Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(N[C@H](C(O)=O)CCC(O)=O)(=O)=O)=CC=1>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][O:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Agent: Cc1ccc(S(=O)(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(Cc3ccccc3)CCO2)cc1
Yield: 77.3 %

Procedure:
To a solution of 4-benzyl-2-(toluene-p-sulphonyloxy)methylmorpholine (18.1 g.) in methanol (100 ml.) is added a solution of (+)-toluene-p-sulphonylglutamic acid (16.0 g.) in methanol (50 ml.) and the mixture is allowed to crystallise during twelve hours. The mixture is filtered and the residue (18.3 g.) is recrystallised from methanol (150 ml.) to obtain the (+)-toluene-p-sulphonylglutamic acid salt of (2S)-4-benzyl-2-(toluene-p-sulphonyloxy)methylmorpholine (14.0 g.), m.p. 184° C. This salt is stirred with a mixture of 2N sodium hydroxide and ether. The ether layer is separated, dried and the ether is distilled to leave optically pure (2S)-4-benzyl-2-(toluene-p-sulphonyloxy)methylmorpholine as an oil from which is prepared the hydrochloride, m.p. 150° C., [α]D25 + 19.4° (c,5 in methanol).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:20])[C:17]([CH3:19])=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:20])[C:17]([CH3:19])=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:33][C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)[CH:10]=3
Reactant: ClCc1cccnc1
Reactant: Cc1cn2c3cc(Br)ccc3c3cc(O)cc(c1=O)c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cn2c3cc(Br)ccc3c3cc(OCc4cccnc4)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
9-bromo-2-hydroxy-5-methyl-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) produced in Example 114 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (315 mg) was added to the suspension. After stirring at room temperature for 30 minutes, 3-picolylchloride (137 mg) was added to the suspension. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (100 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession, and recovered by filtration to obtain the title compound (250 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[CH:12][C:11]([C:24]([O:26]CC)=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=3)=[CH:12][C:11]([C:24]([OH:26])=[O:25])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2cccc(OC)c2)n1
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(-n2nc(C(=O)O)cc2-c2cccc(C(F)(F)F)c2)c1
Yield: 72 %

Procedure:
Starting from 1.6 g (4.1 mmol) of ethyl 1-(3-methoxyphenyl)-5-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxylate from example 21A and 2.3 g (41 mmol) of potassium hydroxide, 1.07 g (2.9 mmol, 72% yield of theory) are obtained as crystals according to the method described in example 7A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+]([O-])=O)[CH:3]=1.[N+:12]([O-:15])([OH:14])=[O:13].[N:16]#[C:17][NH2:18]>CCO>[N+:12]([O-:15])([OH:14])=[O:13].[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:17]([NH2:18])=[NH:16])=[C:3]([N+:12]([O-:15])=[O:13])[CH:4]=1
Reactant: N#CN
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc(O)cc1[N+](=O)[O-]
Yield: 54 %

Procedure:
A mixture of 4-amino-2-nitrophenol (25 mmol, 3.85 g) in EtOH (6 mL) on an ice bath was treated with nitric acid (69% aq soln.; 1.8 mL). To this of cyanamide (50% aq. soln.; 4 mL) was added. The reaction mixture was refluxed under N2 for 22 h. The solvent was evaporated. The dark brown solid residue was washed with EtOH and was dried under high vacuum to afford the title compound as a grey solid (3.53 g, 54%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH:21]1[CH:25]=[CH:24][N:23]=[N:22]1.[CH3:26][O:27][C:28](=[O:31])[CH2:29]Br>>[CH3:26][O:27][C:28](=[O:31])[CH2:29][N:21]1[CH:25]=[CH:24][N:23]=[N:22]1
Reactant: COC(=O)CBr
Reactant: c1c[nH]nn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Agent: [Li+]
Product: COC(=O)Cn1ccnn1

