Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][NH:22][CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1.[C:25]([CH2:27][C:28](O)=[O:29])#[N:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:16][CH:17]2[CH2:24][CH:20]3[CH2:21][N:22]([C:28](=[O:29])[CH2:27][C:25]#[N:26])[CH2:23][CH:19]3[CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[N:11]([CH3:15])[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2ncc(Cl)c(NC3CC4CNCC4C3)n2)nn1C
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncc(Cl)c(NC3CC4CN(C(=O)CC#N)CC4C3)n2)nn1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.1 %

Procedure:
To a solution of 5-chloro-N2-(1,5-dimethyl-1H-pyrazol-3-yl)-N4-(octahydro cyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (522.0 mg, 1.50 mmol) and 2-cyanoacetic acid (127.6 mg, 1.50 mmol) in a mixture of DCM (40 mL) and DMF (10 mL) were added HATU (690.2 mg, 1.82 mmol) and Et3N (313.5 mg, 3.10 mmol). After addition, the reaction mixture was stirred at rt for 1.5 h, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=80/1) to give the title compound as a beige solid (455.2 mg, 73.1%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN.S(=O)(=O)(O)O>C(O)C>[CH3:30][N:10]1[CH:11]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[N:9]1
Reactant: CNN
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g) in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) and concentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1 h at ambient temperature and solvent evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Preparative HPLC chromatography provided the title compound (major isomer) as a clear oil (0.97 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 2 H), 8.17 (d, J=8.7 Hz, 1 H), 8.05 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1 H), 7.70 (m, 1 H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37 (d, J=8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 3.93 (s, 3H); MS: (M+H m/z=393.3).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([OH:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]1CCN2C(=NCCC2)CC1.P(OC)(OC)(OC)=O>O1CCOCC1>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]([CH3:27])[C:18](=[O:22])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(O)c3)nc2N1C1CCCC1
Solvent: COP(=O)(OC)OC
Solvent: C1COCCO1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccn(C)c(=O)c3)nc2N1C1CCCC1
Yield: 45.4 %

Procedure:
To a solution of (R)-8-cyclopentyl-7-ethyl-2-(2-hydroxypyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 14, 200 mg, 0.6 mmol) in 5 mL of 1,4-dioxane, DBU (26 mg, 3 mmol) and PO(OMe)3 (42 mg, 3 mmol) were added, and the mixture was heated to reflux for 18 h, then concentrated under reduced pressure, and extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure and the residue was chromatographed (PE:EA=1:1) to give the title compound as a yellow solid (100 mg, 50% yield). 1H NMR (CDCl3) δ: 7.95 (s, 1H), 7.53 (s, 1H) 7.35 (d, 1H), 7.11 (m, 1H), 4.54 (m, 1H), 4.29 (m, 1H), 3.6 (s, 3H), 3.38 (s, 3H), 2.2-1.6 (m, 10H) and 0.87 ppm (t, 3H); LCMS: 368.2 m/z (M+H)+; ret. Time: 1.53 min (Analytical Method E).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:25]([C:30]([NH:32][C:33]2[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=2)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:37]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]([C:25]4[C:24]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:31])=[CH:41][CH:40]=3)=[O:38])[CH2:6][C:5]=12
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of 0.65 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.52 g of N,N-diisopropylethylamine in 25 ml of methylene chloride is added 1.34 g of 4-[([1,1'-biphenyl]-2-carbonyl)amino]benzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried (Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.02 g of the desired product as a residue. M+ =482.
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[C:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21](=[O:37])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[C:23]=3[F:36])[CH:18]=2)[NH:13][CH:12]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([NH:20][C:21](=[O:37])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[C:24]([N:29]([S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31])[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[C:23]=3[F:36])[CH:18]=2)[N:13]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])[CH:12]=1)(=[O:10])[CH3:9]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]cc(C(C)=O)c3c2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)Nc2cnc3c(c2)c(C(C)=O)cn3S(=O)(=O)CCC)c1F)S(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
TEA (0.0163 mL, 0.117 mmol) and propane-1-sulfonyl chloride (0.00882 mL, 0.0779 mmol) were added to N-(3-acetyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(propylsulfonamido)benzamide (0.195 mL, 0.0390 mmol) in DCM (0.4 mL). The solution was stirred at room temperature for 16 hours before concentration under reduced pressure. The resulting residue was purified via column chromatography (2% MeOH/DCM) to afford impure N-(3-acetyl-1-(propylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2,6-difluoro-3-(N-(propylsulfonyl)propylsulfonamido)benzamide (0.020 g, 0.0308 mmol, 79.1% yield).
Reaction SMILES: C(O[C:9]([N:11]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[S:23]([NH:26][C:27]1[C:32]([O:33][CH3:34])=[N:31][C:30]([Br:35])=[CH:29][N:28]=1)(=[O:25])=[O:24])[CH3:12])=O)C1C=CC=CC=1.[OH-].[Na+]>Br.C(O)(=O)C.O>[CH2:9]([N:11]([C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:18]2[S:23]([NH:26][C:27]1[C:32]([O:33][CH3:34])=[N:31][C:30]([Br:35])=[CH:29][N:28]=1)(=[O:25])=[O:24])[CH3:12])[C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:14]=1
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)C(=O)OCc3ccccc3)cccc12
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N(C)Cc3ccccc3)cccc12
Reaction time: 1 h
Yield: 51.6 %

