Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 45.2 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (2.01 g, 7.23 mmol) was dissolved in DMF (20 ml). To the solution, sodium hydride (320 mg, 8 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 70° C. To the solution, 2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 6 (1.5 g, 7.23 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) and then crystallized from methylene chloride/ethyl acetate to afford tert-butyl 4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (1.5 g, yield 45%) as a white powder.
Reaction SMILES: [OH-].[Na+].O.CC[O:6][C:7]([C@@H:9]([NH:18][C@H:19]([C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH3:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8].C(O)CCC>C(O)C>[CH3:20][C@H:19]([NH:18][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Reaction time: 15 h

Procedure:
A solution of NaOH (6.5 g, 153.6 mmol; assay=94.52%), water (157 ml), ethanol (157 ml, technical grade, contains ˜5% 2-propanol) and Trandolapril (31.5 g, 72.94 mmol; assay=99.7%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 15 hours. After an in-process control showed an almost complete saponification (by HPLC), the clear solution was concentrated in vacuo to an amount of 167.05 g, and n-butanol (160 ml) was added to the concentrated product. This mixture was heated to an internal temperature ranging from about 60° C. to about 70° C., and 2N aqueous hydrochloric acid was added (150.4 mmol), whereupon the pH dropped down from 12.09 to 3.66. The organic layer was separated at an internal temperature of 66° C., and the aqueous layer was extracted again with n-butanol (80 ml) at an internal temperature of 65° C. The combined organic layers were washed twice with water (each 40 ml) at an internal temperature ranging from about 63° C. to about 65° C. The organic layer then obtained (total amount 306.4 g) was concentrated in vacuo at a temperature ranging from about 50° C. to about 60° C., whereupon after concentration to an amount of 190 g a white solid precipitated. This suspension was further concentrated in vacuo to an amount of 75.1 g, and 80 ml MTBE was added to complete the precipitation. The suspension was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 3.5 hours. After filtration, the wet product was washed twice with MTBE (each 80 ml) and dried in vacuo for 15 hours at 40° C. to give Trandolaprilat as disolvate with n-butanol (yield: 36.51 g, 66.67 mmol, 91.4%; assay (0.1N HClO4)=73.5%; HPLC purity=100%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17]C(OCC(Cl)(Cl)Cl)=O)[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.C(O)(=O)C>CO.O1CCCC1.[Zn]>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH2:17])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(NC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: NC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
To 20 g (36 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-(2,2,2-trichloroethoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 154) in 50 ml of methanol and 50 ml of tetrahydrofuran was added 4.69 g (72 mmole) of zinc dust and 16 g (267 mmole) of acetic acid. After stirring for 1 hour the reaction was filtered, concentrated in vacuo, partitioned between diethyl ether and water, washed with 5% aqueous sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and chromatographed on silica gel using methylene chloride and ethyl acetate to yield 6 g of the title compound, a white solid, mp 144°-146° C.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=1.C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=3)[CH2:26][CH2:27]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.1 g of 4-dimethylaminobenzoyl chloride in 130 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 6.08 g of 1-[2-(4-chlorophenyl)-ethyl]-piperazine and 2.74 g of triethylamine in 150 ml of methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with methylene chloride, rendered alkaline with 2N NaOH and washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. The residue is recrystallised from ethanol. 1-[2-(4-chlorophenyl)-ethyl]-4-(4-dimethylaminobenzoyl)piperazine having a melting point of 133°-134° is thus obtained.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([O:27]CC)=[O:26])[CH:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClC1C=C(N2C(C3C=CC=CC=3F)=CC(C(O)=O)=N2)C=CC=1>>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[N:16]=[C:15]([C:25]([OH:27])=[O:26])[CH:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2ccccc2F)n(-c2cccc(Cl)c2)n1
Product: O=C(O)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 54A in analogy to the synthesis of the compound of Example 86A. 1.78 g (79% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl>CCOCC.CN(C)C=O>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]1=[O:13]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: ClCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C1C(=O)N(CCCCCl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (50% dispersion in oil, 1.63 g, 34 mmole) under dry nitrogen was washed with 50 ml of ether to remove the oil. The ether was separated by decantation. Dimethylformamide (25 ml) was added to the ether wet sodium hydride. A solution of 2,3-indolinedione (isatin, 5 g, 34 mmole) and 1,4-dichlorobutane (21.6 g, 18.6 ml, 0.17 mmole) in 200 ml of dimethylformamide was added dropwise over 1 hour, maintaining the temperature at 25°-28° C. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was filtered, and the filtrate evaporated to 30 ml and diluted with 50 ml of methylene chloride. The resulting mixture was again filtered, the filtrate evaporated to dryness and the residue slurried in 200 ml of ether. The ether was decanted from a drum and evaporated to yield the title product [830 mg, Rf 0.55 1:1 ethyl acetate:hexane)].
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15](=[O:29])[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=4)=[N:18]3)=[C:13]([CH2:30][CH3:31])[N:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Pd]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[NH:16][C:15](=[O:29])[C:14]3=[C:13]([CH2:30][CH3:31])[N:12]=[C:11]([C@H:8]4[CH2:9][CH2:10][C@@H:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:6][CH2:7]4)[N:19]3[N:18]=2)=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c(=O)c12
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3ccc(N)cc3)[nH]c(=O)c12

