 1N sodium hydroxide (16 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, to give (1S, 3R, 4R)-2-[(4-methoxyphenyl)sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[OH-].[K+].Cl>O.CCOCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: Fc1ccc(-n2ccc3cc(OCc4ccccc4)ccc32)cc1
Yield: 59.9 %

Procedure:
To 22.3 g (0.1 mol) 5-benzyloxyindole in 110 ml (1.0 mol) 1-bromo-4-fluorobenzene were added 28 g (0.5 mol) powdered potassium hydroxide and 6.4 g (0.1 mol) Cu as powder. The suspension was heated to reflux for 2 h. At RT, ether and water were added, the mixture was acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with a gradient hexane-hexane/EtOAc 19:1-9:1 yielded 19 g (60%) 5-Benzyloxy-1-(4-fluoro-phenyl)-1H-indole as colorless solid, MS: 318 (MH+).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])[CH3:5].[O:14]1[CH2:19][CH2:18]C(=O)[CH2:16][CH2:15]1.[OH-].[Na+]>O1CCCC1.CO>[C:6]([CH:4]=[C:5]1[CH2:18][CH2:19][O:14][CH2:15][CH2:16]1)([OH:8])=[O:7]
Reactant: O=C1CCOCC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=C1CCOCC1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
Methanol (204 ml) was slowly added to a suspension of sodium hydride (5.48 g, 228.2 mmol) in tetrahydrofuran (204 ml) at 0° C. When addition was complete, trimethylphosphonoacetate (34.22 ml, 211.4 mmol) was added to the mixture at such a rate as to maintain the temperature below 12° C. Stirring was continued for a further 10 minutes. To this reaction mixture was added a solution of 2,3,5,6-tetrahydropyran-4-one (16.28 g, 163.0 mmol) in tetrahydrofuran (20 ml), keeping the temperature below 30° C. After the addition was complete, stirring was continued for 30 minutes at room temperature, then methanol (100 ml) and 2M sodium hydroxide (326 ml) was added, and the mixture stirred overnight at room temperature. The resulting solution was concentrated to one half of the original volume, and acidified to pH 1.2 with 6M hydrochloric acid (108 ml). The reaction mixture was partitioned between ethyl acetate and water, the combined organic extracts dried over magnesium sulfate, and solvent removed under reduced pressure to give 4-(carboxymethylene)-2,3,5,6-tetrahydropyran (22.62 g), which was used with no further purification.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].F[C:7](F)(F)[C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1>C1COCC1>[CH2:1]([C:7]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)([CH2:13][CH:11]=[CH2:10])[CH2:9][CH:8]=[CH2:7])[CH:2]=[CH2:3]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(CC=C)(CC=C)c1ccc(N)cc1
Reaction time: 3.5 h
Yield: 87 %

Procedure:
Following a literature procedure (Lin et al. (1997) Synth. Commun., 27: 1975-1980), a 2 M solution of allyl magnesium chloride in THF (0.400 L, 0.800 mol) was diluted with additional THF (1.00 L) and then treated dropwise with a solution of 4-(trifluoromethyl)aniline (19.9 mL, 0.160 mol) in THF (210 mL) at −50° C. under argon. After complete addition the sides of the reaction flask were rinsed with additional THF (150 mL). The resulting solution was heated at reflux. The reaction was monitored by TLC for the complete consumption of 4-(trifluoromethyl)aniline. After 3.5 h, the mixture was concentrated and then CH2Cl2 was added. The organic solution was washed with water, dried (Na2SO4), and filtered. The filtrate was concentrated and chromatographed [silica, CH2Cl2/hexanes (2:1)], affording a pale yellow solid (31.7 g, 87%): 1H NMR δ 2.36-2.43 (m, 6H), 3.48-3.66 (br, 2H), 4.94-5.06 (m, 6H), 5.50-5.64 (m, 3H), 6.62-6.70 (m, 2H), 7.06-7.12 (m, 2H); 13C NMR δ 42.1, 42.6, 115.0, 117.5, 127.6, 135.0, 135.8, 144.1; FABMS obsd 228.1757, calcd 228.1752 [(M+H)+, M=C16H21N].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH2:25][C@H:26]2[CH2:30][CH2:29][CH2:28][NH:27]2)[N:16]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[NH2:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:17]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:34](=[O:35])[CH2:33][C:31]#[N:32])[N:16]=[C:15]([C:3]3[CH:4]=[CH:5][C:6]([O:8][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[CH:7][C:2]=3[F:1])[C:23]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1F)nn2C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Into a 100 mL round-bottom flask, was placed 3-(2-fluoro-4-phenoxyphenyl)-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (278 mg, 0.69 mmol, 1.00 equiv), 2-cyanoacetic acid (36.8 mg, 0.43 mmol, 0.80 equiv), HATU (210 mg, 0.55 mmol, 0.80 equiv), triethylamine (109 mg, 1.08 mmol, 2.00 equiv), and N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C., then diluted with 200 mL of water and extracted with ethyl acetate and the organic layers combined, dried and concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50/1) to give 200 mg (62%) of 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](N)C1C=CC=CC=1.[OH-:26].[Na+].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1>CCOCC.C(O)=O>[C:29]1([CH3:28])[CH:30]=[CH:31][C:32]([S:35]([OH:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1.[CH2:1]([N:8]([C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[N:15]([CH3:17])[CH3:16])[CH:18]=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)[C@@H]1CCCC[C@H]1NCc1ccccc1
Reactant: [OH-]
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O=CO
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1N(C=O)Cc1ccccc1

