Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([CH:29]=[O:30])[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([O:14][C:15]1[CH:16]=[C:17]([C:24]2[S:25][CH:26]=[C:27]([CH:29]([OH:30])[C:2]3[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH3:11])[CH:3]=3)[N:28]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][CH3:23])[CH3:13]
Reactant: CCOc1ccc(-c2nc(C=O)cs2)cc1OCC
Reactant: COc1ccc(Br)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(C(O)c3ccc(OC)c(OC)c3)cs2)cc1OCC
Yield: 48.9 %

Procedure:
60 ml of a tetrahydrofuran solution of a Grignard reagent prepared from 2.4 g of 1-bromo-3,4-dimethoxybenzene was stirred with ice-cooling. Thereto was added 20 ml of a tetrahydrofuran solution of 3 g of 2-(3,4-diethoxyphenyl)-4-formylthiazole. The mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. 10 ml of a saturated aqueous ammonium chloride solution was added. The solvent was removed by distillation. The residue was extracted with 100 ml of chloroform. The extract was washed with 20 ml of water and 20 ml of a saturated aqueous sodium chloride solution, and dried. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: dichloromethane/acetone=99/1 by v/v) and recrystallized from diethyl ether to obtain 2.2 g of 2-(3,4-diethoxyphenyl)-4-[1-hydroxy-1-(3,4-dimethoxyphenyl)methyl]thiazole
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC1O[N:29]=[C:28]([C:31]2C=CC=CC=2)[C:27]=1COC1C=CC(C(O)=O)=CN=1.C(N)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:29][CH:28]([CH3:31])[CH3:27])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Solvent: CC(C)N
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 76 %

Procedure:
As described for example 8b, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (103 mg, 0.3 mmol), instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, was converted, using isopropylamine instead of methylamine, to the title compound (88 mg, 76%) which was obtained as an off white solid. MS: m/e=368.0 [M+H]+.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Si:23]([O:40][CH2:41][CH2:42][CH2:43]/[C:44](=[CH:54]\[S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)/[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=O)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:23]([O:40][CH2:41][CH2:42][CH2:43]/[C:44](=[CH:54]\[S:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)/[C:45](=[S:10])[NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:36]([CH3:38])([CH3:37])[CH3:39])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](OCCC/C(=C\Sc1ccccc1)C(=S)Nc1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Lawesson reagent was added to tetrahydrofuran solution including 2.81 g of (E)-5-(tert-butyldiphenylsilyloxy)-N-phenyl-2-(phenylthiomethylene)pentanamide. The resulting solution was heated under reflux for one night and cooled to room temperature, followed by adding saturated sodium bicarbonate water to extract. The water layer was extracted with ethyl acetate, and the organic layer was mixed and dried with anhydrous magnesium sulfate, then filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.17 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([OH:6])[CH3:5].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:2][CH2:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:6])[CH3:5])[CH2:20][CH2:21]1
Reactant: CC(O)(CCCl)c1ccccc1-c1ccccc1
Reactant: C1COCCN1
Product: CC(O)(CCN1CCOCC1)c1ccccc1-c1ccccc1