Procedure:
580 mg (1.37 mmol) cis-7-(4-tert-butylcyclohexyl)-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 36A) are dissolved in 50 ml tetrahydrofuran and catalytic amounts of palladium (10% on charcoal) are added. The mixture is stirred for 18 hour at room temperature in a 3 bar hydrogen atmosphere. Then the mixture is filtrated and the organic phase evaporated to dryness in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[O:16][CH:17]2[CH:22]([OH:23])[CH:21]([OH:24])[CH:20]([OH:25])[CH:19]([CH2:26][OH:27])[O:18]2)=[O:10])=[CH:5][CH:4]=1.[BH4-].[Na+].ClCCl.CO.N>O1CCCC1.CO.O>[OH:10][CH:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[C:11]1[S:12][CH:13]=[CH:14][C:15]=1[O:16][CH:17]1[CH:22]([OH:23])[CH:21]([OH:24])[CH:20]([OH:25])[CH:19]([CH2:26][OH:27])[O:18]1
Reactant: COc1ccc(C(=O)c2sccc2OC2OC(CO)C(O)C(O)C2O)cc1
Agent: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(C(O)c2sccc2OC2OC(CO)C(O)C(O)C2O)cc1

Procedure:
4.1 g of (4-methoxy-phenyl)-[3-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-thiophen-2-yl]-methanone were dissolved in 200 ml of tetrahydrofuran+20 ml of methanol, and 500 mg of sodium borohydride were added. After the reaction was complete (TLC check, dichloromethane/methanol/conc. ammonia=30:5:0.1; about 30-60 min), water was added and the mixture was extracted three times with ethyl actetate. The combined organic phases were dried over magnesium sulfate and concentrated. 2{2-[Hydroxy-(4-methoxy-phenyl)-methyl]-thiophen-3-yloxy}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol was obtained as crude product which was purified by filtration through silica gel.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]([C:10]2[N:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: N#Cc1ccc(Nc2cccnn2)cc1
Product: N#Cc1ccc(N(Cc2ccc(Br)cc2)c2cccnn2)cc1

Procedure:
3-[(4-Cyanophenyl)amino]pyridazine and 4-bromobenzyl bromide
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34](=O)[O:35]CC(Cl)(Cl)Cl)[N:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[C:24]([C:28]1[CH:32]=[C:31]([NH:33][C:34]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:18]=[CH:17][C:9]3[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=3[C:7]=2[C:19]#[N:20])=[O:35])[N:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccccc2)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c(C#N)c2s1
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To a solution of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) in dimethylsulfoxide (2 mL) were added 2,2,2-trichloroethyl (3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)carbamate (190 mg, 0.485 mmol) and triethylamine (70 μL, 0.508 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=70/30→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diethyl ether to give the title compound (155 mg, 59%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH:12]=[CH:13][O:14][CH3:15])=[CH:7][N:6]=1)=[O:4]>CCO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH2:12][CH2:13][O:14][CH3:15])=[CH:7][N:6]=1)=[O:4]
Reactant: COC=Cc1cnc(C(=O)OC)c(N)n1
Agent: [Pd]
Solvent: CCO
Product: COCCc1cnc(C(=O)OC)c(N)n1
Reaction time: 37 h
Yield: 56.1 %

Procedure:
A solution of 3-amino-5-(2-methoxy-vinyl)-pyrazine-2-carboxylic acid methyl ester (260 mg, 1.24 mmol) and Pd/C 10% (50 mg) in EtOH (10 ml) was stirred at rt and under an atmosphere of hydrogen for 17 h. To complete the reaction, more Pd/C 10% (84 mg) was added and the reaction was stirred under an atmosphere of hydrogen for 37 h. The suspension was filtered off and washed with EtOH and then residual solution was evaporated. The residue was purified by chromatography on silica gel (DCM to DCM/MeOH 9:1) to provide the title compound as yellow solid (147 mg).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.S(OC)(O[CH3:21])(=O)=O>O>[CH3:21][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(-c2ccc(O)cc2)cc1
Yield: 43.8 %

Procedure:
120 ml of water and sodium hydroxide (14.00 g, 0.35 mol) were placed in a conical flask and dissolved. 4,4'-Dihydroxybiphenyl (28.00 g, 0.15 mol) was then added and heated to reflux for 2 hours with stirring using a condenser. Dimethyl sulfate (14.5 ml, 0.15 mol) was added dropwise over about 40 minutes. After addition, the mixture was heated while stirring for 2 hours, and then allowed to cool and filtrated. The filter cake was transferred into 700 ml of water, which was then heated to boiling temperature, and filtrated while still keeping warm. The filtrate was kept at 70° C., and 20% hydrochloric acid was added. White precipitation: formed was washed extensively. Recrystallization from ethanol yielded 4'-methoxy-4-hydroxybiphenyl (13.17 g, Yield: 48.0%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br.Br[CH:12]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:12]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)C(=O)C(Br)c1cccnc1
Agent: Br
Agent: [Na]
Solvent: CO
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)c1cccnc1
Yield: 61.9 %

