Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[Cu][C:23]#[N:24]>CN1CCCC1=O.[Cu]I>[CH:15]1([N:12]2[CH2:13][CH2:14][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:23]#[N:24])[CH:21]=[CH:20][C:5]=4[N:6]=3)[CH2:10][CH2:11]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#C[Cu]
Reactant: Brc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Agent: [Cu]I
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Temperature: 160 °C
Yield: 29.9 %

Procedure:
To a solution of 6-bromo-2-(4-cyclopentylpiperazin-1-yl)benzothiazole (0.54 g, 1.50 mmol) in N-methylpyrrolidin-2-one (100 mL) was added copper(I)iodide (344 mg, 1.80 mmol) and copper(I)cyanide (270 mg, 3.0 mmol). The mixture was heated at 160° C. for 4 h, then allowed to cool to room temperature and filtered. The filtercake was washed with ethyl acetate and the filtrate was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 140 mg (30%) of 2-(4-cyclopentylpiperazin-1-yl)benzothiazole-6-carbonitrile.
Reaction SMILES: Cl.[CH2:2]([NH:9][CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:12]=2[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:23]([CH2:30][C@H:31]1[O:33][CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NC1CCCC2C=C(OC)C=CC=2C1)C1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C1(C)C=CC=CC=1>[CH2:2]([N:9]([CH2:32][C@H:31]([OH:33])[CH2:30][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:10]1[CH2:16][CH2:15][CH2:14][C:13]2[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:12]=2[CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Reactant: COc1ccc2c(c1)CCCC(NCc1ccccc1)C2
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N-Benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine hydrochloride was converted to the corresponding free base in a usual manner. A mixture of (2S)-3-phenoxy-1,2-epoxypropane (75 mg), N-benzyl-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (140 mg), and ytterbium(III) trifluoromethanesulfonate (93 mg) in toluene (2.6 ml) was stirred at room temperature for 3 days and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) over silica gel to afford (2S)-1-[N-benzyl-N-(2-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (200 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(C)c(C)c(O)c1
Product: CCOC(=O)COc1cc(C)cc(C)c1C

Procedure:
Using 2,3,5-trimethylphenol and ethyl bromoacetate, the title compound was synthesized in the same manner as in Reference Example 153. Yield: quantitative. Oily matter.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[NH:8][C:7](=O)[N:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:4]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[N:8]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:6]=1
Reactant: O=c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1

Procedure:
The title compound was prepared from 6-trifluoromethyl-4-(4-trifluoromethylphenyl)-1H-pyrimidin-2-one (8.72 g, 28.3 mmol) and phosphoryl chloride (80 mL) according to the general procedure I. Obtained as a light brown solid (9.13 g, 98%). MS (EI) 326.0 [(M)+]; mp 71.5° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].Cl[C:12]1[N:21]=[C:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.CC(C)([O-])C.[K+].[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCCC1.C(OCC)(=O)C.O1CCOCC1>[C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([O:10][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:21]=2)[CH:7]=[CH:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CNCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(=O)O[C@H]1C=C[C@@H](Oc2nc(N3CCNCC3)nc3ccccc23)C1
Yield: 42.5 %