Procedure:
2.6 g of 1-chloro-3-p-biphenylyl-butan-3-ol are boiled with 30 ml of morpholine for 1.5 hours and the mixture is cooled and worked up in the customary manner to give 1-morpholino-3-p-biphenylyl-butan-3-ol, m.p. 116° -118°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O[NH:64][C:65]([C:67]1[CH:76]=[CH:75][C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[CH:68]=1)=[NH:66]>CN(C=O)C>[CH:68]1[C:69]2[C:74](=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:75]=[CH:76][C:67]=1[C:65]1[N:64]=[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH3:20])[O:12][N:66]=1
Reactant: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(NO)c1ccc2ccccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)c1nc(-c2ccc3ccccc3c2)no1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-8-oxodecanoic acid (1 eq), TBTU (1.2 eq), HOBt (0.2 eq) and DIPEA (5 eq) in DMF was stirred at RT for 5 min; then added N-hydroxynaphthalene-2-carboximidamide was added and the mixture was stirred at RT for 20 min, after which time the mixture was warmed to 110° C. for 2 h. The solvent was removed under reduced pressure and the resulting crude used as such in the next step. MS (ES) C26H33N3O4 requires: 451, found: 452 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:17])([CH3:16])[CH:13]([NH2:15])[CH3:14]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:15][CH:13]([CH3:14])[C:12]([CH3:17])([CH3:16])[CH3:11])=[S:10])=[CH:4][CH:3]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: CC(N)C(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=S)Nc1ccc(Br)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a solution of 4-bromophenyl isothiocyanate (1.50 g, 7.01 mmol) in THF (30 mL) at room temperature was added (±) 3,3-dimethyl-2-aminobutane (1.41 mL, 10.5 mmol) and the reaction was stirred overnight at room temperature. The mixture was concentrated in vacuo and the resulting residue was triturated with diethyl ether and filtered to afford 1.76 g (80%) of 1-(4-bromophenyl)-3-(1,2,2-trimethyl-propyl)-thiourea as a white solid which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]=[O:17]>N1C=CC=CC=1.O>[OH:17][CH2:16][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]#[N:9]
Reactant: N#CC(c1ccccc1)c1ccccc1
Reactant: C=O
Solvent: O
Solvent: c1ccncc1
Product: N#CC(CO)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Reaction time: 40 h
Yield: 79.2 %

Procedure:
To a suspension of 2,2-diphenylacetonitrile (2.0 g, 10.35 mmol) and paraformaldehyde (1.242 g, 41.399 mmol) in pyridine (18 mL) was added Triton B (40% solution in water, 1.022 mL, 2.587 mmol) at 0° C. The suspension instantaneously changed color. The cooling bath was removed and the reaction was stirred at 23° C. for ˜40 hours. The reaction was then acidified with acetic acid (2 mL) and poured into water (150 mL). The aqueous phase was extracted with diethyl ether (2×) and the combined organic extracts were washed with water (2×), 1N HCl (2×) and saturated sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel Biotage chromatography (ethyl acetate/hexane 10% to 50%) to give the title material (1.83 g, 100%) as an oil. HPLC ret. time (Condition A): 1.682 min. 1H NMR (400 MHz, CDCl3) δ ppm: 2.21 (1H, t, J=7.20 Hz), 4.37 (2H, d, J=6.82 Hz), 7.35-7.44 (10H, m).
Reaction SMILES: ClCCl.[CH2:4]([OH:9])[CH2:5][C@@H:6]([OH:8])[CH3:7].[C:10]([Si:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:13])([CH3:12])[CH3:11].[Cl-].[NH4+]>C(N(CC)CC)C>[Si:14]([O:9][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7])([C:10]([CH3:13])([CH3:12])[CH3:11])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](O)CCO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under ice cooling, to a dichloromethane solution (20.0 ml) of (S)-1,3-butanediol (519 mg) were added triethylamine (1.04 ml) and tert-butylchlorodiphenylsilane (1.63 ml), followed by stirring at room temperature overnight. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford (2S)-4-{[tert-butyl(diphenyl)silyl]oxy}butan-2-ol (1.69 g).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:9][C:7]=1[NH2:8].O.O.[Sn](Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:9][C:7]=1[NH:8][NH2:1]
Reactant: O=N[O-]
Reactant: CC(C)Oc1cc(N)c(Cl)cc1Cl
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution of 15.8 g (0.23 mole) of sodium nitrite in 100 mL of water was added to a stirred solution of 50.0 g (0.23 mole) of 2,4-dichloro-5-(1-methylethoxy)aniline in 250 mL of concentrated hydrochloric acid at 0° C. over 30 minutes. After complete addition, the mixture was stirred at 0° C. for 30 minutes. A solution of 114.0 g (0.506 mole) of tin (II) chloride dihydrate in 125 mL of concentrated hydrochloric acid was added dropwise to the reaction mixture. After complete addition, the mixture was stirred for one hour. The resultant white slurry was filtered. The filter cake was added to a 20% aqueous sodium hydroxide solution and stirred for 30 minutes. The basic mixture was filtered, and the filter cake recrystallized from methanol and water to yield 37.0 g of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:20])[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([O:17]CC)=[O:16])[CH2:10]1.[OH-].[Na+].O>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([OH:20])[CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)(c2ccccc2)c2ccccn2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1CCCN(CC(O)(c2ccccc2)c2ccccn2)C1

