Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH3:14])(C)[CH:4]([NH:8][C:9]([O:11][CH3:12])=[O:10])[C:5]([OH:7])=[O:6].[NH2:15][CH:16](CCC#N)C(O)=O>>[C:16]([CH2:14][CH2:3][CH:4]([NH:8][C:9]([O:11][CH3:12])=[O:10])[C:5]([OH:7])=[O:6])#[N:15]
Reactant: N#CCCC(N)C(=O)O
Reactant: COC(=O)NC(C(=O)O)C(C)(C)OC
Product: COC(=O)NC(CCC#N)C(=O)O

Procedure:
This compound was prepared using the procedure used to prepare 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid using 2-Amino-4-cyano-butyric acid. LCMS-ESI+: calc'd for C7H10N2O4: 186.06 (M+); Found: 187.09 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[C:5]2[CH2:18][CH2:19][C:20](O)=[O:21].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)=[C:5]2[CH2:18][CH2:19][C:20]([N:34]1[CH2:33][CH2:32][N:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])[CH2:36][CH2:35]1)=[O:21]
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Product: COc1ccccc1N1CCN(C(=O)CCc2c(-c3ccc(Cl)cc3)[nH]c3ccc(Cl)cc23)CC1

Procedure:
Prepared from 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 30) and 1-(2-methoxyphenyl)piperazine according to the method of Description 32. 1H NMR (250 MHz, CDCl3) δ 8.04 (1H, br s), 7.61 (1H, d, J 1.8 Hz), 7.48 (4H, m), 7.29 (1H, d, J 8.5 Hz), 7.17 (1H, dd, J 8.5, 1.8 Hz), 7.02 (1H, m), 7.00-6.82 (3H, m), 3.86 (3H, s), 3.78 (2H, t, J 4.9 Hz), 3.46 (2H, t, J 4.9 Hz), 3.24 (2H, t, J 7.9 Hz), 2.94 (2H, t, J 4.9 Hz), 2.79 (2H, t, J 4.9 Hz), and 2.68 (2H, t, J 7.9 Hz). m/z (ES+) 508, 510 (M+1).
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C.O>[C:26]1([N:32]2[C:10]3[CH2:9][CH2:8][NH:7][CH2:6][C:5]=3[CH:4]=[N:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: c1ccc(-n2ncc3c2CCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
tert-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (2.1 g, 8.3 mmol) was dissolved in MeOH (100 mL), and water (50 mL) was added followed by the addition of sodium carbonate (0.53 g, 5.0 mmol) and phenyl hydrazine hydrochloride (1.43 g, 9.9 mmol). Finally, acetic acid (1 mL) was added and the resulting reaction mixture was stirred at RT for 1 h. The reaction mixture was made basic by adding saturated aqueous sodium bicarbonate (ca. 20 mL) and the MeOH was removed under reduced pressure. The resulting reaction mixture was extracted with CH2Cl2 (3×40 mL) and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product. Purification by flash chromatography on silica gel using 20% EtOAc in hexanes as the eluent afforded 1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (1.63 g, 66%) as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([NH2:21])=[CH:19][C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:20]([NH:21][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][CH:45]=[C:37]([Cl:36])[CH:38]=3)=[CH:19][C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][N:16]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCN(c2ncc(S(C)(=O)=O)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
To a solution of 0.300 g (0.780 mmol) of (3′-amino-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-carbamic acid tert-butyl ester in methylene chloride (3 mL) under argon, cooled to 0° C., is added 0.136 mL (0.780 mmol) of N,N-diisopropylethylamine followed by 0.110 mL (0.858 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at 0° C. for 15 min then warmed to room temperature and stirred for 2 days during which time the solvent evaporates. The residue is dissolved in methylene chloride (3 mL) and an additional 0.136 mL (0.780 mmol) of N,N-diisopropylethylamine and 0.110 mL (0.858 mmol) of 3-chlorobenzoyl chloride is added. The reaction is stirred overnight at room temperature. The mixture is diluted with ethyl acetate and washed with water followed by aqueous ammonium chloride and then aqueous sodium carbonate. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by preparative thin layer chromatography to give 0.186 g (46.0%) of [3′-(3-chloro-benzoylamino)-5′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl]-carbamic acid tert-butyl ester as a beige foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:25][OH:26]>C1COCC1>[OH:26][NH:25][CH:18]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:17][S:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: NO
Reactant: O=S(=O)(/C=C/c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Solvent: C1CCOC1
Product: O=S(=O)(CC(NO)c1ccccc1)N1CCN(c2ccc(F)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of 1-(4-fluorophenyl)-4-(trans-β-styrenesulfonyl)piperazine (620 mg, 1.79 mmol) in THF (20 ml) was added hydroxylamine (3 ml, 50% aqueous solution). The mixture was stirred for 18 hours. The solvent was evaporated. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried on MgSO4 to give 1-[2-(hydroxyamino)-2-phenylethanesulfonyl]-4-(4-fluorophenyl)piperazine (730 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[CH:9]1.[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:22])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1=C(C2C=CN(C(=O)OCC(Cl)(Cl)Cl)C=C2)SCC(=O)N1
Agent: [S]
Product: CC1=C(c2ccncc2)SCC(=O)N1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (2.14 g) was mixed well with sulfur sublimed (10.7 g) in a mortar and the mixture was stirred at 140° C. for 1.5 hours. Then, the mixture was cooled to ambient temperature. The obtained solid was ground and was extracted with methanol using Soxhlet extractor. Methanol was removed under reduced pressure. The residue was dissolved in 50 ml of 2N hydrochloric acid. The insoluble matter was removed by filtration and the filtrate was adjusted to pH 7.2 by 2N aqueous sodium hydroxide. The resulting precipitates were collected by filtration and the filtrate was extracted with chloroform (20 ml×5 times) and was evaporated to dryness. After combined with the above solid, the residue was recrystallized from isopropanol to give the titled compound (0.88 g, yield 76.5%) as pale yellow plates.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)[NH2:30]>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:30][C:29]1[CH:31]=[CH:32][CH:33]=[C:27]([F:26])[CH:28]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCc1ccccc1
Reactant: Nc1cccc(F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(COCc1ccccc1)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
To a solution of benzyloxyacetic acid (4.65 g, 28 mmol, 4.0 mL) in DCM (52 mL) was added oxalyl chloride (7.7 g, 61 mmol, 5.3 mL) and a drop of DMF. The reaction mixture was stirred at room temperature for 4 h. Excess of oxalyl chloride was removed in vacuo and the crude acyl chloride was diluted into DCM (100 mL) and triethylamine (5.3 mL, 41.6 mmol, 4.2 g) was added followed by 3-fluoroaniline (3.5 g, 32 mmol, 3.0 mL). The reaction mixture was stirred at RT overnight. The reaction was then quenched with 1 M aqueous HCl (100 mL), dried and concentrated in vacuo to afford 7.10 g (95%) of 2-benzyloxy-N-(3-fluoro-phenyl)-acetamide (39) as a yellow oil which was used in the next step without purification. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 69.2, 73.5, 106.9, 107.2, 111.0 (d, JCF=24 Hz), 114.9 (d, JCF=3 Hz), 127.8, 128.2, 128.5, 129.7 (d, JCF=9 Hz), 136.2, and 167.6.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:17]3[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[ClH:1].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)=[O:11])=[CH:5][CH:4]=2)=[CH:24][CH:23]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(Nc1ccc(Br)cc1)C1CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: O=C(Nc1ccc(-c2ccc(CO)cc2)cc1)C1CN2CCC1CC2

