Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:29][O:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[C:32]=1[CH2:33][NH2:34]>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:34][CH2:33][C:32]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:31]=2[O:30][CH3:29])=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(OC)c1CNC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
4-Bromo-2-nitrobenzoic acid (30.0 g, 118.3 mmol) was placed in 300 mL dichloromethane and 16.5 mL triethylamine was added. Then the reaction solution heated up and a change in color from yellow to greenish brown was observed. The mixture was then cooled to 5° C. and isobutyl chloroformate (16 mL, 118.3 mmol) was added by drops without dilution. The reaction mixture was allowed to come to room temperature while stirring and stirring was continued for 1.5 hours. The mixture was cooled again to 5° C. and 2,6-dimethoxybenzylamine (19.8 g, 118.3 mmol) was added by portions. Again 300 mL dichloromethane was added for dilution and stirring was continued for 15 minutes at 5° C. and then for 12 hours at room temperature. The clear reaction mixture ultimately changed color from red to brown and the reaction was monitored by thin-layer chromatography. The batch was extracted with water, the separated organic phase was extracted with 5% citric acid (2×), washed with sodium bicarbonate solution until neutral (1×) and extracted with saturated sodium chloride solution. The organic phase was dried over sodium sulfate, the solvent was removed in vacuo. The residue was dissolved in diethyl ether/pentane solvent and the precipitate which gradually formed therefore was ultimately filtered out. Crystalline 4-bromo-N-(2,6-dimethoxybenzyl)-2-nitrobenzamide was isolated. Yield: 35.4 g (89.6 mmol, 76%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2[S:12][CH:13]=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.O>[S:12]1[CH:13]=[CH:14][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:11]1=2
Reactant: CCOC(=O)c1cccc2ccsc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of benzo[b]thiophene-7-carboxylic acid ethyl ester (1.0 g, 48 mmol) in methanol (10 mL) and water (10 mL) is added sodium hydroxide (5 g, excess). The solution is stirred at room temperature for 30 min; at which point all the ester has been consumed. The reaction mixture is adjusted to pH 1 by adding 6M HCl solution, and extracted with DCM. The combined organic layers are filtered through a silica plug to afford the title compound as a yellow solid (505.2 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[CH3:17][O:18][C:19](=[O:34])[C:20]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=1.Cl>ClC(Cl)C>[CH3:17][O:18][C:19](=[O:34])[C:20]1[CH:29]=[C:28]([S:30](=[O:31])(=[O:32])[NH:4][C:3]2[C:2]([F:1])=[CH:8][C:7]([F:9])=[CH:6][C:5]=2[F:10])[CH:27]=[C:22]([C:23]([O:25][CH3:26])=[O:24])[CH:21]=1
Reactant: Nc1c(F)cc(F)cc1F
Reactant: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C(=O)OC)cc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Temperature: 0 °C

Procedure:
2.94 g (20 mmol) of 2,4,6-trifluoroaniline is dissolved in 50 ml of dichloroethane with exclusion of moisture, 3.16 g (40 mmol) of pyridine is added and the solution is cooled to 0° C. With this temperature being maintained, a solution of 5.85 g (20 mmol) of 5-chlorosulfonylisophthalic acid dimethyl ester in 50 ml of dichloroethane is instilled. It is stirred for 30 more minutes at 0° C. and 5 more hours at room temperature. The suspension is shaken out three times with 2N hydrochloric acid and twice with water, the organic phase is dried on sodium sulfate, filtered, concentrated by evaporation and the residue is chromatographed on silica gel 60 (Merck) with ethyl acetate/hexane. The fractions, concentrated by evaporation, of corresponding polarity yield 6.34 g (15.72 mmol)=78.6% of the theoretical yield is obtained as a partially crystalline product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[F:16][C:17]([F:22])([F:21])[C:18](O)=O>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[C:18]([C:17]([F:22])([F:21])[F:16])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:5]=1
Reactant: COc1ccc(CCN(C)C)c(N)c1N
Reactant: O=C(O)C(F)(F)F
Product: COc1ccc(CCN(C)C)c2[nH]c(C(F)(F)F)nc12