Procedure:
Ethyl 1-[2-(2-pyridyl)-2-phenyl-2-hydroxyethyl]piperidine-3(S)-carboxylate (0.187 g, 0.527 mmol) was dissolved in EtOH (5 mL), 1N NaOH (0.791 mL, 0.791 mmol) and H2O (5 mL) added, and the reaction mixture heated at reflux for 3 hr. Neutralization with 1N HCl (to a pH of 6) and concentration to dryness gave the title compound which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([N:13]1[CH2:17][C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])=[CH:15][C:14]1=[O:26])[CH2:5][CH:6]1[CH:10]2[CH2:11][CH2:12][CH:7]1[CH2:8][CH2:9]2.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:7]12[CH:6]([CH2:5][CH:4]([N:13]3[CH2:17][C:16]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])=[CH:15][C:14]3=[O:26])[C:3]([OH:27])=[O:2])[CH:10]([CH2:9][CH2:8]1)[CH2:11][CH2:12]2
Reactant: COC(=O)C(CC1C2CCC1CC2)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1C2CCC1CC2)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
In a flask was placed 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (35 mg, 0.089 mmol) in tetrahydrofuran (2 mL). To this mixture at 25° C. was added a solution of lithium hydroxide monohydrate (8 mg, 0.18 mmol) in water (2 mL) and stirred for 1.5 h at 25° C. The mixture was treated with a 1N aqueous hydrochloric acid solution to pH=2 and was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 3-bicyclo[2.2.1]hept-7-yl-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (32 mg, 97%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18](N)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].[OH2:22]>CC(C)=O>[ClH:21].[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([OH:19])=[O:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: NC(=O)COCCN1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)COCCN1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
III.1.A. 13.9 g (0.05 mol) of 2-(4-benzyl-1-piperazinyl)ethoxyacetamide are dissolved in 15 ml of water in a 100 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. 31 ml (0.375 mol) of aqueous 37% hydrochloric acid solution are added. The mixture is heated at 60° C. for 1 hour. The water is removed on a rotary evaporator under reduced pressure at 60° C. The white solid obtained is taken up in 75 ml of acetone and is stirred for 1 hour at room temperature. The mixture is filtered and 19.7 g of 2-(4-benzyl-1-piperazinyl)ethoxyacetic acid dihydrochloride are obtained in the form of white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[C:20]1([CH3:31])[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[CH:22][CH:21]=1>O1CCCC1>[CH2:9]([O:8][C:6](=[O:7])[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH2:29][CH2:28][CH2:27][CH2:26][C:23]1[CH:22]=[CH:21][C:20]([CH3:31])=[CH:25][CH:24]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH3:10]
Reactant: Cc1ccc(CCCCBr)cc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCc1ccc(C)cc1)(C(=O)OCC)c1ccccc1
Yield: 55 %