Procedure:
90 mg (0.26 mmol) of N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide hydrochloride, 50 mg (0.31 mmol) of 4-(hydroxymethyl)phenylboronic acid, 190 mg (0.57 mmol) of cesium carbonate and 20 mg (0.03 mmol) of bis(diphenylphosphino)ferrocenepalladium(II) chloride are reacted in 1 ml of 1,2-dimethoxyethane by the general method. 5.9 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: C([N:8]1[CH:13]([CH2:14][F:15])[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:23][F:24])C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[F:24][CH2:23][CH:9]1[CH2:10][NH:11][CH2:12][CH:13]([CH2:14][F:15])[NH:8]1
Reactant: [H][H]
Reactant: FCC1CN(Cc2ccccc2)CC(CF)N1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: FCC1CNCC(CF)N1
Yield: 137.6 %

Procedure:
A mixture of a suspension of 5.03 g (0.015 mole) of 1,4-dibenzyl-2,6-bis(fluoromethyl)piperazine isomer B [prepared as described in step (b) above] in 130 ml of methanol and 6 ml of concentrated aqueous hydrochloric acid was stirred vigorously under a stream of hydrogen at room temperature for 1 hour in the presence of 0.6 g of 20% w/w palladium-on-carbon. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was mixed with 50 ml of water, and the resulting insoluble materials were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was washed with ethanol, to afford 3.10 g of 2,6-bis(fluoromethyl)piperazine (isomer B) dihydrochloride as a colorless powder, melting at 207°-225° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Nc1ccc(C(C)(C)C)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 95.7 %