Procedure:
A solution of trans-N-benzyl-N',N'-dimethyl-1,2-cyclohexanediamine (9.29 g., 0.04 mole) prepared as in Procedure IV, but using benzylamine instead of benzylmethylamine, in 40 ml. of formic acid is refluxed 20 hr., and poured into 200 g. of ice. It is basified with 15% NaOH and extracted well with ether. The extract is washed with H2O and with saturated salt solution, is dried (MgSO4) and evaporated. The residue is converted with 2 mole of p-TSA in ether. The resulting gum is crystallized from MeOH-ether to give 13.64 g. of title compound, m.p. 201°-201.5°. The analytical sample melts at 202°-203°. uv:sh 210 nm (ε 27,850); sh 222 (25,600); sh 227 (12,350); sh 243 (302); sh 248 (375); λmax 254 (472); 258 (556); 261 (562); 268 (399); sh 272 (175). ir:NH 2720, 2560; C=O 1670, 1650; C=C 1600, 1495; SO3 /other 1225, 1170, 1120, 1030, 1010, 815, 705, 685. nmr in D2O (100 MHz) is in accord. Mass spectrum M+ 260.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16](=O)[O:17]C(C)(C)C)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(O)(C)(C)C>O>[C:11]([O:15][C:16]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Yield: 97.9 %

Procedure:
A mixture of 68.59 grams (0.5 mol) of tyramine (β-hydroxyphenylethylamine), 109.13 grams (0.5 mol) of di-t-butylcarbonate, 27.83 grams (0.275 mol) of triethylamine and 2700 ml of 80:20 t-butanol:deionized water solution was stirred for 16 hours at room temperature. The volume of the reaction mixture was reduced to 500-600 ml using a rotary evaporator. The viscous solution was extracted three times with 500 ml portions of chloroform. The chloroform extractions were combined, dried with anhydrous sodium sulfate, filtered and the chloroform was removed under reduced pressure. The product crystallized slowly to form a waxy solid and was recrystallized from acetonitrile. Based on method of preparation, there was obtained 116.13 grams (98% yield) of N-t-butoxycarbonyl tyramine (N-BOC-tyramine). The identity of the chainstopper was further confirmed by 1H NMR analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][O:31][CH2:32][C:33](Cl)=[O:34]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:33](=[O:34])[CH2:32][O:31][CH3:30])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@@H](C)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 19 mg, 50 μmol) and methoxyacetyl chloride (16 mg, 150 μmol). Yield 23 mg (99%).
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Br:20][C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[Br:20][C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23]([N:7]1[C:8](=[O:9])[CH:3]2[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]1=[O:6])=[O:24]
Reactant: O=C(Cl)c1cc(Br)ccc1Br
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(c1cc(Br)ccc1Br)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,5-Dibromobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,5-dibromobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1.[NH2:17][C:18]1[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[NH:26][C:27](=[O:30])[O:28][CH3:29].N1C=CC=C(C)C=1.CS(Cl)(=O)=O>CC#N>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=2[NH:26][C:27](=[O:30])[O:28][CH3:29])=[O:9])[N:4]([C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][N:11]=2)[N:3]=1
Reactant: O=C(O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: COC(=O)Nc1cc(Cl)cc(Cl)c1N
Agent: CS(=O)(=O)Cl
Solvent: Cc1cccnc1
Solvent: CC#N
Product: COC(=O)Nc1cc(Cl)cc(Cl)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
3-Bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (100 mg, 0.33 mmol) and methyl (2-amino-3,5-dichlorophenyl)carbamate prepared in Step 2 (77 mg, 0.33 mmol, 1.0 eq) were mixed with 1 mL of CH3CN. 3-Picoline (0.07 mL, 0.66 mmol, 2.0 eq) was added to the mixture thus obtained, followed by stirring for 30 minutes. After 30 minutes, methanesulfonyl chloride (0.04 mL, 0.5 mmol, 1.5 eq) was slowly added to the mixture. Upon completion of the dropwise addition, the mixture was heated to 40° C. and subjected to a reaction for 24 hours. After confirming the termination of the reaction by using TLC, the solvent was removed, and the residue thus obtained was purified by column chromatography using 20% EtOAc/hexane solution, 50% EtOAc/hexane solution and 100% EtOAc in turn to yield the title compound (130 mg, yield: 75%).
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([C:3]1[C:7]([C:29]([CH:26]2[CH2:28][CH2:27]2)=[O:30])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: O=C(Cl)C1CC1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C1CC1
Temperature: 25 °C