Procedure:
Nitriles were reacted with LiHMDS or KHMDS to benzamidines which were converted to triazole by melting with hydrazides. The triazoles were coupled with 2-bromoacetic acid methyl ester under basic conditions to give the desired triazole-1-yl-acetic acid methyl ester together with different quantities of the isomeric systhem. The triazole-1-yl-acetic acid methyl ester was hydrolyzed with LiOH to the coresponding acid. The isomeres were either seperated before ore after hydrolysis of the ester. Finally, the triazole-1-yl-acetic acides were coupled with aryl substituted piperazines to the desired products.
Reaction SMILES: [CH:1]([O:4][P:5]([CH2:11][O:12][C@H:13]([CH3:20])[CH2:14]OS(C)(=O)=O)([O:7][CH:8]([CH3:10])[CH3:9])=[O:6])([CH3:3])[CH3:2].[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24]([Cl:31])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([N:26]=[CH:27][N:28]2[CH2:14][C@H:13]([O:12][CH2:11][P:5]([O:4][CH:1]([CH3:2])[CH3:3])([O:7][CH:8]([CH3:9])[CH3:10])=[O:6])[CH3:20])=[C:24]([Cl:31])[N:23]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CC(C)OP(=O)(CO[C@H](C)COS(C)(=O)=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)OP(=O)(CO[C@H](C)Cn1cnc2c(Cl)nc(N)nc21)OC(C)C
Temperature: 25 °C
Yield: 34.8 %

Procedure:
(R)-2-O-[(Diisopropylphosphono)methyl]-1-O-methanesulfonyl-1,2-propanediol (2.0 g, 6.02 mmol) was mixed with 2-amino-6-chloropurine (1 23 g, 7.22 mmol) and cesium carbonate (3.92 g, 12.0 mmol) in 40 mL of acetonitrile. The mixture was gently refluxed under nitrogen atmosphere for 24 hours, then allowed to cool to room temperature, and filtered. The solvent was removed under reduced pressure The residue was purified by flash chromatography on silica gel twice (first time, methylene chloride:acetone=3:1 to 0:1; second time, methylene chloride:methanol=15:1 to 10:1). The title compound (0.85 g, 35% yield) was isolated as a glassy material which was crystallized from ethyl acetate-diethyl ether: mp 133°-135° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4[NH2:28])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>ClCCCl.O.C(Cl)Cl.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:27])[F:26])=[CH:20][C:19]=4[NH:28][S:39]([CH3:38])(=[O:41])=[O:40])[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a solution of 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamine, (Example 163), (0.25 g, 0.65 mmol), N,N-diisopropylethylamine (0.57 mL, 3.3 mmol) in 1,2-dichloroethane (6.5 mL) was added methanesulfonyl chloride (0.12 mL, 1.6 mmol, Aldrich). The mixture was stirred at 40° C. for 72 h. After cooling to room temperature, the reaction mixture was treated with satd NaHCO3 and H2O and extracted with EtOAc (2×75 mL). The combined extracts were washed with H2O (75 mL) and brine (75 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 30 to 60% EtOAc/hexanes) afforded a pale yellow solid. To the solid was added MeOH (5 mL), CH2Cl2 (5 mL) and K2CO3 (0.050 g). The reaction mixture was stirred at room temperature for 24 h and then diluted with H2O and extracted with EtOAc (2×75 mL). The combined extracts were washed with H2O (75 mL), brine (75 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 30 to 60% EtOAc/hexanes) afforded the title compound as a white solid. Mp: 203–204° C. MS (ESI, pos. ion) m/z: 461.0 (M+1).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:17][O:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(OCCCN)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(OCCCNCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1
Reaction time: 8 h