Procedure:
A reactor was charged with acetic acid (8.7 L), followed by N-(4-tert-butylphenyl) acetamide (Preparation 110, 6.0 kg, 31.4 mol), The mixture was stirred for ten minutes, followed by the addition of acetic anhydride (6.47 kg, 63.4 mol) slowly at room temperature. The reaction was stirred for fifteen minutes. A solution of fuming nitric acid (3.56 kg, 56.5 mol) in acetic acid (2.1 L) was added slowly at 20-25° C., and stirred at that temperature for another 2 hours. The reaction mixture was added to ice water (42 L) at 10-15° C. and the mixture stirred for one hour. The resulting solids were collected by filtration, washed with water (17 L) and dried at 65-70° C. to provide 7.1 kg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[CH:7]2.O=P(Cl)(Cl)[Cl:24].[Cl-].C([NH+](CC)CC)C>C(#N)C>[Cl:24][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1ccc2c(OCCN3CCCCC3)ccc(Cl)c2[nH]1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: Clc1ccc2c(OCCN3CCCCC3)ccc(Cl)c2n1
Temperature: 120 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
8-chloro-5-(2-(piperidin-1-yl)ethoxy)quinolin-2(1H)-one (275 mg, 0.9 mmol, 1 eq.) was placed in acetonitrile (2.3 mL) in the presence of POCl3 (418 μL, 4.5 mmol, 5 eq.) and triethylammonium chloride (1 g, 4.5 mmol, 5 eq.). The reaction mixture was stirred at 120° C. during 3 hours. The mixture was then concentrated under reduced pressure and, after adding water to the residue (5 mL), was stirred at room temperature during 30 minutes. Then the resulting precipitate was washed with water and filtered to give 2,8-dichloro-5-(2-(piperidin-1-yl)ethoxy)quinoline (228 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21](O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].S(Cl)(Cl)=O.[Br:29][CH2:30][CH2:31][CH2:32][OH:33]>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:21]([O:33][CH2:32][CH2:31][CH2:30][Br:29])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCCCBr
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCBr)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (107 g, 0.32 mol) in CH2Cl2 (520 mL) and DMF (100 mL) was cooled to 0° C. and thionyl chloride (28 mL, 0.39 mol) slowly added. The mixture was stirred at room temperature for 1 hour, then cooled to 5° C. Distilled 3-bromopropanol (35 mL, 3.9 mol) was slowly added, and the solution stirred for 1 hour at room temperature. The solution was then washed with water and the organic layer dried over sodium sulfate and evaporated under reduced pressure. The product was recrystallized from ethyl acetate to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-bromopropoxycarbonyl)-1,4-dihydropyridine (12, mp=146° C.).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:10]([F:13])([F:12])[CH:9]([C:14]3[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[N:3]=1.[H-].[Na+].[CH2:32](Br)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>CN(C=O)C>[CH2:32]([O:20][C:17]1[CH:16]=[N:15][C:14]([CH:9]2[C:10]([F:12])([F:13])[C:11]3[C:2]([F:1])=[N:3][C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:19][CH:18]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCOc1cc2c(c(F)n1)C(F)(F)C(c1ncc(O)cn1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1cnc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2(F)F)nc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
10 mmol of 1,8,8-trifluoro-7-(5-hydroxypyrimidin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo, and the residue is chromatographed on silica gel, giving 9 mmol of 7-[5-(octyloxy)pyrimidin-2-yl]-1,8,8-trifluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][N:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:28]2[N:29]=[CH:30][CH:31]=[N:27]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4nccn4)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Yield: 31.9 %

