Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[N:9]=[C:8]2Cl.[NH2:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([Cl:13])[N:9]=[C:8]2[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22]
Reactant: Cc1ccccc1N
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2c(Nc3ccccc3C)nc(Cl)nc12
Yield: 60.3 %

Procedure:
8-Methoxy-2,4-dichloroquinazoline (3.7 g, 0.016 mol) was stirred in a mixture of water (85 ml), tetrahydrofuran (125 ml), o-toluidine (1.7 g, 0.016 mol) and sodium acetate (2.2 g, 0.027 mol) for a total of 4 days with heating to 50° for a total of 32 hours and the addition of a total of 20 ml 0.01 mol NaOH dropwise over this period maintaining the pH at 7. The reaction mixture was evaporated in vacuo and crystallised from ethanol/water to give 8-methoxy-4-(2-methylphenylamino)-2-chloroquinazoline (2.89 g, 60%) m.p. 218°-220°.
Reaction SMILES: C([O:5][C:6]([C@@H:8]([N:10]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([N:20]=[N+]=[N-])[C:11]1=[O:23])[CH3:9])=[O:7])(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>[Pd]>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[NH2:20][C@H:12]([C:11]([NH:10][C@H:8]([C:6]([OH:7])=[O:5])[CH3:9])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@H](N=[N+]=[N-])[C@H]1c1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O
Reaction time: 15 h
Yield: 94 %

Procedure:
After 1-(1(S)-t-butoxycarbonylethyl)-3(S)-azido-4(R)-phenylazetidin-2-one (300 mg., 0.95 mmol) was stirred in trifluoroacetic acid (2 ml.) at room temperature for 15 hours, the solvent was removed by distillation under reduced pressure. The thus obtained oil (360 mg.) was hydrogenated in 25 ml. of ethanol at 50° C. for 15 hours under ambient pressure using a 10% Pd-C (300 mg.) as a catalyst to give trifluoroacetic acid salt of L-phenylalanyl-L-alanine (311 mg., yield: 94%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([O:1][CH2:2][CH2:3][O:4][CH2:5][N:6]2[CH:13]=[C:12]([F:14])[C:10](=[O:11])[NH:9][C:7]2=[O:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1[nH]c(=O)n(COCCO)cc1F
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCn2cc(F)c(=O)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.4 %

Procedure:
1-(2-Hydroxyethoxy)methyl-5-fluorouracil (1 g) obtained in Example 1 was dissolved in pyridine (5 ml) and to the solution was added p-toluenesulfonylchloride (1.12 g) under cooling in an ice bath, and then the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was poured into ice-water and the resulting oil was extracted with chloroform (30 ml). The chloroform layer was washed with hydrochloric acid and then with water, and dried over magnesium sulfate to give crystalline 1-(2-p-toluenesulfonyloxyethoxy)methyl-5-fluorouracil (1.2 g).
Reaction SMILES: O[CH:2]([NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:11]=1)=[O:9])[C:3](Cl)([Cl:5])[Cl:4]>C(O)(=O)C.C(OCC)(=O)C.O.[Zn]>[Cl:5][C:3]([Cl:4])=[CH:2][NH:7][C:8]([C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=2)[N:11]=1)=[O:9]
Reactant: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC(O)C(Cl)(Cl)Cl)c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)NC=C(Cl)Cl)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
1.0 g (0.0022 mol) of N-(1-hydroxy-2,2,2-trichloroethyl)-4-methoxy-6-{3-(trifluoromethyl)phenoxy}-2-pyridine carboxamide was dissolved in about 10 ml of acetic acid. The obtained solution was mixed with 0.29 g (0.0022×2.0 mol) of zinc dust and stirred at about 50° C. for about 5 hours. The reaction solution was distributed in ethyl acetate-water and washed with saturated sodium bicarbonate water and saturated brine. The organic phase of the solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: CO[C:3](OC)([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:4].O.Cl.C([O:24]CC)C>O1CCCC1.[Cl-].[Na+].O>[C:9]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]([O:5][CH2:3][CH:4]=[O:24])=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: COC(C)(OC)Oc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCOc1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
The acetal from Step 1 (2.10 g) was dissolved in 10 mL of tetrahydrofuran and 1 mL of distilled water was added to the yellow solution, followed by 1 mL of concentrated hydrochloric acid. This mixture was stirred rapidly overnight, then a small amount of saturated aqueous brine solution was added to the reaction mixture, followed by 50 mL of diethyl ether. The organics were extracted into the ether layer and the aqueous layer was washed twice more with diethyl ether. The ether layers were combined, dried over anhydrous magnesium sulfate, and evaporated. The residue was triturated with a 10% solution if isopropyl alcohol in chloroform, leaving a white solid. This solid was again triturated with a small amount of methanol in dichloromethane. The yield of filtrates from the above two triturations was 1.84 g (71% ) of 4-biphenyloxyacetaldehyde.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>O1CCCC1.C(OCC)(=O)C>[CH3:21][N:22]([CH3:26])[C:23](=[O:24])[O:18][C:15]1[CH:16]=[C:17]2[C:12]([CH2:11][CH2:10][CH2:9][N:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: CN(C)C(=O)Cl
Reactant: Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1ccc2c(c1)N(Cc1ccccc1)CCC2
Reaction time: 0.5 h

Procedure:
A solution of 1-benzyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) in dry tetrahydrofuran (THF, 8 ml) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, N,N-dimethyl carbamoyl chloride (265 mg/ml, 3.14 mM) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 8k as solid. Yield: 0.796 g, 76.19%.
Reaction SMILES: [CH:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[C:23]1([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([NH:15][C:12]([C:7]3([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH2:8][CH2:9][CH2:10][CH2:11]3)=[O:14])[CH2:17]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Reactant: O=C(O)C1(C2CCCCC2)CCCC1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C1(C2CCCCC2)CCCC1

Procedure:
1-Cyclohexyl-1-cyclopentanecarboxylic acid and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-cyclohexyl-1-cyclopentanecarboxamide.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([NH2:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1.Cl.C[CH:26]([NH2:41])[C:27]1C=[CH:31][C:30](CCC2C=CC=CC=2)=[CH:29][CH:28]=1>>[ClH:1].[CH3:2][CH:3]([N:23]=[C:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:41]1)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:6][CH:5]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CCCCCCCCCCCCCc1ccc(C(C)N)cc1
Agent: Cl
Product: CCCCCCCCCCCCCc1ccc(C(C)N=C2CCCCCN2)cc1

Procedure:
Following essentially the same procedure described in Example IV but substituting α-methyl-ρ-tridecylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-(α-methyl-ρ-tridecylbenzylimino)hexahydroazepine hydrochloride having a M.P. 183°-5° C.
Reaction SMILES: C(N1C2C3N(C(C4C=CC=C(OC)C=4)C4C=CC(C(N(CC)CC)=O)=CC=4)C(C1CC2)CC3)C1C=CC=CC=1.C([N:47]1[CH:51]2[CH:52]3[N:56]([CH:57]([C:72]4[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=4)[C:58]4[CH:63]=[CH:62][C:61]([C:64]([N:66]5[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]5)=[O:65])=[CH:60][CH:59]=4)[CH:55]([CH:48]1[CH2:49][CH2:50]2)[CH2:54][CH2:53]3)C1C=CC=CC=1>>[CH:52]12[N:56]([CH:57]([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([O:78][CH3:79])[CH:73]=3)[C:58]3[CH:59]=[CH:60][C:61]([C:64]([N:66]4[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71]4)=[O:65])=[CH:62][CH:63]=3)[CH:55]([CH2:54][CH2:53]1)[CH:48]1[NH:47][CH:51]2[CH2:50][CH2:49]1
Reactant: COc1cccc(C(c2ccc(C(=O)N3CCCCC3)cc2)N2C3CCC2C2CCC3N2Cc2ccccc2)c1
Agent: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Product: COc1cccc(C(c2ccc(C(=O)N3CCCCC3)cc2)N2C3CCC2C2CCC3N2)c1

Procedure:
The procedure of Example 5.1 was repeated, but using instead of the compound prepared in Example 4.1 the compound {4-[(10-benzyl-9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-(3-methoxyphenyl)methyl]phenyl}-piperidin-1-yl-methanone of Example 4.3. The compound {4-[(9,10-diazatricyclo[4.2.1.12,5]dec-9-yl)-(3-methoxyphenyl)-methyl]phenyl}-piperidin-1-yl-methanone was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([F:12])[C:7]=1[O:8]COC.Cl.O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([F:12])[C:7]=1[OH:8]
Reactant: CCOC(=O)CCc1cc(F)c(OCOC)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 3,5-difluoro-4-(methoxymethoxy)benzenepropanoate (2.3 g, 8.4 mmol) in ethanol (12 mL) was added hydrochloric acid (0.5 mL), and the mixture was stirred at 50° C. for 1 hour. After the reaction solution was returned to room temperature, water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=9:1 to 1:1) to give the title compound (1.7 g, yield 88%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][NH:7][C:8](=[O:19])[NH:9][C:10]1[S:11][CH:12]=[C:13]([CH3:18])[C:14]=1[C:15]([O-])=[O:16])[CH3:2].[O-]CC.[Na+]>CCO>[CH3:18][C:13]1[C:14]2[C:15](=[O:16])[N:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:8](=[O:19])[NH:9][C:10]=2[S:11][CH:12]=1
Reactant: CCOC(=O)CCNC(=O)Nc1scc(C)c1C(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1c(=O)[nH]c2scc(C)c2c1=O
Yield: 77.9 %

Procedure:
To a solution of 2-(3-(3-ethoxy-3-oxopropyl)ureido)-4-methylthiophene-3-carboxylate (470 mg, 1.5 mmol) in EtOH (10 mL) was added sodium ethoxide (203 mg, 2.19 mmol, freshly prepared). The reaction was heated at reflux for 4 h, concentrated, acidified with 1N HCl until PH=1 then extracted with EA (2×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to give ethyl 3-(5-methyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (330 mg, 82% yield) as a yellow thick oil. LCMS: MH+ 255 and TR=0.718 min. Used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=O)=[C:5]([OH:18])[CH:4]=1)[CH3:2].Cl.[NH2:20][OH:21]>>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([C:7](=[N:20][OH:21])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:5]([OH:18])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)c2ccc(F)cc2)c(O)c1
Reactant: NO
Agent: Cl
Product: CCc1ccc(C(=NO)c2ccc(F)cc2)c(O)c1

Procedure:
4-Ethyl-4'-fluoro-2-hydroxybenzophenone (21.0 g, 80% pure) was treated with hydroxylamine hydrochloride (24.0 g) in a manner similar to that in Example 3, to give, after recrystallisation from benzene, the title compound as a white crystalline solid (10.7 g), m.p. 130°-2° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([C:22]#[N:23])=[N:8][C:9]([S:12][CH2:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[CH:10][CH:11]=1.O.O.Cl[Sn]Cl>O.Cl>[F:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([F:20])[CH:17]=1)[CH2:13][S:12][C:9]1[N:8]=[C:7]2[C:22]([NH2:1])=[N:23][NH:5][C:6]2=[CH:11][CH:10]=1
Reactant: N#Cc1nc(SCc2cc(F)cc(F)c2)ccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Nc1n[nH]c2ccc(SCc3cc(F)cc(F)c3)nc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution cooled to 0° C. of NaNO2 in 3 ml of water is added drop by drop to a solution at 0° C. of 3-amino-6-(3,5-difluorobenzylthio)picolinonitrile (1.587 mmol, 0.44 g) in 15 ml of 6 N HCl solution. After 15 minutes, a solution cooled to 0° C. of SnCl2.2H2O diluted in 4 ml of 12 N HCl is added drop by drop. The reaction medium is then stirred at 25° C. for 1 hour. The solution is extracted with ethyl acetate and then washed using saturated NaHCO3 solution and then saturated NaCl solution. The organic phase is collected, dried on magnesium sulfate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration of the organic phases, 0.07 g (15%) of black crystals.
Reaction SMILES: [CH2:1]([C:3]1([CH2:32][CH3:33])[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)[N:5]([C:17]([NH:19][C@H:20]([CH2:28][CH:29]=[CH2:30])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[O:18])[C:4]1=[O:31])[CH3:2]>[Pd].C(O)C>[CH2:32]([C:3]1([CH2:1][CH3:2])[C@H:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14](=[O:16])[CH3:15])=[CH:12][CH:13]=2)[N:5]([C:17]([NH:19][C@H:20]([CH2:28][CH2:29][CH3:30])[C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])[C:4]1=[O:31])[CH3:33]
Reactant: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(C)=O)cc1)c1ccc(C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(C)=O)cc1)c1ccc(C)cc1
Reaction time: 0.33 h

Procedure:
A solution of (4S)-3,3-diethyl-1-[(R)-α-allyl-(4-methyl)benzylaminocarbonyl]-4-[(4-acetyl)phenoxy]azetidin-2-one (1.3 gm, 2.9 mmol) and 100 mg of 10% palladium on carbon in ethanol (15 mL) was hydrogenated at 40 p.s.i. for 20 min. The reaction was then filtered and evaporated to afford 1.3 gm (quantitative) of clean title compound without further purification.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[C:25](Cl)(=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)Cl
Reactant: CCCCCCCCNC(=O)[C@H]1CCCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)CCCCCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-(+)-2-piperidinecarboxylic acid n-octyl amide (23) (100 mg; 0.416 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. Triethylamine (63 mg; 0.624 mmol) is added and the solution cooled in an ice-bath. Octanoyl chloride (74 mg; 0.458 mmol) is added dropwise via syringe. The solution is stirred for 15 minutes and then allowed to warm to ambient temperature. After stirring for an additional 4.5 hours, the solution is poured onto saturated sodium bicarbonate solution and extracted with methylene chloride (20 mL). The methylene chloride extract is washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography using a gradient elution (0%→40% ethyl acetate in hexanes) affording the desired product (28) as an oil. ISMS: MH+367.4
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18](O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)[CH3:2]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3F)CC2)c1
Reactant: CCOc1ccccc1O
Product: CCOc1ccccc1OC(CCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1F

Procedure:
Prepared by Procedure A and Scheme AN using 2-ethoxyphenol and N-(3-{1-[6-(2-fluorophenyl)-6-hydroxyhexyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 561.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C:12]2=[O:20])=[O:10])=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([C:21](=[O:23])[CH3:22])[C:12]2=[O:20])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccccc2N1C(=O)Nc1ccc(F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C1C(=O)N(C(=O)Nc2ccc(F)cc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a stirred slurry of 811 mg (3.0 mmole) of N-(4-fluorophenyl)-2-oxindole-1-carboxamide in 4 ml of N,N-dimethylformamide was added 806 mg (6.6 mmole) of 4-(N,N-dimethylamino)pyridine. Stirring was continued for a few minutes, and then the slurry was cooled in an ice-bath and a solution of 337 mg (3.3 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added. Stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 60 ml of ice-water and 2.2 ml of 3N hydrochloric acid. The solid which precipitated was recovered by filtration. It was recrystallized from acetonitrile to give 600 mg of the title compound as dark crystals, mp 181°-182° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([N:13]3[CH2:18][CH2:17][C:16]([CH3:20])([OH:19])[CH2:15][CH2:14]3)[CH2:9]2)=[C:4]([F:21])[CH:3]=1.[O:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33][CH2:32]2>>[F:21][C:4]1[CH:3]=[C:2]([N:1]2[CH2:33][CH2:32][C:31]3[C:36](=[CH:37][CH:38]=[C:29]([O:28][CH2:27][C@@H:23]4[CH2:24][CH2:25][CH2:26][O:22]4)[CH:30]=3)[C:35]2=[O:34])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]2[CH2:14][CH2:15][C:16]([OH:19])([CH3:20])[CH2:17][CH2:18]2)[CH2:9]1
Reactant: O=C1OCCc2cc(OC[C@@H]3CCCO3)ccc21
Reactant: CC1(O)CCN([C@@H]2CCN(c3ccc(N)cc3F)C2)CC1
Product: CC1(O)CCN([C@@H]2CCN(c3ccc(N4CCc5cc(OC[C@@H]6CCCO6)ccc5C4=O)cc3F)C2)CC1

