Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C@H:15]2[CH2:17][C@@H:16]2[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[CH2:20]([O:19][CH2:18][C@H:16]1[CH2:17][C@@H:15]1[C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[N:11][CH:12]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(COC[C@H]2C[C@@H]2c2cncc(OCc3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cncc([C@H]2C[C@@H]2COCc2ccccc2)c1
Reaction time: 4 h
Yield: 84.4 %

Procedure:
To a solution of 3-(benzyloxy)-5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]pyridine (210 mg, 608 μmol) in EtOAc (10 mL) and methanol (5.0 mL) was added 10% palladium on carbon (42 mg). The atmosphere was exchanged with H2 (3 times), and the mixture was stirred under H2 for 4 h. The resulting mixture was filtered through a cotton plug, and the filtrate was concentrated and azeotroped with toluene (3×5 mL) to give 5-[(1S,2S)-2-(benzyloxymethyl)cyclopropyl]-3-pyridinol as a light-yellow oil (131 mg, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][CH2:21][OH:22])([CH:16]([CH3:18])[CH3:17])[O:12][C:11]2=[O:23])[CH3:9])=[CH:4][CH:3]=1.CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][C:21]([OH:26])=[O:22])([CH:16]([CH3:17])[CH3:18])[O:12][C:11]2=[O:23])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)C1(CCCO)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)C1(CCC(=O)O)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one. (41 mg, 0.1 mmol) in acetone (10 mL) was added Jones reagent (2.5 M, 1 mL) at 0° C. The mixture was stirred at room temperature for 1 h, concentrated, and extracted with EtOAc. The organic layer was concentrated to give the crude product 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan -6-yl)propanoic acid (51 mg, 95% yield), which was used for the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([C:5]([C:7]2([CH3:10])[CH2:9][CH2:8]2)=[NH:6])[CH2:4]C1.[Cl:11]([O-:15])(=[O:14])(=[O:13])=[O:12].[NH4+].[CH3:17]S(C)=O>>[Cl:11]([O-:15])(=[O:14])(=[O:13])=[O:12].[NH3+:6][CH:5]1[C:7]2[CH2:9][CH2:8][CH2:17][C:10]=2[CH2:4][CH2:2]1
Reactant: CS(C)=O
Reactant: CC1(C(=N)C2CC2)CC1
Agent: Cl
Agent: [NH4+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: [NH3+]C1CCC2=C1CCC2
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a solution of 1-cyclopropyl-1-(1-methylcyclopropyl)methanimine hydrochloride (0.060 g, 0.38 mmol) in 0.60 ml of dimethyl sulfoxide was added 0.088 g (0.75 mmol) of ammonium perchlorate. The mixture was heated with stirring at 100° C. for 20 hours. The solvent was distilled out in vacuo and ether was added to the residue. Precipitated crystals was obtained and recrystallized from ethanol to afford 0.36 g (Yield: 43%) of the desired compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH2:21]1[CH:23]([CH:24](O)C#N)[CH2:22]1>CC(O)=O.C1COCC1.[OH-].[Na+]>[CH:23]1([CH2:24][N:4]2[CH2:5][CH2:6][CH:2]([OH:1])[CH2:3]2)[CH2:21][CH2:22]1
Reactant: OC1CCNC1
Reactant: N#CC(O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC1CCN(CC2CC2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
3-Hydroxy-pyrrolidine (5.65 g, 65 mmol, 1.0 equiv) was dissolved in 100 mL of 1% AcOH in THF and cooled to 0° C. Na(OAc)3BH (24 g, 114 mmol, 1.75 equiv) and cyclopropylcarboxaldehyde (5.0 g, 71 mmol, 1.1 equiv) were added and the resulting mixture was stirred at 0° C. for 1 h and room temperature overnight (16 h). The reaction was diluted with 200 mL of 2 N NaOH, and the product was extracted 3×200 mL of CH2Cl2. The organic extracts were combined, dried over Na2SO4, decanted and concentrated to yield the desired product as a free-flowing oil (7.26 g, 79%) which was used without further purification; MS, m/z 142=M+1.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:15][S:16](O)(=[O:18])=[O:17])=[CH:5][C:4]1([CH3:21])[CH3:20])C.CN1C2C(=CC=C(OC)C=2)C(CS(O)(=O)=O)CC1(C)C.P(Cl)(Cl)(Cl)(Cl)[Cl:43]>>[CH3:1][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]([CH2:15][S:16]([Cl:43])(=[O:18])=[O:17])[CH2:5][C:4]1([CH3:21])[CH3:20]
Reactant: CCN1c2cc(OC)ccc2C(CS(=O)(=O)O)=CC1(C)C
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)O
Product: COc1ccc2c(c1)N(C)C(C)(C)CC2CS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
(1-Methyl-7-methoxy-2,2-dimethyl-1,2,3,4-tetrahydroquinol-4-yl)-methane-sulfonic acid chloride (19) is prepared similarly to compound (16) using compound (3) and phosphorus pentachloride except that it is stirred for 18 hours at room temperature.
Reaction SMILES: [N:1]1([CH:7]=[CH:8][CH:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH3:10])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H][H]>[Pd].C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH3:10])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: [H][H]
Reactant: CC(C=CN1CCCC1=O)N1CCCC1=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(CCN1CCCC1=O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60 g of 1,3-bis-(1-pyrrolidonyl)butene, 1000 ml of glacial acetic acid and 10 g of 10% palladium on carbon were mixed under inert gas. Subsequently, hydrogen was passed in while stirring at room temperature. The hydrogen uptake was complete after about 30 min. Reaction was allowed to continue at room temperature for a further 90 min. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The oily crude product was subsequently distilled under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[OH:20].N1C=CC=CC=1.O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[O:20][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: OB(O)c1cccnc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])cc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 6.4 %