Procedure:
To a solution of (1S,4R)-4-acetoxycyclopent-2-en-1-ol [manufactured by Fluka Co., cf. Tetrahedron, 46, 3155 (1990)] (2.00 g) and 2,4-dichloroquinazoline (2.80 g) in tetrahydrofuran (52 ml) is added potassium t-butoxide (1.90 g) with stirring under ice-cooling, and the mixture is stirred under ice-cooling for 70 minutes. The reaction mixture is diluted with ethyl acetate, and washed with water. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is briefly purified with medium pressure column chromatography (eluent, chloroform) to give an oily substance. The oily substance is dissolved in dioxane (16 ml), and the solution is added dropwise to a solution of piperazine (3.25 g) in dioxane (19 ml) with stirring at 50° C., and the mixture is stirred at the same temperature for 1.5 hour. The reaction mixture is diluted with ethyl acetate and washed with water. The ethyl acetate solution is dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure, and the resulting residue is purified by medium pressure liquid column chromatography (eluent, chloroform:methanol=10:1, v/v) to give 4-[(1S,4R)-(4-acetoxycyclopent-2-en-1-yl)oxy]-2-(1-piperazinyl)quinazoline (2.12 g) as oil.
Reaction SMILES: C([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:9](=[O:11])[O-:10])C1C=CC=CC=1.[CH3:21][O:22][C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([CH3:34])[CH:26]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]([O:10][C:9]([NH:8][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:28]2[CH:29]=[CH:30][C:25]([C:23]([O:22][CH3:21])=[O:24])=[CH:26][C:27]=2[CH3:34])=[CH:18][CH:19]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(B(O)O)c(C)c1
Reactant: O=C([O-])N(CCc1ccc(Br)cc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc(CCNC(=O)OCc3ccccc3)cc2)c(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of N-benzyl-N-[2-(4-bromophenyl)ethyl]-carbamate (1.3 g) in 1,2-dimethoxyethane (20 ml) was added [4-(methoxycarbonyl)-2-methylphenyl]boronic acid (792 mg), tetrakis(triphenylphosphine)palladium (360 mg) and aqueous solution of sodium carbonate (2M, 4.1 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[[(benzyloxy)carbonyl]amino]ethyl]-2-methyl-1,1′-biphenyl-4-carboxylate (660 mg).
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH3:29])[CH:23]=1.[OH-].[Na+]>O1CCCC1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[C:24]([CH3:29])[CH:23]=1
Reactant: Cc1cc(F)ccc1N
Reactant: O=C(O)C1(C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1NC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid (1.0 g, 8.0 mmol) was suspended in tetrahydrofuran (20 mL), and triethylamine (1.1 mL, 8.0 mmol) was added. After stirring at room temperature for 1 hr, the mixture was cooled in an ice bath. Under ice-cooling, thionyl chloride (0.58 mL, 8.0 mmol) was added dropwise, and the mixture was stirred as it was for 30 min. To this mixture was dropwise added a solution of 4-fluoro-2-methylaniline (3.9 g, 31 mmol) in tetrahydrofuran (2.0 mL) under ice-cooling, and the reaction mixture was warmed to room temperature and stirred overnight. An aqueous sodium hydroxide solution (1N, 50 mL) was added, and the mixture was washed twice with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (1N), and the mixture was extracted twice with ethyl acetate. The mixed organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane-ethyl acetate was added to the residue, and the precipitate was collected by filtration to give the title compound (1.1 g, 60%) as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:40])[CH2:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH3:15][O:16][C:17](=[O:40])[CH2:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]2[CH:26]=[CH:27][C:28]([C:2]3[CH:3]=[CH:4][C:5]([NH:8][C:9]4[CH:13]=[CH:12][N:11]([CH3:14])[N:10]=4)=[CH:6][N:7]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1
Reactant: Cn1ccc(Nc2ccc(Br)nc2)n1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccn(C)n4)cn3)cc2)CC1
Temperature: 80 °C

Procedure:
To a solution of (6-bromopyridin-3-yl)-(1-methyl-1H-pyrazol-3-yl)-amine (0.15 g, 0.6 mmol, 1.0 equiv) and {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.23 g, 0.7 mmol, 1.1 equiv) in 5 Ml DME was added 0.5 Ml saturated potassium carbonate solution followed by 5 mg Pd(PPh3)4 catalyst. The reaction was then heated to 80° C. for 2 h. Removal of volatiles in vacuo followed by silica gel chromatography (20% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.26 (m, 2H) 1.54 (qd, J=12.59, 2.40 Hz, 2H) 1.68 (br. S., 1H) 1.87 (d, J=11.12 Hz, 5H) 2.31 (d, J=6.57 Hz, 2H) 3.66 (s, 3H) 3.82 (s, 3H) 5.86 (s, 1H) 7.33 (d, J=8.34 Hz, 2H) 7.59 (d, J=2.02 Hz, 1H) 7.80 (d, J=8.84 Hz, 1H) 7.93 (d, J=8.34 Hz, 2H) 7.97 (dd, J=8.84, 2.78 Hz, 1H) 8.65 (d, J=2.27 Hz, 1H) 8.83 (s, 1H); (M+H)+405.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:19])([CH3:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:8]=[C:7]([O:20][CH2:21][O:22][CH3:23])[CH:6]=1.[Li]CCCC.[B:29](OC)([O:32]C)[O:30]C.Cl>C1COCC1.O>[CH3:23][O:22][CH2:21][O:20][C:7]1[CH:8]=[C:9]([C:11]([CH3:18])([CH3:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:10]=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]=1[B:29]([OH:32])[OH:30]
Reactant: CCCCCCC(C)(C)c1cc(OCOC)cc(OCOC)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1cc(OCOC)c(B(O)O)c(OCOC)c1
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1,3-Bis(methoxymethoxy)-5-(1,1-dimethylheptyl)-benzene (50) (1 equiv.) was dissolved in dry THF (10 mL). The solution was cooled to −10° C. and n-BuLi (1.1 equiv. using 1.6 solution in hexanes) was added dropwise. The mixture was stirred for an additional 1.5 h, then it was cooled to −78° C. and (MeO)3B (5 equiv.) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with water, stirred for 30 min and the pH was adjusted to 4 with dilute aqueous HCl. The mixture was extracted with EtOAc, the organic layer was dried (MgSO4) and the solvent was evaporated. Purification by flash column chromatography (hexane-acetone) gave the title compound in 81% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A suspension consisting of 1,1′-(4-bromobutylidene)bis[4-fluorobenzene] (25 g, 77 mmol) and potassium phthalimide (17 g, 92 mmol) in 300 mL DMF was stirred at 50° C. for 16 hours, cooled to 25° C., and poured into 900 mL of cold H2O. The mixture was extracted with ethyl acetate (3×300 mL), and the combined extracts were washed with H2O (2×1 L), followed by brine (700 mL), then dried over anhydrous sodium sulfate. Evaporation of solvent in vacuo afforded 28.6 g of a golden oil, which was triturated with 250 mL 2,2,4-trimethylpentane containing 5% 2-propanol, and the solid thus obtained was collected by filtration and dried at 50° C. in vacuo, to give 28.7 g (97%) of titled compound as a white powder; mp 69-70° C. APCI-MS m/z 391.1 (M−).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:19][CH2:18][C:17]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])([CH3:20])[CH:16]([OH:27])[CH:15]=[CH:14][CH:13]([CH3:28])[CH:12](/[C:29](/[CH3:56])=[CH:30]/[CH:31]=[CH:32]/[C:33]([O:50][CH:51]([O:53][CH2:54][CH3:55])[CH3:52])([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([O:41][CH:42]([O:44][CH2:45][CH3:46])[CH3:43])[CH2:39][CH3:40])[O:11][C:9](=[O:10])[CH2:8]1)[CH3:5])[CH3:2].C(N(CC)CC)C.ClC(O[C:68]1[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=1)=O.[C:77]([O:80]CC)(=[O:79])C>ClCCl>[CH2:1]([O:3][CH:4]([O:6][CH:7]1[CH2:19][CH2:18][C:17]([O:21][CH:22]([O:24][CH2:25][CH3:26])[CH3:23])([CH3:20])[CH:16]([O:27][C:68]2[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=2)[CH:15]=[CH:14][CH:13]([CH3:28])[CH:12](/[C:29](/[CH3:56])=[CH:30]/[CH:31]=[CH:32]/[C:33]([O:50][CH:51]([O:53][CH2:54][CH3:55])[CH3:52])([CH3:49])[CH2:34][CH:35]2[O:48][CH:36]2[CH:37]([CH3:47])[CH:38]([O:41][CH:42]([O:44][CH2:45][CH3:46])[CH3:43])[CH2:39][CH3:40])[O:11][C:9](=[O:10])[CH:8]1[C:77]([OH:80])=[O:79])[CH3:5])[CH3:2]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=O
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(Oc2ccc([N+](=O)[O-])cc2)/C=C/C(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(Oc2ccc([N+](=O)[O-])cc2)C=CC(C)C(/C(C)=C/C=C/C(C)(CC2OC2C(C)C(CC)OC(C)OCC)OC(C)OCC)OC(=O)C1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (8E,12E,14E)-3,6,16,21-tetrakis(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (139 mg, 0.17 mmol) in dichloromethane (2.5 mL) were added triethylamine (88 mg, 0.87 mmol), N,N-dimethylaminopyridine (64 mg, 0.52 mmol) and 4-nitrophenyl chloroformate (105 mg, 0.52 mmol) under ice cooling, followed by stirring at room temperature under nitrogen atmosphere for one hour. The reaction mixture was diluted with ethyl acetate, and then washed with a saturated aqueous solution of sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 100 μm; ethyl acetate:hexane=20:80) to give the title compound (134 mg, 80%) as a colorless oil.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].Br[CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([O:10][CH2:11][CH3:12])=[O:9].O>C(O)C.CCOCC>[CH2:2]([O:1][CH:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:3]
Reactant: CC[O-]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)OCC
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCC(OCC)C(=O)OCC