Procedure:
Phenylmalonic acid diethyl ester (8.8 mmol) dissolved in 5 ml absolute tetrahydrofuran is added dropwise to 20 ml absolute tetrahydrofuran and sodium hydride (9.7 mmol). Then 4-p-tolylbutyl bromide (8.8 mmol) dissolved in 10 ml absolute tetrahydrofuran is added after 15 minutes. It is heated for 3 days under reflux. The solvent is concentrated in a vacuum. The residue is taken up in 50 ml ethyl acetate and extracted with 2×50 ml water. The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation. It is purified by chromatography on silica gel (heptane/ethyl acetate 9:1). Yield 55% colourless oil.
Reaction SMILES: [F:1][C:2]1([F:65])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([N:42]5[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:4][CH2:3]1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>C(O)C>[F:65][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:37]=[CH:38][C:39]([N:42]5[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]5)=[CH:40][N:41]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:53]([F:64])[C:54]2[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:59]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCN(c2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(OCc4ccc(OC)cc4)CC(C)(C)C5)CC3)nc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1CCN(c2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a solution of 98 mg (0.11 mmol) of 4-(4,4-Difluorocyclohexyl)-2-(1-{5-[4-(ethoxycarbonyl)piperidin-1-yl]pyrimidin-2-yl}piperidin-4-yl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 13, in 2 ml of ethanol, 1 ml of 4 N hydrogen chloride/1,4-dioxane solution was added, and the reaction solution was stirred at 50° C. for 3 hours. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was poured into the reaction solution under ice cooling and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-60/40 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 69 mg of the title compound as a light brown solid (yield: 81%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[C:7]5[CH2:6][CH2:5][O:4][C:12]=5[CH:11]=[CH:10][N:9]=4)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:34])=[CH:31][CH:30]=1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, off-white solid (103 mg, 88%), MS (ISP) m/z=469.3 [(M+H)+], mp 226.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-chlorobenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:26])[C:24]#[CH:25]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:26][CH2:23][C:24]#[CH:25])=[O:12])[CH2:8]1
Reactant: C#CCN
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
A mixture of 4.85 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride and 2.8 g (0.02 mole) of anhydrous potassium carbonate in 20 ml of tetrahydrofuran was stirred while 1.1 g (0.02 mole) of 2-propynylamine was added dropwise from a needle and syringe. After stirring for 30 min, a small piece of ice was added and stirring continued for 17 hr. The reaction mixture was diluted with 200 ml of water then extracted with 3×50 ml of methylene chloride. The combined extracts were dried by passing through Whatman phase separating paper then concentrated in vacuo to an oily residue (3.73 g). This residue was dissolved in 30 ml of methylene chloride and chromatographed in three portions (3 runs) on a spinning TLC plate (chromatotron) with an ethyl acetate-methylene chloride gradient from 10%-100% ethyl acetate. A white solid (1.8 g) was obtained on concentration of the product fractions. Recrystallization from isopropyl ether yielded 0.93 g (17.9%) of white crystalline product, m.p. 121°-123° C.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]([F:20])([F:19])[CH2:10][CH2:11][Si:12](OC)([O:15][CH3:16])[O:13][CH3:14].[SiH4].CCCCCC>C(OCC)C.CCCCCC>[F:20][C:9]([F:8])([F:19])[CH2:10][CH2:11][Si:12]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([O:13][CH3:14])[O:15][CH3:16]
Reactant: Cl[Mg]C1CCCC1
Reactant: CO[Si](CCC(F)(F)F)(OC)OC
Agent: [SiH4]
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[Si](CCC(F)(F)F)(OC)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under nitrogen, a 500 ml Schlenk flask was cooled to room temperature, charged with 150 ml of diethyl ether and cyclopentylmagnesium chloride (0.055 mol, 27.7 ml) and warmed slightly to 30° C. A 100 ml Schlenk flask was purged with nitrogen and charged with 75 ml hexane and 3,3,3-trifluoropropyltrimethoxy silane (10 ml, 0.0504 mol). The silane/hexane solution was added dropwise via cannula to the Grignard/diethyl ether mixture producing a white cloudy mixture. After addition (1.25 hrs.), the Grignard containing flask was rinsed once with 25 ml of hexane. The reaction mixture was stirred at room temperature for one hour.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][C:12]([CH:14]([CH3:16])[CH3:15])=O>C(O)(=O)C.C(O)C>[CH3:11][C:12]1[C:14]([CH3:16])([CH3:15])[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=2[N:9]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)C(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)C(C)=N2

Procedure:
A mixture of 0.18 mole of 4-methoxy-phenylhydrazine, 0.27 mole of methyl-isopropyl ketone, five drops of acetic acid and 300 ml of ethanol was refluxed for 3 hours and then the solvent was evaporated. The dark residue (28 g of hydrazone) was dissolved in 125 ml of ethanol. After adding 54 ml of a 15 % by weight solution of concentrated sulphuric acid in ethanol the mixture was refluxed for 2.5 hours. The white precipitate (ammonium sulphate was filtered and the filtrate was diluted with 750 ml of water, neutralized with a few ml of aqueous 5N NaOH and extracted with ether. The dried extract was distilled in vacuo.