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.22 g) in tetrahydrofuran (5 ml) at -78° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -65° C., n-butyllithium (0.21 ml of a 2.5M solution in hexanes). After stirring for a further 5 minutes cyclopropanecarbonyl chloride (0.13 ml) was added and the mixture allowed to warm to room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (5 ml) and extracted twice with ether (25 ml). The combined organic layers were washed with water (50 ml), dried (Na2SO4) and evaporated to give a brown oil which was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 195-197° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[O:18]1[CH2:19][CH2:20][CH:15]([O:14][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[OH:1])[CH2:16][CH2:17]1
Reactant: OC1CCOCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OC1CCOCC1)c1ccc([N+](=O)[O-])cc1O
Temperature: 45 °C
Yield: 29.4 %

Procedure:
2-Hydroxy-4-nitro-benzoyl chloride (0.82 g, 4.07 mmol) in THF (15 mL) was added portionwise to a solution of 4-hydroxytetrahydropyran (0.8 mL, 8.1 mmol) in pyridine (4 μL) at 0° C., followed by a catalytic amount of 4-(dimethylamino)-pyridine (DMAP). The mixture was maintained overnight at 40-50° C. then diluted with water and extracted with ethyl acetate. The organic extract was washed successively with saturated sodium bicarbonate solution, water and brine solution, dried and concentrated to give a residue which was triturated with a mixture of DCM and petroleum ether. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate/petroleum ether (2-15%) to give 2-hydroxy-4-nitro-benzoic acid tetrahydro-pyran-4-yl ester (0.32 g, 29%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH:27]([NH2:38])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH:27]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(N)c1cccc2ccccc12
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 9, 2.75 mmol), R-(+)-1-(1-naphthyl)ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl}-3,4,5,6-tetrahydrophthalamide as white crystals (0.950 9, 64.7% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCCCO
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(NCCCCO)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1.09 g (4.65 mmol) of 4-oxoazepane-1-carboxylic acid tert-butyl ester and 864 μl (9.30 mmol) of 4-aminobutan-1-ol were suspended in 40 ml of ethanol, stirred at room temperature for 40 minutes, 532 μl (9.30 mmol) of glacial acetic acid were added, and the mixture was stirred for a further 10 min. Sodium triacetoxyborohydride (1.97 g, 9.30 mmol) was added, and the mixture was stirred at room temperature overnight and evaporated to dryness in vacuo. The residue was taken up in water and extracted 4 times with EA. The organic phase was dried over sodium sulfate, filtered and evaporated.
Reaction SMILES: C(O)C.[O:4]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:20])[C:18]#N)[CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-:21].[K+].[OH2:23]>>[O:4]([C:11]1[CH:12]=[C:13]([CH:17]([CH3:20])[C:18]([OH:23])=[O:21])[CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: [OH-]
Reactant: O
Reactant: CC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [K+]
Solvent: CCO
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 90 %

Procedure:
Ethanol (5 ml) and 1 ml of water were added to 191 mg of alpha-(m-phenoxyphenyl)propionitrile, and 490 mg of potassium hydroxide was added. The mixture was heated under reflux for 5 hours. The reaction mixture was cooled, and 10 ml of water was added. The mixture was washed with 10 ml of ether three times. Conc. hydrochloric acid was added to the aqueous layer to adjust its pH to below 1, and then it was extracted with 10 ml of ether three times. The extract was washed with 20 ml of water two times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methylene chloride and ether) to afford 187 mg (yield 90%) of alpha-(m-phenoxyphenyl)-propionic acid as a colorless oil. The IR spectrum of this product coincided completely with that of an authentic sample.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:5][CH:4]=1.IC.[C:21](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:21][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:11]=2)[CH:7]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
A mixture of ethyl 6-(trifluoromethyl)-1H-indole-2-carboxylate (100 mg, 0.39 mmol), iodomethane (36 microL, 0.58 mmol), and potassium carbonate (134 mg, 0.97 mmol) in DMF was stirred at room temperature for 7 hours. Then, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane (three times). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (20:1-10:1) to give 95.3 mg (90% yield) of the title compound as a white solid: