Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[C:4]([O:15][CH3:16])[CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH2:33])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][NH:33][C:12]([C:8]2([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[O:15][CH3:16])[CH2:9][CH2:10][CH2:11]2)=[O:14])=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(Cl)ccc1C1(C(=O)O)CCC1
Reactant: NCCc1ccc(OCc2ccccc2)cc1
Product: COc1cc(Cl)ccc1C1(C(=O)NCCc2ccc(OCc3ccccc3)cc2)CCC1

Procedure:
N-{2-[4-(Benzyloxy)phenyl]ethyl}-1-(4-chloro-2-methoxyphenyl)cyclobutanecarboxamide was prepared analogously to example 65 from 1-(4-chloro-2-methoxyphenyl)cyclobutanecarboxylic acid (3.45 g, 14.3 mmol) and 2-[4-(benzyloxy)phenyl]ethanamine (4.2 g, 15.92 mmol). Yield: 4.7 g (10.45 mmol, 66%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([OH:11])[C:9]#[CH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:12]1([CH2:18][C@H:19]([OH:22])C=C)[CH2:17]CCC[CH2:13]1.C(Cl)(=O)CC(C)C>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH:1]1([CH2:7][C@H:8]([O:11][C:19](=[O:22])[CH2:18][CH:12]([CH3:17])[CH3:13])[CH:9]=[CH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#C[C@@H](O)CC1CCCCC1
Reactant: C=C[C@@H](O)CC1CCCCC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)CC(=O)Cl
Product: C=C[C@H](CC1CCCCC1)OC(=O)CC(C)C

Procedure:
1-Cyclohexyl-3-butyn-2(S)-ol is reduced by partial hydrogenation in the presence of Lindlar catalyst to 1-cyclohexyl-3-buten-2(S)-ol and reacted analogously to Example 5 with isovaleric acid chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].[F-].[Cs+]>C(COC)OC.C(O)C>[CH:28]([C:30]1[CH:35]=[CH:34][C:33]([C:12]2[CH:11]=[CH:10][C:9]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:32][CH:31]=1)=[O:29]
Reactant: CCOC(=O)CCc1ccc(OS(=O)(=O)C(F)(F)F)c(OCCCOC)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCO
Product: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCCOC)c1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
Ethyl 3-[3-(3-methoxypropoxy)-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl]propanoate (5 g, 12 mmol) was dissolved in dimethoxyethane (70 mL) and ethanol (7 mL). 4-Formylbenzeneboronic acid (2.0 g, 13 mmol) was added and argon was bubbled in the mixture, for 15 minutes. Cesium fluoride (4 g, 26 mmol) and tetrakistriphenylphosphine palladium (0.69 g, 0.6 mmol) were added and the mixture was brought to reflux under an argon atmosphere for 4 hours. After cooling to room temperature, solvents were evaporated under reduced pressure and the residue was dissolved in ethyl acetate/water (100 mL/100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 9/1) to yield 3.42 g (76%) of the desired product as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][NH2:16])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a stirred solution of 3-(4,4-diphenylpiperidin-1-yl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH2CL2 (3×10 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 4:1:0.2) to give 1.35 g (66%) of tan solid, which was characterized spectroscopically.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:15][C:16]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=1[NH2:18]>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:15][C:16]3[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=3[NH2:18])=[N:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(N)c(CCl)c1
Agent: Cl
Product: COc1ccc2[nH]c(SCc3cc(C)ccc3N)nc2c1
Yield: 41.8 %

Procedure:
The title compound (1.95 g) was prepared by the method of Example 1 using 2.81 g of 2-mercapto-5-methoxybenzimidazole instead of 2-mercaptobenzimidazole and 3.00 g of 2-(chloromethyl)-4-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline. Anal. Calc'd. for C16H17N3OS: C, 64.19; H, 5.72; N, 14.04; S, 10.71. Found: C, 63.71; H, 5.80; N, 13.86; S, 10.60.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[Cl:24]Cl.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH2:14][CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[C:23]=1[Cl:24]
Reactant: CCC1N=C(c2ccccc2F)c2cc(N)ccc2N(C)C1=O
Reactant: ClCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCC1N=C(c2ccccc2F)c2c(ccc(N)c2Cl)N(C)C1=O

Procedure:
13 g (0.042 M) of rac-7-amino-3-ethyl-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one are dissolved in 70 ml of concentrated hydrochloric acid at -10° C. and chlorine gas is then conducted in at -10° C. until the starting material can no longer be detected by thin-layer chromatography. The mixture is neutralised slowly with a mixture of ice and 10% sodium carbonate solution and the mixture is extracted several times with methylene chloride. The organic solution is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is purified on a 300 g silica gel column with methylene chloride/ethyl acetate (10:1) and crystallised from ethanol. There is obtained rac-7-amino-3-ethyl-6-chloro-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one which melts at 250° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][C:11]=2[C:12]=1[CH3:13].[CH2:24](Br)[C:25]#[CH:26]>CC(C)=O>[CH2:26]([N:21]1[CH2:22][CH2:23][CH:18]([C:15]2[CH:16]=[CH:17][C:10]3[O:9][C:8]([CH3:7])=[C:12]([CH3:13])[C:11]=3[CH:14]=2)[CH2:19][CH2:20]1)[C:25]#[CH:24]
Reactant: C#CCBr
Reactant: Cc1oc2ccc(C3CCNCC3)cc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCC(c2ccc3oc(C)c(C)c3c2)CC1
Temperature: 25 °C

Procedure:
4.15 g (0.030 mol) of anhydrous potassium carbonate are added to a solution of 2.29 g (0.010 mol) of 4-(2,3-dimethyl-5-benzofuranyl)-piperidine (c.f. Example 1) in 25 ml of acetone, and a solution of 1.3 g (0.011 mol) of 2-propynyl bromide in 11 ml of acetone is added dropwise in the course of 10 minutes, with stirring. The reaction mixture is heated to 40° for 4 hours and then cooled to room temperature and the inorganic salts are filtered off. The filtrate is evaporated in a rotary evaporator. The brown oil which remains has, in the thin layer chromatogram (silica gel/5% methanol/chloroform), a main spot at an Rf value of about 0.7, in addition to 4 secondary spots. The resulting oil is chromatographed on 50 g of silica gel using chloroform as the solvent and eluting agent, whereupon 1-(2-propynyl)-4-(2,3-dimethyl-5-benzofuranyl)-piperidine is obtained, as the main fraction, as a yellowish oil with an Rf value of about 0.7. This base is dissolved in about 3 ml of methanol and converted into the hydrochloride by acidifcation with hydrogen chloride solution and the hydrochloride is made to crystallise by adding about 20 ml of ether and is filtered off with suction. The hydrochloride thus obtained as white crystals melts at 224°-225°.
Reaction SMILES: [H-].[Na+].[Br-].[C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:6])=[O:5].[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1.Cl>O1CCCC1.O>[F:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]([OH:6])=[O:5])=[CH:37][CH:36]=1
Reactant: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCCC=Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 0.65 g, 16 mmol) was added portionwise at room temperature to a stirred solution of (8-carboxy-octyl)-triphenyl-phosphonium bromide (2.8 g, 5.6 mmol) in tetrahydrofuran (30 mL) at room temperature, then after 1 hour 4-fluorobenzaldehyde (700 mg, 5.64 mmol) was added portionwise to the reaction mixture and the solution stirred for 2 days at room temperature. On reaction completion, water (10 ml) was added and the solution acidified to pH 3 with concentrated hydrochloric acid. The product was extracted with ethyl acetate, the organic layer dried over magnesium sulfate, filtered and evaporated. Chromatography (SiO2, heptane-ethyl acetate 4:1) afforded 10-(4-fluoro-phenyl)-dec-9-enoic acid (280 mg, 19%) as a colorless oil.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC(c2ccc3nsnc3c2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc3nsnc3c2)=C(Br)C1=O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 2.164 mmol) in CHCl3 (15 mL), NBS (0.462 g, 2.590 mmol) was added portionwise at RT. The reaction mixture was then stirred for 2 h and diluted with DCM (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.45 g, 69%) as a yellow oil.
Reaction SMILES: Cl(O)(=O)(=O)=O.[OH:6][CH:7]([C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:15][CH:16]=1)[C:8]([O:10][CH3:11])=[O:9]>C(OC(C)(C)C)(=O)C>[C:17]([O:6][CH:7]([C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:15][CH:16]=1)[C:8]([O:10][CH3:11])=[O:9])([CH3:22])([CH3:18])[CH3:14]
Reactant: COC(=O)C(O)c1csc(-c2ccccc2)n1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)C(OC(C)(C)C)c1csc(-c2ccccc2)n1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 4 mL) was added at −10° C. to a solution of methyl 2-hydroxy-2-(2-phenyl-1,3-thiazol-4-yl)acetate (6a) (800 mg, 3.2 mmol) in terbutyl acetate (25 mL). After 1 hour, the reaction was quenched with a saturated solution of sodium bicarbonate (20 mL) and extracted with dichloromethane (2×20 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (6b) as a white pale oil (410 mg, 1.34 mmol, 42%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16]>>[OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[N+:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[O-:20]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: CC(C)(C)NO
Product: CC(C)(C)[N+]([O-])=Cc1cc(OC(F)(F)F)ccc1O

Procedure:
The title compound was prepared according to the procedure described in Example 1 using 2-hydroxy-5-trifluoromethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 81.8% yield as a yellow crystalline solid, m.p. 82.6° C. (Rf=0.40 on a silica gel plate using 7:3 hexanes/EtOAc as an eluant).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14]([CH3:15])=[O:24])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2ccc(Br)cc2)n1
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2ccc(Br)cc2)n1

Procedure:
A solution of 4-(4-Bromo-phenyl)-2-methylsulfanyl-pyrimidine (1.1 g, 3.91 mmol) in DCM (33 ml) was cooled to 0° C. and treated within 1 hour with several portions of mCPBA (content 70%, 1.1 g, 4.46 mmol) under TLC-control. The reaction mixture was washed with 2N-solution of sodium carbonate, the organic phase dried over sodium sulfate, filtered and evaporated to dryness and purified by chromatography on silicagel (acetone/hexanes:50/50 to 75/25) to give the title compound as white crystals. Yield: 700 mg (60%).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[NH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[C:22]1=[O:37].[CH3:38][C:39]1[CH:44]=[CH:43][C:42]([S:45][CH2:46][CH2:47][C:48](O)=[O:49])=[CH:41][CH:40]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[O:37]=[C:22]1[CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:34])([F:35])[F:36])[CH2:24][CH2:25][CH2:26][N:21]1[NH:20][C:48](=[O:49])[CH2:47][CH2:46][S:45][C:42]1[CH:43]=[CH:44][C:39]([CH3:38])=[CH:40][CH:41]=1
Reactant: NN1CCCC(c2ccccc2C(F)(F)F)C1=O
Reactant: Cc1ccc(SCCC(=O)O)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(SCCC(=O)NN2CCCC(c3ccccc3C(F)(F)F)C2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
EDC (9.01 g), HOBT (6.34 g) and IPEA (21.8 ml) were added to a solution of 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (8.08 g) and 3-[(4-methylphenyl)thio]propionic acid (7.37 g) in DMF (80 ml) under cooling in an ice water bath. The reaction solution was stirred at room temperature for four hours. Ethyl acetate and a sodium bicarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (13.51 g). The property values of the compound are as follows.
Reaction SMILES: OS(O)(=O)=O.O[CH2:7][CH:8]([NH:10][C@@H:11]([CH3:21])[C@@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[OH:13])[CH3:9].[OH-].[Na+].[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[F:20][C:16]1[CH:15]=[C:14]([C@H:12]2[O:13][CH2:7][C@H:8]([CH3:9])[NH:10][C@@H:11]2[CH3:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(CO)N[C@@H](C)[C@H](O)c1cccc(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H]1CO[C@H](c2cccc(F)c2)[C@@H](C)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To concentrated H2SO4 (75 ml) was added a solution of (1R*,2S*)-2-[[(1RS)-2-hydroxy-1-methylethyl]amino]-1-(3-fluorophenyl)propanol (21.6 g, 0.095 mole) in dichloromethane (100 ml) at 0° C. The resulting mixture was stirred for 16 hours at room temperature and diluted with ice water. The aqueous phase was basified with 40% aqueous sodium hydroxide and extracted with diethyl ether. The diethyl ether layers were combined, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure to yield the crude reaction product as the free base. The crude product was dissolved in diethyl ether and treated with ethereal hydrogen chloride. Recrystallization from ethanol-diethyl ether mixtures gave 17.7 g of (+-)-(2R*,3R*,5S*)-2-(3-fluorophenyl)-3,5-dimethylmorpholine hydrochloride as a white solid, m.p. 268°-269° C.
Reaction SMILES: [C:1]1([C:7]([O:13]C)=[C:8](OC)OC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.CO>[Cl-].[Cl-].[Zn+2].[Cl-].OCC[N+](C)(C)C>[OH:13][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22]
Reactant: O=Cc1ccccc1
Reactant: COC(OC)=C(OC)c1ccccc1
Agent: C[N+](C)(C)CCO
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=C(CC(O)c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of phenyl trimethoxy ethylene (0.005 mol) and benzaldehyde (0.005 mol) in ZnCl2-Choline chloride (2:1) melt (0.5 ml) was stirred mechanically for 10 minutes and silylated intermediate was pipetted out and treated with HCl(1N)/MeOH (1:10) to give pure 3-hydroxy 1,3-diphenyl-1-propanone quantitatively.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2.[SH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH2:12][CH2:11]2
Reactant: Sc1ccccn1
Reactant: O=C1CCc2cc(OCCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCCSc3ccccn3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(5-bromo-pentoxy)-3,4-dihydro-carbostyril and 2-mercapto-pyridine.
Reaction SMILES: C(O[K])(C)(C)C.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]([C:21](=[O:30])[C:22]2[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=2F)([OH:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]2([C:21](=[O:30])[C:22]3[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=3[O:20]2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Agent: CC(C)(C)O[K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccc(Br)cc1C2=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
A 1 M solution of tBuOK (54.10 ml, 54.10 mmol) in THF was added to a solution of 4-(5-bromo-2-fluoro-benzoyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (14.5 g, 36.07 mmol) in THF (200 ml) and the mixture was stirred at 70° C. After 30 min, the solution was poured into ice water (150 ml) and the product was extracted with AcOEt. The combined organic layers were washed with water (50 ml), brine (50 ml), dried over Na2SO4, then filtered and evaporated to give a pale yellow oil. Purification by column chromatography (hexane/AcOEt: 80/20 to AcOEt) gave 1.5 g of 5-bromo-3-oxo-spiro[benzofuran-2(3H), 4′-piperidin]-1′-carboxylic acid tert-butyl ester as a yellow crystalline solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(OC([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH2:20]Cl)=O)C>CO>[OH:15][C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[CH:18]=[CH:19][CH2:20][N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1
Reactant: c1ccc2c(c1)CNC2
Reactant: CCOC(=O)Oc1ccccc1C=CCCl
Solvent: CO
Product: Oc1ccccc1C=CCN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
The process for the preparation of this compound and its physical properties will be given below. A solution of 5.8 grams of isoindoline in 20 milliliters of methanol is added dropwise to a solution of 3.3 grams of o-ethoxycarbonyloxycinnamyl chloride in 30 milliliters of methanol, and the resulting mixture is stirred for 1 hour at room temperature. After completion of the reaction, the methanol is distilled off, and the residue is extracted with chloroform. The chloroform layer is then purified by silica gel column chromatography and recrystallized from ethanol to obtain 1.2 grams (yield 35%) of N-(o-hydroxycinnamyl)-isoindoline as crystals having a melting point of 161°-163° C. (decomposition).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7](/[C:16]1[C:25]([CH3:26])=[C:24]([O:27]C(=O)C)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CO.Cl>O>[CH:7](/[C:16]1[CH:25]([CH3:26])[C:24](=[O:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[CH:8]\[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCC/C=C/c1nc2ccccc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCCC/C=C/C1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.1 %

Procedure:
30 ml of an aqueous solution of 6.30 g (45.6 mmols) of potassium carbonate was added to a solution of 2.47 g (7.60 mmols) of 2-(trans-1-nonenyl)-3-methyl-4-acetoxyquinoline, 250 ml of methanol and 50 ml of water and stirred at room temperature for 13 hours. This solution was neutralized with 1N hydrochloric acid, after which the solvent was distilled off under reduced pressure, to which 100 ml of chloroform was added, followed by washing with water and drying with sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=1:2) to obtain 1.66 g (yield 77%) of 2-(trans-1-nonenyl)-3-methyl-4-quinolone.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](Cl)=[N:9][CH:10]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27](=[O:29])[CH3:28])[CH3:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[C:27]([NH:26][C@H:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:8]3[N:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=3)[CH2:17][CH2:16]2)=[CH:19][CH:20]=1)[CH3:25])(=[O:29])[CH3:28]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(C(=O)O)cn3)CC2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 1.52 g (8.5 mmol) 2-chloropyrimidine-5-carboxylic acid methyl ester in 80 mL NMP are added 2.1 g (8.5 mmol (S)—N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 2.9 mL (17.1 mmol) DIPEA and the mixture is stirred for 4 h at 100° C. The solvent is removed in vacuo. The residue is treated with 100 mL MeOH and 10 mL 4N sodium hydroxide solution is added. The mixture is stirred for 1 h at 60° C. After cooling to rt 4N HCl solution is added until the pH is acidic. The precipitate is collected and dried to yield the desired product.
Reaction SMILES: O[CH:2]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1)[C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:5][C:4]=1[CH3:18].[H][H]>[Pd]>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:2][C:3]2[C:4]([CH3:18])=[CH:5][C:6]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:7][C:8]=2[CH3:9])=[CH:20][C:21]=1[CH:27]([CH3:29])[CH3:28]
Reactant: COc1ccc(C(O)c2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1C(C)C

Procedure:
730 mg (1.66 mmol) of tert-butyl 4-[hydroxy(4-methoxy-3-isopropylphenyl)methyl]-3,5-dimethylphenylcarbamate (Example V) are hydrogenated with 700 mg of Pd/C (10%) and with 1 bar of hydrogen at RT for 4 hours. The mixture is filtered through kieselguhr, the solvent is removed in vacuo, and purification by chromatography results in 578 mg (91%) of tert-butyl 4-(4-methoxy-3-isopropylbenzyl)-3,5-dimethylphenylcarbamate.