Procedure:
A solution of pyridine-3-boronic acid (0.68 g, 5.5 mmol) and 2-methyl-5-nitro phenol (0.85 g, 5.5 mmol) in DCM (10 mL) was treated with pyridine (1.00 mL, 12.4 mmol), copper acetate (1.5 g, 8.3 mmol) and powdered 4A molecular sieves (330 mg). The reaction mixture was stirred for 7 days at RT open to air. The mixture was poured into water (50 mL) and extracted with DCM (2×50 mL). The combined organic phases were washed with saturated aq NaHCO3 (25 mL), water (25 mL), satd NH4Cl (2×25 mL) and brine (25 mL), dried (Na2SO4), concentrated in vacuo and purified via chromatography on silica gel to provide 3-(2-methyl-5-nitrophenoxy)pyridine (81 mg, 6% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (dd, J=4.6, 1.0 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.99 (dd, J=8.0, 2.0 Hz, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.39-7.30 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z: 231.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:3].[NH2:12][C:13]1[N:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[N:14]=1>C(O)C.Cl>[ClH:19].[NH2:12][C:13]1[N:18]=[C:17]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:2](=[O:3])[CH3:1])=[CH:6][CH:7]=2)[CH:16]=[C:15]([CH3:20])[N:14]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(Nc2cc(C)nc(N)n2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a mixture of 4-aminoacetanilide 14 (3.55 g, 23.64 mmol) and 2-amino-4-chloro-6-methylpyrimidine 15 (3.73 g, 26 mmol) in ethanol (50 mL) was added. C.HCl (2 drops). The reaction mixture was stirred under reflux conditions for 2 h, cooled to 20° C. and the product was filtered washed with more ethanol and dried to give essentially pure 16 (6.38 g, 92%); mp (EtOH) 203-207° C.; 1H NMR [(CD3)2SO] δ 12.60 (br, 1 H, N+H), 10.50 (br 1 H, NH), 10.02 (s, 1 H, NH), 7.60-7.58 (br m, 6 H, NH2 & ArH), 6.13 (s, 1 H, H-5″), 2.26 (s, 3 H, CH3), 2.04 (s, 3 H, CH3); HRMS (FAB+), calc. for C13H16N5O (M+1) m/z 258.1355, found 258.1346.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)(=[O:3])[CH3:2].C(O[CH2:29][N:30]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:31][Si](C)(C)C)CCC.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][CH:5]1[CH2:6][C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:8]2[CH:9]([CH2:29][N:30]([CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:31]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OC1CC(c2ccccc2)(c2ccccc2)C=CC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC1CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
15 drops of trifluoroacetic acid are added to a solution of 86 g of 6-acetoxy-4,4-diphenyl-2-cyclohexenone and 96 cm3 of N-butoxymethyl-N(trimethylsilylmethyl)benzylamine in 1000 cm3 of dichloromethane. The reaction mixture is stirred at room temperature for 15 hours, 2 g of sodium carbonate are then added and the mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 7 cm, height 70 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (20/80 by volume) and collecting fractions of 200 cm3. Fractions 6 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 70 g of (3aRS,5RS,7aRS)-5-acetoxy-2-benzyl-7,7-diphenylperhydroisoindol-4-one are obtained in the form of a honey (melting point below 40° C.).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][NH:25]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[Cl:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][N:25]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Clc1cccc2c1CCCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCCc2c(Cl)cccc21
Yield: 36.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 184 mg of 5-chloro-1,2,3,4-tetrahydroquinoline (can be prepared according to WO 20040116388), and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 141 mg of 2-[2-(5-chloro-3,4-dihydroquinolin-1(2H)-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[N:7]([C:16](=[O:26])[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([C:16]([N:7]2[C:8]3[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[C:5]([CH2:4][C:3]([OH:28])=[O:2])=[C:6]2[CH3:27])=[O:26])=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: COC(=O)Cc1c(C)n(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc([N+](=O)[O-])cc1