Procedure:
1-[(R)-1-(4-Amino-2-fluoro-phenyl)-pyrrolidin-3-yl]-4-methyl-piperidin-4-ol was reacted with 6-[(S)-1-(Tetrahydro-furan-2-yl)methoxy]-isochroman-1-one by method AC. The product with the molecular weight of 523.65 (C30H38FN3O4) was obtained in this way; MS (ESI): 524 (M+H+).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1)C1C=CC=CC=1.O1CCCC1>CO.[C].[Pd]>[OH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(O)cc1OC
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of methyl 4-benzyloxy-2-methoxybenzoate (3.08 g) in methanol (5 mL)/tetra hydrofuran (7.5 mL) was added 10% palladium-carbon (0.3 g) at room temperature under an atmosphere of argon, and the mixture was stirred at that temperature for 2 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford the title compound (2.02 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C@H:10]([CH3:12])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH2:15]([O:14][C:9](=[O:13])[C@H:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:12])[CH3:16]
Reactant: CCOC(=O)[C@H](C)O
Reactant: Oc1ccc(F)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](C)Oc1ccc(F)cc1
Temperature: -5 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
Under argon, 100 g (0.892 mol) of 4-fluorophenol (2) was combined with 105.2 g (0.892 mol) of (S)-ethyl lactate and 233.8 g (0.892 mol) of triphenylphosphine in 1200 mL of tetrahydrofuran (THF). The reaction mixture was cooled to −5° C., and 180.4 g (0.892 mol) of diisopropylazodicarboxylate (DIAD) in 500 ml of THF was dropwise added. The ice bath was removed, and stirring was continued at room temperature for 18-22 hr. THF was then evaporated in vacuo, and 1400 mL of hexane-ether (80:20) was added to the residue, and the remaining solid was removed by filtration. The filtrate was then washed with 2×600 mL of 1N NaOH, followed by 2×600 mL of water and 600 mL of brine. The washed filtrate was then dried over MgSO4, filtered and then evaporated to give 185 g of (R)-ethyl-2-(4-fluorophenoxy)-propionate, 7, as a light yellow oil in 98% yield, Bp 80° C. at 0.7 mm Hg. The reaction is shown as follows:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(O[C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([C:71]([O:73][CH3:74])=[O:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1)(=O)=O.[CH:77]1([C@H:83]2[CH2:88][CH2:87][C@H:86]([N:89]3[CH2:94][CH2:93][NH:92][CH2:91][CH2:90]3)[CH2:85][CH2:84]2)[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O>[CH:77]1([C@H:83]2[CH2:88][CH2:87][C@H:86]([N:89]3[CH2:90][CH2:91][N:92]([C:59]4[CH:64]=[CH:63][C:62]([C:65]5[CH:70]=[CH:69][C:68]([C:71]([O:73][CH3:74])=[O:72])=[CH:67][CH:66]=5)=[CH:61][CH:60]=4)[CH2:93][CH2:94]3)[CH2:85][CH2:84]2)[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82]1
Reactant: C1CCC([C@H]2CC[C@H](N3CCNCC3)CC2)CC1
Reactant: COC(=O)c1ccc(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N3CCN([C@H]4CC[C@H](C5CCCCC5)CC4)CC3)cc2)cc1
Temperature: 110 °C
Reaction time: 23 h

Procedure:
To a mixture of cesium carbonate (2.54 g), palladium(II) acetate (62 mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (260 mg) in toluene (6 ml) was successively added methyl 4′-trifluoromethylsulfonyloxy-1,1′-biphenyl-4-carboxylate (1 g) and 1-(trans-4-cyclohexylcyclohexyl)-piperazine (835 mg) in stream of nitrogen. The mixture was stirred at ambient temperature for 45 minutes and at 110° C. for further 23 hours. After cooling to room temperature, water and dichloromethane was added to the reaction mixture. The resulting precipitate was collected by filtration and washed with water and dried to give methyl 4′-[4-(trans-4-cyclohexylcyclohexyl)-1-piperazinyl]-1,1′-biphenyl-4-carboxylate (684.8 g).