Procedure:
5-(N-Benzyloxycarbonyl-N-methylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.40 g) was suspended in 33% hydrobromic acid in acetic acid (5 ml) and the mixture was stirred for 1 hour. Evaporation afforded a yellow residue which was dissolved in water (20 ml ), basified to pH 10 with 1N aqueous sodium hydroxide and extracted with ethyl acetate (3×25 ml). The combined organic extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (30 g), eluting with a gradient of 20-50% ethyl acetate in hexane, affording 5-(N-benzyl-N-methyl-amino)-N-(5-bromo-3-methoxy2-pyrazinyl)-1-naphthalenesulphonamide (0.095 g); 1H NMR (d6DMSO): 2.72 (s,3H), 3.90 (s,3H), 4.25 (s,2H), 7.2-7.4 (m,6H), 7.58 (t,1H), 7.68 (t,1H), 7.80 (s,1H), 8.32 (dd,1H), 8.46 (d,1H), 8.64 (d,1H), 11.48 (br,1H); mass spectrum (+ve FAB, methanol/NBA); 513(M+H)+.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O.[C:12](O)(=O)C>N1C=CC=CC=1>[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)(=[O:9])[CH3:12].[C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)O
Agent: COC(=O)c1cccnc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1cccnc1
Reaction time: 60 h

Procedure:
An electrically heated tubular reactor with an i. d. of 12 mm was filled with 15 ml (≈15 g) of catalyst prepared according to EP-A-0 352 674, example 1. Over a period of 60 h, a mixture of methyl nicotinate (78 g), water (149 g) and acetic acid (523 g) was metered using a precision pump to the reactor operating at 410° C. From the reaction mixture, 30.5 g of 3-acetylpyridine, 8.5 g of pyridine and 9.0 g of methyl nicotinate were obtained. This corresponded to a yield of 45% 3-acetylpyridine at a methyl nicotinate conversion of 88% (selectivity 50%). The selectivity of pyridine formation was 19%.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:12]=2[CH:13]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CCO>[OH:22][N:21]=[C:18]([C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:13][C:12]=2[CH:14]=1)[NH2:19]
Reactant: C[C@@H]1CCCN1CCc1cc2cc(C#N)ccc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CCCN1CCc1cc2cc(C(N)=NO)ccc2o1
Temperature: 95 °C
Yield: 50.6 %