Procedure:
600 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dimethylamine is heated under reflux for 3 hours with 10 ml of trifluoroacetic acid. After concentration, the residue is recrystallized from isopropanol, thus obtaining 908 mg of 7-methoxy-4-[2-(N,N-dimethylamino)ethyl]-2-trifluoromethylbenzimidazole, trifluoroacetate, mp 182°-185° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.[C:11]1([NH:17]N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>[Cl-].[Zn+2].[Cl-]>[OH:10][C:7]1[CH:6]=[CH:5][C:4]([C:2]2[NH:17][C:11]3[C:16]([CH:1]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=1
Reactant: NNc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: Oc1ccc(-c2cc3ccccc3[nH]2)cc1
Reaction time: 1 h
Yield: 42.2 %

Procedure:
4-Hydroxyacetophenone phenylhydrazine (47 g.) was fused with 250 g. zinc chloride (10 min. at 180° C.), poured into 3 1. of 0.3 N HCl, heated and stirred for one hour on the steam bath, cooled to 0° and filtered. The precipitant was extracted with boiling pet. ether and allowed to stand. 2-(4-Hydroxyphenyl)indole (17 g., m.p. 224°-229°) was isolated. A well-stirred mixture of 2-(4-hydroxyphenyl)indole (0.1 mole), iodoethane (0.1 mole) and sodium bicarbonate (0.12 mole) in 200 ml. of acetone was refluxed overnight. After 400 ml. of water was added, the product 2-(4-hydroxyphenyl)-1-ethylindole (A) was filtered out. Then A was reacted with 4,4'-bis(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce Compound VII.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(I)cc1
Reactant: C=Cc1ccccc1
Product: N#Cc1ccc(/C=C/c2ccccc2)cc1

Procedure:
4-Iodobenzonitrile (57 mg, 0.25 mmol) and styrene (43 μL, 0.375 mmol) were coupled using the procedure described above to give 63% conversion to (E)-4-cyanostilbene by GC analysis.
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[C:11]1([C:21](Cl)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>O1CCCC1>[CH3:2][C:3]1([CH3:10])[NH:7][C:6](=[O:8])[N:5]([C:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:22])[C:4]1=[O:9]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC1(C)NC(=O)NC1=O
Agent: [K]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione potassium salt (1.47 g) was suspended in tetrahydrofuran (5 mL), 1-naphthoyl chloride (1.46 g) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was filtered with a membrane filter (0.25 μm). The resulting organic layer was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to obtain 674 mg of white crystals.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:28])=S.[Na+].[Na+].O>C(O)(=O)C>[C:1]1([S:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:12][CH:13]=2)=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCOc1ccc(Sc2ccccc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1ccc(S(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 86 %

Procedure:
In 85 g of acetic acid was dissolved 12 g of 4-(2-methoxyethoxy)phenyl phenyl sulfide obtained in Synthesis Example 1-29. While the solution was maintained at an internal temperature of 30° C., 4.5 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 18 hours, after which under ice cooling, a mixture of 1.2 g sodium thiosulfate pentahydrate and 15 g water was added dropwise to quench the reaction. The solution was combined with 80 g of methylene chloride and 40 g of water for extraction. The organic layer was separated, washed with water, and concentrated in vacuum. On subsequent crystallization from ethyl acetate/hexane, 11 g of the target compound, 4-(2-methoxyethoxy)phenyl phenyl sulfoxide was obtained as white crystals. Yield 86%.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[NH+]1C=CC=CC=1.[F:17][C:18]([F:23])([F:22])[C:19]([CH3:21])=O.O>C1(C)C=CC=CC=1>[CH3:21][C:19]1([C:18]([F:23])([F:22])[F:17])[NH:1][CH:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]1
Reactant: NC(CO)c1ccccc1
Reactant: CC(=O)C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluolsulphonate were added to 55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l). The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C. and the solid formed was filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27]O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:23]5[S:22][CH:26]=[CH:25][CH:24]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1cccs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4cccs4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), 2-thienylmethanol (121 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg). The mixture was stirred under sonication at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (45 mg) as an off-white solid.
Reaction SMILES: [NH2:1]N.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:15])[NH:13][N:14]=2)=[CH:5][CH:4]=1.O.NN>C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:11]1[C:12](=[O:15])[NH:13][N:14]=[C:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH:10]=1
Reactant: NN
Reactant: O=c1ccc(-c2ccncc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: Oc1ccc(-c2ccncc2)nn1
Agent: [K+]
Solvent: O
Product: Nc1cc(-c2ccncc2)n[nH]c1=O
Yield: 69 %