Procedure:
3-tert-Butyldimethylsilyloxybenzaldehyde (1.5 g, 6.34 mmol) was dissolved in 1,2-dichloroethane (10.0 mL). Subsequently, 3-(4-methoxyphenoxy)propylamine (1.5 g, 8.25 mmol) was added thereto, and the resultant mixture was stirred for 20 minutes. At room temperature, sodium triacetoxyborohydride (1.75 g, 8.25 mmol) and acetic acid (495 mg, 8.25 mmol) were added thereto, and the mixture was stirred overnight. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The reaction mixture was extracted with chloroform, and the organic layer was washed with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=50/1), whereby the target compound was obtained (1.9 g, 78%).
Reaction SMILES: [CH3:1][C:2]([NH2:6])([C:4]#[CH:5])[CH3:3].[CH:7]1([C:10](O)=[O:11])[CH2:9][CH2:8]1>>[CH3:1][C:2]([NH:6][C:10]([CH:7]1[CH2:9][CH2:8]1)=[O:11])([C:4]#[CH:5])[CH3:3]
Reactant: C#CC(C)(C)N
Reactant: O=C(O)C1CC1
Product: C#CC(C)(C)NC(=O)C1CC1

Procedure:
The title compound was prepared from 2-methylbut-3-yn-2-amine and cyclopropanecarboxylic acid following the procedure described in Preparation 4.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C([Li])CCC.[NH2:16][C:17]1[N:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:18]=1[C:19](N(OC)C)=[O:20]>O1CCCC1>[NH2:16][C:17]1[C:18]([C:19]([C:6]2[CH:7]=[C:2]([F:1])[C:3]([CH3:10])=[CH:4][C:5]=2[O:8][CH3:9])=[O:20])=[CH:25][CH:26]=[C:27]([Cl:29])[N:28]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: COc1ccc(F)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C)c(F)cc1C(=O)c1ccc(Cl)nc1N
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-fluoro-3-methylanisole (0.75 mL, 802 mg, 5.55 mmol, Aldrich 97%) in anhydrous tetrahydrofuran (5 mL) at −78° C., was added slowly a solution of n-butyllithium in hexanes (2.5 M, 2.22 mL, 5.55 mmol, Aldrich). The reaction was stirred at −78° C. for 10 mins before it was allowed to warm to −25-0° C. and stirred for 1.5 hour. The resulting aryllithium reagent was cooled back to −78° C. and reacted with 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide as described in Example 7 to give (2-Amino-6-chloro-pyridin-3-yl)-(5-fluoro-2-methoxy-4-methyl-phenyl)-methanone as an off-white solid. HRMS, observed: 295.0645, Calcd for (M+H)+: 295.0644.
Reaction SMILES: [Cl:1][C:2]#[C:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH:20]=[C:21]([Cl:23])[Cl:22])[CH:15]=[C:14]([Cl:24])[C:13]=1[O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]#[C:2][Cl:1]
Reactant: OCCCCOCC#CCl
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClC#CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 79.1 %