Procedure:
A mixture of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (2.0 g, 5.23 mmol), 1H-1,2,3-triazole (552 mg, 7.98 mmol) and K2CO3 (2.20 g, 15.95 mmol) in dry DMF (40 ml) was heated at 80° C. under N2 atmosphere for 2 h. After cooling to room temperature, the reaction mixture was poured onto ice-water (400 ml), and the resulting precipitate was filtered, washed with water, and dried to give a dirty white solid. This was subjected to flash chromatography, and on elution with pet. ether/EtOAc/Et3N, (6.7:3:0.3), gave firstly 3β-acetoxy-17-(2H-1,2,3-triazol-2-yl)-16-formylandrosta-5,16-diene (Compound 15) (684 mg, 28%), mp 145-148° C. 1H NMR (300 MHz, CDCl3): δ 1.09 (3H, s, 18-Me), 1.26 (3H, s, 19-Me), 2.04 (3H, s, 3β,-OAc), 4.61 (1H, m, 3α-H), 5.42 (1H, d, J=4.2 Hz, 6-H), 7.85 (2H, s, 4′ and 5′-H) and 10.55 (1H, s, 16-CHO). Analysis calculated for C24H31O3N3: C, 70.37; H, 7.63; N, 10.27. Found: C, 70.30; H, 7.95; N, 9.87. Further elution with pet. ether/EtOAc/Et3N, (6:4:0.3) gave 3β-acetoxy-17-(1H-1,2,3-triazol-1-yl) -16-formylandrosta-5,16-diene (Compound 16) (1.48 g, 62%), mp 215-217° C. 1H NMR (300 MHz, CDCl3): δ 1.08 (3H, s, 18-Me), 1.18 (3H, s, 19-Me), 2.04 (3H, s, 3β-OAc), 4.63 (1H, m, 3α-H), 5.43 (1H, d, J=4.2 Hz, 6-H), 7.85 (2H, s, 4′ and 5′-H) and 9.94 (1H, s, 16-CHO). Analysis calculated for C24H31O3N3: C, 70.37; H, 7.63; N, 10.27. Found: C, 70.37; H, 7.86; N, 10.10.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(OCC)(=O)C>[CH2:21]([O:28][C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:34])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
In 50 ml of THF was dissolved 4.99 q of N-benzyloxycarbonyl-L-proline (29) and after adding thereto 2.23 g of triethylamine and 2.39 g of ethyl chloroformate, the reaction was maintained for 20 minutes under ice-cooling. To the reaction mixture was added 2.79 g of aniline and the reaction was performed for one hour under ice-cooling. The solvent was distilled off, the residue thus formed was dissolved in ethyl acetate, and the solution was washed, in succession, with an aqueous solution of 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution, and then a saturated aqueous sodium chloride solution. The organic layer thus formed was dried by anhydrous sodium sulfate and then concentrated to dryness. The residue was recrystallized from chloroform-ethyl acetate-hexane to provide 5.20 g of (S)-1-benzyloxycarbonyl-N-phenyl-2-pyrrolidine-carboxamide (93) having a melting point of 143°-144° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)=[CH:10][CH:9]=1.CO.[OH-].[K+]>O1CCCC1.O>[C:36]([O:35][C:33]([NH:32][CH:4]([CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:40])=[O:2])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(CSCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(CSCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert-Butoxy carbonylamino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]-propionic acid methyl ester, 0.18 g (0.32 mmol) in 10 mL of tetrahydrofuran and 5 mL of methanol was added 1.62 mL of 1.0M aq. KOH. The solution was stirred for 1 h at room temperature. The solution was diluted with 10 mL of water and acidified to pH 1-2. The aqueous was extracted with 3×30 mL portions of diethyl ether. The organic layers were combined, washed with sat. aq. NaHCO3, sat. aq. NaCl, dried (MgSO4). The solution was concentrated to the desired product in 0.10 g (57%) as an off-white solid. MP 250° C. decomp, Rf 0.09 (100% Ethyl Acetate); 1H NMR (DMSO-d6) 8.57 (d, 2H, J=9.3), 8.52-8.46 b (m, 5H), 7.60-7.58 (m, 6H), 7.51 (d, 2H, J=9.3), 4.11 (m, 1H), 3.86 (s, 3H), 2.81 (dd, 1H, J=14.8, 5.0 Hz), 2.67 (dd, 1H, J=15.3, 10.3), 1.39 (s, 9H). LCMS m/z calcd for C31H31N3O4S: 541.2 found 542.6(M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N[CH2:19][CH:20]([C:22]1C=CC(OC)=C(OC2CCCC2)[CH:23]=1)O>>[CH:1]1([O:2][C:3]2[CH:4]=[C:5]([CH:11]3[O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]3)[CH:6]=[CH:7][C:8]=2[O:9][CH3:10])[CH2:23][CH2:22][CH2:20][CH2:19]1
Reactant: COc1ccc(C2CNC(=O)CO2)cc1OC
Reactant: COc1ccc(C(O)CN)cc1OC1CCCC1
Product: COc1ccc(C2CNC(=O)CO2)cc1OC1CCCC1
Yield: 42.7 %

Procedure:
According to the same procedure as in Example 1(2) to (3), using 2-amino-1-(3-cyclopentyloxy-4-methoxyphenyl)ethanol instead of 2-amino-1-(3,4-dimethoxyphenyl)ethanol, the above-described compound (yield 42.7%) was obtained as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Cl:28])C(=O)C1>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:28])[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccnc(Cl)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC#N
Product: ClCc1ccnc(Cl)c1

Procedure:
10 g of 2-chloro-4-methylpyridine are dissolved in 30 ml of CH3CN and a mixture of AIBN (3 g) and NCS (30 g) is added. The resulting mixture is refluxed for 4 hours. After removing the solvent, the crude product is further purified by distillation (boiling point: 70° C., 20 mtorr).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:11][C:10]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C(C=CC=1)CCl)C=C>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:12]=[CH:11][C:10]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:37][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(CCCc2ccc(NS(=O)(=O)c3ccccc3)cc2OCc2ccccc2)cc1
Agent: C=CCOc1cccc(CCl)c1
Product: O=C(O)c1ccc(CCCc2ccc(NS(=O)(=O)c3ccccc3)cc2OCc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 4-[3-(2-benzyloxy-4-benzenesulphonamidophenyl)propyl]benzoate by a similar method to that of Example 1, (A).