Procedure:
The following procedure describes the preparation of the entitled compound by reacting hydrazine with 6-(4-pyridinyl)-3(2H)-pyridazinone, the tautomeric form of 6-(4-pyridinyl)-3-pyridazinol. A mixture containing 10 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 70 ml. of hydrazine hydrate was heated on a steam bath for 3 days and the excess hydrazine distilled off in vacuo. The remaining residue was heated with about 300 ml. of methanol and the solid was collected by filtration. The solid was combined with the corresponding solid obtained from another run starting with 15.7 g. of 6-(4-pyridinyl)-3(2H)-pyridazinone and 21 ml. of hydrazine hydrate and the combined solids were dissolved in aqueous potassium carbonate solution and reprecipitated by addition of acetic acid. The precipitate was dried for 9 hours at 40° C. over P2O5 and then overnight at 80° C. After its NMR spectrum had shown the solid still to contain acetic acid, it was next dried in a vacuum oven at 80° C. for 2 days to yield 18.2 g. (69% yield) of 4-amino-6-(4-pyridinyl)-3(2H)-pyridazinone, m.p.>300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([N:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[CH:39][N:40]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 27.8 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.936 g, 2.68 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 10.8 mmol) were added to toluene (5 ml) and heated to 100° C. 1 hour. Diethyl ether (10 ml) was added causing a solid to precipitate. This solid was collected by filtration, washed with diethyl ether, and dried in vacuo yielding 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a yellow solid (0.42 g, 28%). MS (APCI); M++1: Calc'd 564.29. Found 564.3.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:17])([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[O:5][C:4](=[O:18])[C:3]=1[O:19]CC1C=CC=CC=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[OH:19][C:3]1[C:4](=[O:18])[O:5][C:6]([CH3:17])([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=2)[C:2]=1[OH:1]
Reactant: CC(C)Cc1ccc(C2(C)OC(=O)C(OCc3ccccc3)=C2O)cc1
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: CC(C)Cc1ccc(C2(C)OC(=O)C(O)=C2O)cc1
Yield: 82.9 %

Procedure:
Hydrogenolysis of 800 mg (2.3 mmol) of 4-hydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-3-phenylmethoxy-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provided 500 mg (84% yield) of 3,4-dihydroxy-5-methyl-5-[4-(2-methylpropyl)phenyl]-2(5H)-furanone as a light yellow crystalline material: mp 135-150° C. dec. 1H NMR (acetone-d6) δ 7.40-7.17 (m, 4H), 2.46 (d, 2H, J=7.1 Hz), 1.87-1.82 (m, 1H), 1.82 (s, 3H), 0.87 (d, 6H, J=6.6 Hz). 13C NMR (acetone-d6) δ 169.5, 157.2, 142.4, 138.0, 129.8, 125.9, 117.9, 81.3, 45.3, 30.8, 24.5, 22.5. Anal Calcd for C15H18O4 +0.25 H2O: C, 67.53; H, 6.99. Found: C, 67.78; H, 7.09.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:3])[NH2:2].[ClH:21].O>C(OCC)(=O)C>[ClH:21].[ClH:21].[N:8]1([CH2:7][CH2:6][O:5][CH2:4][C:1]([NH2:2])=[O:3])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCC(N)=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: NC(=O)COCCN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
1.4 g (0.005 mol) of tert-butyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.1. and 14 ml of a 3M solution of hydrochloric acid in ethyl acetate are introduced into a 50 ml three-necked round-bottomed flask fitted with a water-cooled condenser and a mechanical stirrer. The mixture is stirred at room temperature for 2 hours. The precipitate is filtered off and is washed with ethyl acetate. 1.3 g (100%) of 2-(1-piperazinyl)ethoxyacetamide dihydrochloride are obtained.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][C:14]=1[Cl:25])OC1C=CC=CC=1)#[N:2].[NH:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:27].ClCCl>C(O)(C)C>[Cl:25][C:14]1[CH:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:1]([NH2:2])[N:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:27]=1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1Cl)Oc1ccccc1
Reactant: NNc1ccccn1
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1nc(Nc2ccc(N3CCOCC3)cc2Cl)nn1-c1ccccn1
Temperature: 115 °C
Yield: 76.8 %