Procedure:
To a mixture of 0.20 g of 4-(3-chloro-2-propynyloxy)butanol, 0.32 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 0.32 g of triphenylphosphine and 15 ml of tetrahydrofuran was slowly added dropwise 0.27 g of diisopropyl azodicarboxylate with stirring under ice cooling. After stirring at room temperature for 24 hours, the reaction mixture was concentrated. The residue was subjected to silica gel chromatography, which afforded 0.38 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3-chloro-2-propynyloxy)butyloxy)benzene (yield, 71%), nD23.5 1.5511.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:31])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([O:24]C)=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:18]([CH3:31])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([OH:24])=[O:23])=[O:16])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1cc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)c(C)cc1C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2CCC2)c(C(=O)O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
To a solution of methyl 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzoate (compound 230.3, 1.50 g, 3.60 mmol, 1.00 equiv) in methanol (10 mL) was added aqueous sodium hydroxide (577 mg, 14.4 mmol, in 5 mL water) dropwise at 0° C. The resulting solution was stirred for 2 h at 60° C. in an oil bath. After cooling to ambient temperature, the organic solvent was removed under reduced pressure. The pH of the remaining aqueous layer was adjusted to 3-4 with hydrogen chloride (aq., 2 M). The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield 1.20 g (83%) of the title compound as a white solid. m/z (ES+) 403 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[C:9]([Cl:16])=[C:10]([CH3:15])[C:11]([Cl:14])=[CH:12][CH:13]=1)=[O:6].[H-].[Na+]>CN(C)C=O>[Cl:16][C:9]1[C:10]([CH3:15])=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=1[N:7]1[CH2:2][CH2:3][CH2:4][C:5]1=[O:6]
Reactant: Cc1c(Cl)ccc(NC(=O)CCCCl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Cl)ccc(N2CCCC2=O)c1Cl
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of 3-(4-chlorobutyryl)amino-2,6-dichlorotoluene (2.80 g) in N,N-dimethyl formamide (30 ml) was added sodium hydride (60% oil dispersion, 440 mg) in one portion at 5° C. The mixture was stirred for 10 minutes at 5° C. and then for 2 hours at 60° C. The cooled mixture was poured into ice water. The separated oil was extracted with dichloromethane. The organic layer was washed with water three times, dried, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give 1-(2,4-dichloro-3-methylphenyl)-2-pyrrolidinone (1.95 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[C:10]([CH2:12][N:13]([CH2:32][CH:33]3OCCO3)[C:14]([C:16]3[NH:17][CH:18]=[C:19]([C:21](=[O:31])[C:22]4[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=4[F:30])[CH:20]=3)=[O:15])[N:11]=[C:5]2[CH:4]=1)#[N:2].CS(O)(=O)=[O:40]>CC#N.O>[O:15]=[C:14]1[C:16]2[NH:17][CH:18]=[C:19]([C:21](=[O:31])[C:22]3[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=3[F:28])[C:20]=2[CH:33]=[CH:32][N:13]1[CH2:12][C:10]1[N:11]=[C:5]2[CH:4]=[C:3]([C:1]([NH2:2])=[O:40])[CH:8]=[CH:7][N:6]2[CH:9]=1
Reactant: N#Cc1ccn2cc(CN(CC3OCCO3)C(=O)c3cc(C(=O)c4c(F)cc(F)cc4F)c[nH]3)nc2c1
Reactant: CS(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: NC(=O)c1ccn2cc(Cn3ccc4c(C(=O)c5c(F)cc(F)cc5F)c[nH]c4c3=O)nc2c1
Temperature: 95 °C

Procedure:
The product from step B (430 mg, 0.884 mmol) was dissolved in methanesulfonic acid (2.0 mL) and heated to 95° C. in an oil bath for 25 min. After cooling in an ice-water bath, the reaction mixture was diluted with 2:3 MeCN—H2O (3 mL) and purified by reverse phase HPLC (C-18 column) to give the title compound (174 mg). LC/MS: m/z 467(M+H). 1H-NMR (d6-DMSO, 500 MHz): δ 5.46 (s, 2H), 7.01 (d, 1H), 7.33 (t, 2H), 7.58-7.59 (m, 2H), 7.61 (s, 1H), 7.79 (s, 1H), 7.91 (d, 1H) 8.12 (d, 1H), 8.33 (s, 1H), 8.72 (d, 1H), 13.12 (s, 1H).
Reaction SMILES: [C:1]1(C(CCCC)CN)[CH:6]=CC=C[CH:2]=1.Cl.[C:15]1([CH:21]([CH2:50]C(C)C)[CH2:22][N:23]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH2:41][C:42](=[CH:46][C:47]([OH:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:26]=2[Cl:35])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:35].[C:15]1([CH:21]([CH2:50][CH2:2][CH2:1][CH3:6])[CH2:22][N:23]([CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH2:41][C:42](=[CH:46][C:47]([OH:49])=[O:48])[CH:43]=[CH:44][CH:45]=2)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[C:26]=2[Cl:35])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: CCCCC(CN)c1ccccc1
Agent: Cl
Product: CCCCC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1

Procedure:
The titled compound was prepared from 2-phenylhexylamine (J. Chem. Soc. Perk. Trans. 1: Organic and Biorganic Chemistry (1976), (1), 33-8) in the same manner as the preparation of N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine, hydrochloride, Example 189e-h. MS (ESI) 562 (MH+)
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=1
Reactant: OC1(c2ccccc2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2ccccc2)CCCC1
Temperature: 25 °C