Procedure:
A solution of 4.9 g (12.8 mmol) of methyl-1-(p-nitrobenzoyl)-5-methoxy-2-methyl-3-indolylacetate in 40 ml of acetic acid containing 400 mg of p-toluene-sulfonic acid is refluxed for 20 hours and then concentrated in vacuo. p The gummy residue is extracted with ethyl acetate.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].[CH3:7][C:8]([Si:11](Cl)([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1.O>CN(C)C=O>[Si:11]([O:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])([C:8]([CH3:10])([CH3:9])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CO[Si](C)(C)C(C)(C)C
Yield: 97876664 %

Procedure:
Methyl glycolate (0.776 ml, 0.905 g, 10.0 nmol) was added to a suspension of TBDMS-Cl (1.81 g, 12.0 mmol) and imidazole (1.7 g, 25.0 mmol) in dry dimethylformamide (DMF) (2.0 ml) at 0° C., under stirring. After 90 min stirring at RT, water (25 ml) was added, and the resulting mixture was extracted with ethyl ether (3×15 ml). The organic phases were combined, washed with water (3×15 ml), dried (Na2SO4) and evaporated to give methyl (t-butyldimethylsilyloxy)acetate (2.0 g, 100%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:15]=1[CH2:16][O:17][CH3:18])=[C:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]=[CH:10][CH:9]=3)#[N:2].Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:18][O:17][CH2:16][C:15]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:7][C:6]=2[CH:5]=[N:4][C:3]=1[C:1](=[N:27][OH:28])[NH2:2]
Reactant: COCc1c(C#N)ncc2[nH]c3cccc(Oc4ccccc4)c3c12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COCc1c(C(N)=NO)ncc2[nH]c3cccc(Oc4ccccc4)c3c12

Procedure:
A mixture of 329 mg (0.001 mol) of 3-cyano-4-methoxymethyl-5-phenoxy-beta-carboline, 100 mg of hydroxylamine hydrochloride, 20 ml of ethanol (99%) and 0.52 ml of a 20% aqueous potassium carbonate solution is refluxed for 22 hours. The reaction mixture is filtered and the filtrate concentrated. The residue is mixed with 10 ml of water, the crystalline solid is filtered off and washed with water.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:15][C:16]1[C:23]([Br:24])=[CH:22][C:19]([CH:20]=[O:21])=[C:18]([CH3:25])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:26](O)[CH2:27][OH:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:8]([O:15][C:16]1[C:23]([Br:24])=[CH:22][C:19]([CH:20]2[O:28][CH2:27][CH2:26][O:21]2)=[C:18]([CH3:25])[CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(OCc2ccccc2)c(Br)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2ccccc2)c(Br)cc1C1OCCO1
Yield: 71 %