Procedure:
The product from Example 87B (2.5 g, 9.83 mmol) in EtOH (200 mL) was stirred at 25° C. for 10 minutes. The mixture was treated with hydroxylamine hydrochloride (1.71 g, 24.6 mmol) and potassium carbonate (4.49 g, 32.48 mmol) and the resulting mixture was heated at 95° C. for 16 h with stirring. The reaction mixture was subsequently cooled, filtered through celite, and concentrated under reduced pressure. The crude product was purified with flash chromatography to provide the title compound (1.43 g, 51% yield). MS (ESI) m/e 288 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:38][C:39]([OH:42])([CH3:41])[CH3:40])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]1)[N:20]=[C:19]([CH3:37])[N:18]=2>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]([CH2:38][C:39]([CH3:41])([OH:42])[CH3:40])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]1)[N:20]=[C:19]([CH3:37])[N:18]=2
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N2CCNCC2)c2nc(-c3ccccc3Cl)n(CC(C)(C)O)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
Add trifluoroacetic acid (10 mL) to a solution of tert-butyl 4-[8-(2-chlorophenyl)-9-(2-hydroxy-2-methyl-propyl)-2-methyl-purin-6-yl]piperazine-1-carboxylate (1.9 g, 0.0038 mol) in dichloromethane (10 mL) at 0° C. and stir for 2 h at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to give the title compound (1.5 g). ES/MS m/z 401 (M+1).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[NH:15][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C(=O)C>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14](=[O:17])[N:15]([CH3:24])[CH:16]=2)=[O:10])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CC(c1ccccc1)c1ccccc1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccccc2)c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 86 %

Procedure:
To a solution of 5-(3,3-diphenyl-propionyl)-1H-pyridin-2-one (60 mg, example 160, step 5) in N,N-dimethylacetamide (1 ml) were added powdered potassium carbonate (30 mg) and iodomethane (30 mg). The mixture was stirred at room temperature for 5.5 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 85:15) to give the title compound (54 mg) as a colorless solid, MS (ESI+): m/z=318.2 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.[Br:7][CH:8]([CH:11]=O)[CH:9]=O.C(O)C>>[Br:7][C:8]1[CH:9]=[C:4]2[CH:3]=[N:2][NH:1][C:5]2=[N:6][CH:11]=1.[Br:7][C:8]1[CH:9]=[N:6][C:5]2[N:1]([N:2]=[CH:3][CH:4]=2)[CH:11]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1ccn[nH]1
Solvent: CCO
Product: Brc1cnc2[nH]ncc2c1
Product: Brc1cnc2ccnn2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1H-pyrazol-5-amine x79 (25 g, 1 eq, 0.3 mol) and bromomalonaldehyde x9 (45.4 g, 1 eq, 0.3 mol) ethanol (250 ml) is refluxed for 2 hours. After cooling, the reaction mixture is stirred at room temperature overnight. The solvent is removed under reduced pressure and the crude is purified using chiral chromatography affording 5-bromo-1H-pyrazolo[3,4-b]pyridine x80 (yield: 2.1%; LC-MS (MH+): 198/200) and 6-bromopyrazolo[1,5-a]pyrimidine x81 (yield: 13.8%; LC-MS (MH+): 198/200).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][CH2:41][CH2:42][CH2:43][Cl:44]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:40][CH2:41][CH2:42][CH2:43][Cl:44])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(O)c(C#N)cc34)cc2)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Reaction time: 0.83 h