Procedure:
6.9 g (0.3 mol) of sodium metal were added to a solution of 38.6 g (0.3 mol) of 4-chlorophenol in 200 ml of absolute methanol. When the sodium had dissolved completely, the solution was heated under reflux and 33.7 g (0.1 mol) of 1-bromo-3,3-dimethyl-1-pyridin-3-yl-butan-2-one hydrobromide were added. The reaction mixture was heated under reflux overnight. It was allowed to cool and was concentrated in vacuo. The residue was taken up in diethyl ether and the ether mixture was washed twice with 2 N sodium hydroxide solution, once with water and once with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The residue was recrystallized from n-hexane. 18.8 g (62% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-pyridin-3-yl-butan-2-one of melting point 50° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([N:12]([CH2:17][CH2:18][O:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:21])[CH:8]=2)[O:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:31][CH2:32][CH2:33][CH2:34]Br)[CH3:30]>CCCCCCC.CC(=O)OCC>[CH2:29]([O:31][CH2:32][CH2:33][CH2:34][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:22])([CH3:1])[CH2:11][CH:10]2[N:12]([CH2:17][CH2:18][O:19][CH3:20])[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:30]
Reactant: CCOCCCBr
Reactant: COCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOCCCOc1ccc2c(c1)C(N(CCOC)S(C)(=O)=O)CC(C)(C)O2

Procedure:
0.5 g (1.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-(2-methoxyethyl)methanesulfonamide (Example 16b) was reacted with potassium carbonate and 3-ethoxy-1-bromopropane analogously to Example 1g. After column chromatography on silica gel using n-heptane/EA (5:1), 0.35 g of oily product was obtained.
Reaction SMILES: C1O[C:4]2([C:7]([OH:15])([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=3)[C:6]([CH3:16])=[CH:5]2)[O:3]C1.OS(O)(=O)=O>C1COCC1.O.CCOCC>[OH:15][C:7]1([C:8]2[CH:9]=[CH:10][C:11]([I:14])=[CH:12][CH:13]=2)[C:4](=[O:3])[CH:5]=[C:6]1[CH3:16]
Reactant: CC1=CC2(OCCO2)C1(O)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CC1=CC(=O)C1(O)c1ccc(I)cc1
Reaction time: 4 h
Yield: 87 %

Procedure:
To a solution of 4-hydroxy-4-p-iodophenyl-3-methyl-2-cyclobuten-1-one ethylene acetal (80 mg, 0.23 mmol dissolved in THF:H2O (3:1, 8 ml) was added dropwise 1N H2SO4 (3 ml) at room temperature. The reaction mixture was stirred for 4 h. The mixture was then diluted with ether (10 ml), and the organic fraction was separated from the aqueous phase by repeated extractions with ether (2×5 ml). The ether layer was dried over Na2SO4 and concentrated in vacuo to give a pale yellow oil (62 mg, 87%). 1H NMR (CDCl3) δ7.80 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 6.40 (s, 1H), 3.10 (s, 1H), 2.20 (s,3H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.Cl[C:27]1[C:36]2[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=2)[N:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C>[CH3:38][O:37][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][C:33]=1[O:39][CH3:40])[N:30]=[CH:29][CH:28]=[C:27]2[O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)c2ccc(O)cc2)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C#N)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Under argon, 4-(4-hydroxybenzoyl)benzonitrile (230 mg) obtained in Example 123 and 4-dimethylaminopyridine (138 mg) were added to xylene (5 ml), and the admixture was stirred at room temperature for 1 hour. 4-Chloro-6,7-dimethoxyquinoline (230 mg) was added, and the admixture was refluxed with heat for 20 hours. The reaction mixture was partitioned between saturated aqueous sodium hydrogen carbonate and chloroform, and the chloroform layer was then dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate and then by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 199 mg of the title compound (yield: 47%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1>>[Cl:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:7][CH:6]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOC(=O)c3ccc(Cl)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with 4-chlorobenzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-[2-(4-chloro-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS : 616 (M+H)+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[C:17]12([CH2:27][C:28](OC)=[O:29])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>O1CCCC1.CCCCCC.C(O)(=O)C>[O:29]=[C:28]([CH2:27][C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COC(=O)CC12CC3CC(CC(C3)C1)C2
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)CC12CC3CC(CC(C3)C1)C2)OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 49.6 g (0.400 moles) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc. dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 41.7 g (0.200 mole) methyl (1-adamantyl)-acetate was added dropwise at a rate that kept the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78°, the reaction mixture was allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 50 ml water, the aqueous phase extracted with 100 ml portions of methylene chloride (4x), the combined orgaic extracts were backwashed with water (4 × 100 ml), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p 209°-212° (<0.02 mm) to give dimethyl 2-oxo-3-(1-adamantyl)propylphosphonate (2a ).