Procedure:
A mixture of N-cyano-N′-(2-chloro-4-morpholino-phenyl)-O-phenylisourea (0.10 g, 0.28 mmol) and 2-hydrazinopyridine (0.046 g, 0.42 mmol) in iso-propanol (3 mL) was heated at 115° C. for 20 h. The precipitate was filtered, washed with iso-propanol and purified by flash chromatography (SiO2) eluted with 2:98 methanol: dichloromethane to provide the title compound (0.080 g, 79% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[F:32][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCC(N2CCCC2)CC1
Yield: 46 %

Procedure:
The title compound was synthesized in analogy to example 51, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a yellow solid (46%).
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br[CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:42][CH2:43][C:44]([OH:47])([CH3:46])[CH3:45])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:38])([CH3:39])[CH3:40])([CH3:36])[CH3:35])[CH2:18]1)([C:29]([CH3:31])([CH3:32])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(C)(O)CCBr
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)CCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 93 %

Procedure:
17-Acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (67.7 mg, 0.112 mmol), 1-bromo-3-hydroxy-3-methylbutane (93.5 mg, 0.560 mmol), 1M potassium hydroxide methanol solution (1 ml) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 31(1) (at room temperature for 30 min.), worked up and purified by preparative thin layer chromatography (2 sheets (each 0.5 mm thickness), hexane:ethyl acetate=3:1, developed once) to give the titled compound (67.4 mg, 93%) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C@H:5]([C:13]([OH:15])=[O:14])[NH:4]1.[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.Cl>O.O1CCCC1>[C:16]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:19]([S:22]([N:4]2[C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:3]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Sodium hydroxide (13.6 g) is dissolved in water (300 ml), and therein is suspended (3R)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (30.0 g) and thereto is added tetrahydrofuran (120 ml). To the resulting solution is added 4-biphenylylsulfonyl chloride (42.9 g), and the mixture is stirred at room temperature for one hour. The reaction mixture is acidified with 10% hydrochloric acid under ice cooling, and is diluted with water, and then extracted twice with ethyl acetate. The extract is washed with water and an aqueous saturated saline solution, dried over sodium sulfate and then treated with active carbon. Undissolved materials are filtered off from the extract, and the solvent is distilled off under reduced pressure. The residue is recrystallized from ethyl acetate-hexane to give (3R)-N-(4-biphenylylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (36.5 g) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:16]1[C:21]([CH:22]=O)=[CH:20][C:19]2[O:24][CH2:25][O:26][C:18]=2[CH:17]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[N:1]1([C:6]2[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][CH2:22][C:21]3[CH:16]=[CH:17][C:18]4[O:26][CH2:25][O:24][C:19]=4[CH:20]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NCCOc1ccc(-n2ccnc2)cc1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: c1cn(-c2ccc(OCCNCc3ccc4c(c3)OCO4)cc2)cn1
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To 2-[4-(imidazol-1-yl)phenoxy]ethylamine (4.0 g, 20 mmol) dissolved in MeOH (150 mL) was added piperonal (3.0 g, 20 mmol) and acetic acid (1.5 mL). After stirring for 1 h, NaBH3CN (2.6 g, 40 mmol) was added. After stirring for 18 hour, the solvent was removed in vacuo and the residue was chromatographed on silical gel with 2% methanol in methylene chloride to give 3.5 g of N-[2-(4-(imidazol-1-yl)phenoxy)ethyl]-N-[(1,3-benzodioxol-5-yl)methyl]amine, 1H NMR (DMSO-d6) 8.12 (s, 1), 7.62 (s, 1), 7.54 (d, 2), 7.08-7.02 (m, 3), 6.90 (s, 1), 6.82-6.75 (m, 2), 5.94 (s, 2), 4.03 (t, 2), 3.62 (s, 2), 3.32 (s, 1), 2.80 (t, 2) ppm.