Procedure:
N-(4-(6-Cyano-7-hydroxy-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (200 mg), potassium carbonate (65 mg) and 1-bromo-4-chlorobutane (81 μl) were suspended in dimethylformamide (3 ml), and the suspension was heated and stirred for 1 hour and 50 minutes. The reaction solution was poured into saturated saline and extracted with ethyl acetate. After drying the organic layer over magnesium sulfate, it was passed through NH silica (Fuji Silicia Chemical) and washed in ethyl acetate, and the filtrate was concentrated. The obtained solid was washed with ether and dried to obtain 110 mg of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:12][CH2:11][CH2:10][C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cccc(OS(C)(=O)=O)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
9.09 g (79.6 mmole) methanesulfonyl chloride was slowly added to a solution of 5 g (36.2 mmole) 3-hydroxyphenethyl alcohol and 9.14 g (90.5 mmole) triethylamine in 150 ml dichloromethane at 0° C. After stirring at room temperature over night the salts were filtered off, the organic phase was washed with sodium bicarbonate and brine, dried (magnesium sulfate) and evaporated in vacuo to give 9.3 g (yield 87%) of 3-(methylsulfonyloxy)phenethyl methanesulfonate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(O)[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C(=O)=O.CC(C)=O.CCN(S(F)(F)[F:40])CC.[Cl:43]CCl>>[ClH:43].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[CH2:16][CH2:15][C:14]([CH2:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([F:40])[CH2:13][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CC1(O)CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccccc1
Reactant: ClCCl
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Product: Cl
Product: O=C(CC1(F)CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccccc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-benzoylmethyl-4-piperidinol (III-13) is firstly prepared according to the method of synthesis and post-treatment in Example 13. 1.41 g (4.0 mmol) of N-(benzo[d][1,3]dioxol-5-ylmethyl)-4-benzoylmethyl-4-piperidinol is dissolved into 20 ml of anhydrous dichloromethane and cooled with dry ice-acetone with temperature controlled at below <−70° C. The reaction solution is added a dichloromethane solution (8 mol, 25 ml) of DAST under protection of nitrogen gas. After completion of addition, the temperature is maintained at −75° C. and reacting for 1 hour, and the temperature is raised slowly and maintained at −10° C. and reacting for 2 hours. Then operating according to the post-treatment method in General Method six obtains 0.61 g of a white crystal, with yield of 37.2%.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C=O.[CH3:18]C(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl.O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH3:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(I)cc2)CCNCC1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN1CCC(C#N)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of the crude 4-(4-iodo-phenyl)-piperidine-4-carbonitrile (˜4.7 mmol) in ClCH2CH2Cl (100 mL) was added formaldehyde (1.92 mL of a 37% solution in H2O, 23.65 mmol, 5 eq.) and HOAc (1 mL, 1% v/v). The mixture was stirred for 0.5 h at room temperature and then NaBH(OAc)3 (1.48 g, 7 mmol, 1.5 eq.) was added. The reaction mixture was stirred for 16 h and then quenched by the addition of saturated aqueous NaHCO3 solution (50 mL). The resulting mixture was extracted with EtOAc (200 mL) and the organic layer was washed with saturated aqueous NaHCO3 solution (50 mL) and saturated brine (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated by rotary evaporation to give the crude 4-(4-iodo-phenyl)-1-methyl-piperidine-4-carbonitrile (1.5 g, 97%) as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.84 (dd, 2H), 7.36 (dd, 2H), 3.08 (dt, 2H), 2.60 (m, 2H), 2.50 (s, 3H), 2.20 (m, 4H).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.F[C:39](F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C1(OC)C=CC=CC=1>[C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([CH2:26][C:27]3[O:28][C:29]4[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][C:30]=4[CH:31]=3)[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)[CH2:9]1)(=[O:5])[CH3:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O[C@H]2CCN(C(C)=O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.3 g of ethyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate was dissolved in 3 ml of anisole. 25 ml of trifluoroacetic acid was added to the above solution with ice cooling, and the resulting mixture was stirred at room temperature for 1 hour. After distilling off trifluoroacetic acid under reduced pressure, the residue thus obtained was adjusted to pH 10-11 with saturated sodium bicarbonate aqueous solution, extracted with chloroform, and then dried. At room temperature, the resulting organic layer was mixed with 2 ml of triethylamine and then with 555 mg of acetyl chloride, followed by stirring at the same temperature for 0.5 hours. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography using a chloroform/ethanol mixture as an eluant to obtain 1.8 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([O:23][Si](C)(C)C)(C#N)[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10][C:11]([CH3:19])=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:3][CH:2]([C:4]1[C:5](=[O:23])[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10][C:11]([CH3:19])=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:1]
Reactant: CC1=CC=C(C(C)C)C(C#N)(O[Si](C)(C)C)CC(C)=CCCC(C)=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1=CC=C(C(C)C)C(=O)CC(C)=CCCC(C)=CCC1
Reaction time: 48 h
Yield: 84.4 %

Procedure:
The above cyanohydrine trimethylsilyl ether compound, 2-(1-methylethyl)-5,9,13-trimethyl-1-trimethylsiloxy-2,4,8,12-cyclotetradecatetraen-1-carbonitrile (657 mg, 1.7 mmol) was dissolved in 10% aqueous tetrahydrofuran (10 ml). To the solution on an ice-water bath was added a solution of 1M tetra n-butylammonium fluoride in tetrahydrofuran (0.02 ml), and the mixture was stirred and then allowed to stand at room temperature for 2 days. Most of the tetrahydrofuran was removed in vacuo and the residue was dissolved in ethyl ether. The ether layer was dried over MgSO4, filtered, concentrated, and subjected to silica gel column chromatography (solvent: n-hexane/ethyl acetate=30:l) to obtain the ketone compound, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraen-1-one (411 mg, 85%).