Procedure:
To a suspension of 4-(benzyloxy)-5-bromo-2-methylbenzoic acid (16.6 g, 51.7 mmol) in chloroform (80 mL) were added oxalyl chloride (5 mL, 56.9 mmol) and N,N-dimethylformamide (6 drops), and the mixture was stirred for an hour at room temperature. And then the reaction solution was concentrated to obtain 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride. Then to a chloroform suspension (60 mL) of N,O-dimethylhydroxylamine hydrochloride (5.55 g, 56.9 mmol) and triethylamine (15 mL, 103 mmol) cooled in ice was added dropwise a chloroform solution (60 mL) of 4-(benzyloxy)-5-bromo-2-methylbenzoyl chloride, and the mixture was stirred for an hour at room temperature. To the reaction solution cooled in ice were added water and chloroform to separate an organic layer. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide. To a tetrahydrofuran solution (150 mL) of the 4-(benzyloxy)-5-bromo-N-methoxy-N-methylbenzamide was added at −10° C. lithium aluminum hydride (1.96 g, 51.7 mmol), and the mixture was stirred for an hour at the same temperature. To the reaction solution were added 1 M hydrochloric acid, and then ethyl acetate to separate an organic layer. The organic layer was washed with 1 M hydrochloric acid, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde. To a toluene solution (120 mL) of the 4-(benzyloxy)-5-bromo-2-methylbenzaldehyde were added ethylene glycol (30 mL, 517 mmol) and p-toluenesulfonic acid monohydrate (0.50 g, 2.58 mmol), and heated to reflux for 1.5 hours with a Dean-Stark apparatus. To the reaction solution was added ethyl acetate to separate an organic layer. The organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1). In addition, the residue was further purified with NH type silica gel column chromatography (chloroform) to obtain the title compound (12.8 g, 71%, 3 steps) as a colorless powder.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:63]1[CH:64]=[CH:65][C:66]([N+:69]([O-:71])=[O:70])=[N:67][CH:68]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:63]2[CH:68]=[N:67][C:66]([N+:69]([O-:71])=[O:70])=[CH:65][CH:64]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: C=CCN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
315 mg (2.5 mmol) of N-allylpiperazine were dissolved in 5 ml of toluene under an argon atmosphere. 93 mg (0.1 mmol) of tris-(dibenzylideneacetone)-dipalladium(0) (Pd2 dba3), 126 mg (0.2 mmol) of 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (BINAP), 1.14 g (3.5 mmol) of cesium carbonate and 515 mg (2.54 mmol) of 5-bromo-2-nitropyridine were then added and the mixture was stirred at 120° C., in a microwave oven, for 4 hours. After the reaction mixture had cooled down to room temperature, a saturated aqueous solution of ammonium chloride was added. After that, the aqueous reaction mixture was extracted three times with in each case 50 ml of ethyl acetate. After the organic phase had been dried over sodium sulfate, the drying agent had been filtered off and the solvent had been evaporated down to dryness, the residue was chromatographed through silica gel using ethyl acetate/methanol (4:1), with 304 mg (46% of theory) of the title compound being obtained.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[N:24]=[CH:23][C:22]([CH:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:48]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:48][C:17]([C:19]4[N:24]=[CH:23][C:22]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)[CH2:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 0.67 h
Yield: 82.6 %

Procedure:
To a solution (5 mL) of diethyl (6-{5-[4-(cyclopropylsulfonyl)phenyl]-4-oxo-6-(tetrahydro-2H-pyran-4-yl)hexanoyl}pyridin-3-yl)malonate (150 mg) in acetic acid was added ammonium acetate (300 mg), and the mixture was stirred at 110° C. for 40 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (120 mg, yield 83%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1.5:1, volume ratio). MS: 595 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([Si:10]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18](OCC)=[O:19])[CH2:14][CH2:13]1)([CH3:9])[CH3:8].C(OCC)(=O)C.N>C1COCC1>[CH:26]([Si:10]([CH:7]([CH3:9])[CH3:8])([CH:23]([CH3:25])[CH3:24])[O:11][CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][OH:19])[CH2:16][CH2:17]1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1CCC(O[Si](C(C)C)(C(C)C)C(C)C)CC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)[Si](OC1CCC(CO)CC1)(C(C)C)C(C)C
Reaction time: 2 h
Yield: 98 %

Procedure:
Lithium aluminum hydride (6.0 g) was suspended in THF (200 ml). Ethyl 4-triisopropylsilyloxycyclohexylcarboxylate (37) (43.4 g) was added dropwise to the suspension in the temperature range of −20° C. to −10° C., and the mixture was stirred at the same temperature range for 2 hours. After the completion of reaction had been confirmed by means of GC analysis, ethyl acetate and a saturated aqueous solution of ammonia were added successively to the reaction mixture under ice-cooling, and the deposits were removed by filtration through Celite. The filtrate was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and dried over anhydrous magnesium sulfate. Distillation of the solvent under reduced pressure gave 4-triisopropylsilyloxycyclohexyl methanol (s38) (37.1 g). The yield based on the compound (s37) was 97.9%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:16]#[N:17])=[C:4]([SH:18])[N:3]=1.Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:18][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([C:28]([NH:30][CH3:31])=[O:29])[CH:23]=2)[C:5]([C:16]#[N:17])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: CNC(=O)c1cc(CCl)ccn1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(CSc2nc(N)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g (3.96 mmol) of 2-amino-4-phenyl-6-sulphanylpyridine-3,5-dicarbonitrile, 0.96 g (4.36 mmol) of 4-(chloromethyl)-N-methylpyridine-2-carboxamide hydrochloride and 1.33 g (15.84 mmol) of sodium bicarbonate are dissolved in 20 ml of DMF and stirred at RT for 2 h. 500 ml of water are added to the reaction mixture. The precipitate is filtered off and washed with water.