Procedure:
1-phenylcyclohexan-1-ol (24.9 mmol), p-toluenesulfonic acid (500 mg) and toluene (200 mL) are mixed together in a 500 mL 3 neck flask fitted with a thermometer and Dean Stark trap and stirred at reflux for 4 hours under a nitrogen atmosphere. The reaction is then allowed to cool to room temperature and concentrated under reduced vacuum. The crude material is then taken into methylene chloride, washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum. This material can then be purified via silica gel chromatography employing the Water's Prep 2000 and eluting with a solvent of hexane/methylene chloride 9:1 to yield the intermediate title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:11][CH:10]=1
Reactant: BrCCCCBr
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCCCBr)cc1
Yield: 82 %

Procedure:
Condensation of 1,4-dibromobutane with 4-methoxyphenol according to A. M. Ismaiel et al. (J Med Chem (1993) 36, 2519-25) gives an 82% yield of 1-(4-methoxyphenoxy)-4-bromobutane. By condensing 670 mg (2.58 mmol) of this derivative with 700 mg (2.35 mmol) of N-methyl-N-[4-piperidyl]-4H-3,1-benzothiazin-2-amine, obtained in Example 16-2, in 8 ml of dry DMF in the presence of 630 mg (5.8 mmol) of 98 Na2CO3 /02 KI according to the procedure of Example 16-3, the compound of formula 22 is prepared in a yield of 58%: ##STR46##
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]([OH:15])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)CC(CCCCc1ccccc1)Sc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC(CCCCc1ccccc1)Sc1ccccc1
Reaction time: 5 h

Procedure:
To a solution of t-butyl 7-phenyl-3-phenylsulfanylheptanoate (1.8 g; 6.5 mmol) in CH2Cl2 (20 mL) is slowly added trifluoroacetic acid (6 mL). The reaction is stirred 5 hours and concentrated in vacuo to yield 7-phenyl-3-phenylsulfanylheptanoic acid which is used directly in Step I.
Reaction SMILES: O1CCCC1.Cl.[N:7]1([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(N(CC)CC)C>[C:28]([N:10]1[CH2:11][CH2:12][N:7]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[C:18]([O:24][CH3:25])[CH:19]=3)[N:14]=2)[CH2:8][CH2:9]1)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc2nc(N3CCN(C(=O)C=Cc4ccccc4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 10 ml. of tetrahydrofuran were added 1.2 g. of 2-(piperazin-1-yl)-4-amino-6,7-dimethoxyquinazoline.hydrochloride and 1.33 g. of triethylamine and the resulting mixture was stirred for 30 minutes. Thereafter, 0.66 g. of cinnamoyl chloride was added thereto and the resulting mixture was stirred at room temperature overnight. The crystalline substance thus separated was recovered by filtration, washed thoroughly with water and ethanol and then dried to afford 0.66 g. of the desired product.
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][C@H:12]3[C@H:17]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)=[CH:9][C:4]=2[CH2:3][O:2]1.FC(F)(F)C(O)=O.ClCCl>C1(C)C=CC=CC=1>[CH2:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][C@H:12]3[C@H:17]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH2:16][CH2:15][NH:14][CH2:13]3)=[CH:9][C:4]=2[CH2:3][O:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc3c(c2)COC3)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Fc1ccc([C@@H]2CCNC[C@H]2COc2ccc3c(c2)COC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.9 %

Procedure:
To tert-butyl (3S,4R)-3-[(1,3-dihydro-2-benzofuran-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine-1-carboxylate (4.1 g, 9.6 mmol) described in Production Example 1-4 was added a mixed solution of trifluoroacetic acid (5 mL) and dichloromethane (30 mL) under ice cooling, followed by stirring at room temperature for 90 minutes. Toluene (30 mL) was added to the reaction mixture, and the solvent was distilled away under reduced pressure. The residue was purified by NH silica gel column chromatography (methanol:ethyl acetate=1:20) to give the title compound (2.7 g, 84% yield).