Procedure:
To a solution of sodium ethoxide in ethanol, prepared from sodium (1.46 g) and ethanol (35 ml) a solution of ethyl 2-bromohexadecanoate (20.3 g) in ethanol (25 ml) was added. After refluxing for 3 h water was added and the product was taken up in ether. After evaporation of the ether and fractionation of the residue there was obtained 10.8 g ethyl 2-ethoxyhexadecanoate b.p. 112°-114° (0.01 mm), nD23 1.4393.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C:11](=[C:12]([N+:22]([O-:24])=[O:23])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[N+:22]([C:12]1[C:13](=[O:21])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C:11]=1[CH2:10][CH2:9][C@@H:8]1[C@@H:18]2[CH2:19][CH2:20][C@@:3]2([CH3:4])[C@H:5]1[CH2:6][CH2:7][C:2]2=[O:1])([O-:24])=[O:23]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C([N+](=O)[O-])C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: C[C@]12CCC(=O)C([N+](=O)[O-])=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 17β-hydroxy-4-nitroandrost-4-en-3-one (4-nitrotestosterone, 10.56 g, 31.7 mM) in acetone (900 ml) cooled to -6° C. is treated with Jones reagent (10.0 ml). After the excess reagent is decomposed with methanol, the solids are removed by filtration. The filtrate is concentrated, for example on a rotary evaporator under vaccum, then purified by flash chromatography on silica gel to give 4-nitroandrost-4-ene-3,17-dione, m.p. 205-205.5° C. dec.(acetone-hexane).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[NH:5]1[CH2:8][CH:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=3)=[N:14][CH:15]=2)[CH2:6]1.[OH-].[Na+]>CO>[CH:2]([N:5]1[CH2:6][CH:7]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][N:21]=[C:20]4[NH:27][C:28]3[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=3)=[N:14][CH:15]=2)[CH2:8]1)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OC5CNC5)cn4)cc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N1CC(Oc2ccc(Oc3ccc4ncnc(Nc5ccn(C)n5)c4c3)nc2)C1
Reaction time: 0.17 h

Procedure:
Acetone (0.019 ml, 0.26 mmol) was added to a methanol solution (1 ml) of 6-{[5-(azetidin-3-yloxy)pyridin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (50 mg, 0.13 mmol) obtained in Example 6-5), stirred for 10 minutes, then a methanol solution (1.7 ml, 0.26 mmol) of 0.15 M zinc cyanotrihydroborate was added and stirred for 1 hour. 1 N sodium hydroxide was added to the reaction solution, then extracted with a mixed solution of chloroform/methanol (9:1). The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by thin-layer silica gel column chromatography (chloroform:methanol=90:10) to obtain 6-({5-[(1-isopropylazetidin-3-yl)oxy]pyridin-2-yl}oxy)-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine. The compound was dissolved in methanol, then aqueous 5 M hydrochloric acid solution (0.017 ml, 0.085 mmol) was added and concentrated under reduced pressure to obtain the entitled compound (40 mg, yield: 67%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Yield: 102.6 %

Procedure:
A solution of 4-chloro-3-nitro-pyridine (2.0 mmol, 0.32 g), triethylamine (3.0 mmol, 0.42 mL) and piperazine-1-carboxylic acid tert-butyl ester (2.5 mmol, 0.47 g) in dioxane (2 mL) was irradiated using microwave for 8 minutes at a temperature of 150° C. The reaction mixture was concentrated in vacuo, and the resulting residue was purified using flash column chromatography on silica gel (eluent: ethyl acetate) to provide 4-(3-nitro-pyridin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid (633 mg, quantitative yield). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 6.87 (d, J=6.0 Hz, 1H), 3.68-3.56 (m, 4H), 3.32-3.18 (m, 4H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#[N:2].ClC1[C:19]([C:20]([OH:23])([CH3:22])[CH3:21])=[C:18]([O:24][CH3:25])[N:17]=[C:16]([O:26][CH3:27])N=1.[H-].[Na+].CN(C=[O:34])C>>[OH:34][C:3]1([C:4]2[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=2)[C:7]#[N:8])[C:1]2[N:2]=[C:16]([O:26][CH3:27])[N:17]=[C:18]([O:24][CH3:25])[C:19]=2[C:20]([CH3:22])([CH3:21])[O:23]1
Reactant: CN(C)C=O
Reactant: Cc1cc(C#N)cc(CC#N)c1
Reactant: COc1nc(Cl)c(C(C)(C)O)c(OC)n1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(OC)c2c(n1)C(O)(c1cc(C)cc(C#N)c1)OC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
3-Cyanomethyl-5-methyl-benzonitrile (0.067 g, 0.432 mmol) and 2-(4-Chloro-2,6-dimethoxy-pyrimidin-5-yl)-propan-2-ol (0.100 g, 0.432 mmol) was dissolved in DMF (1.5 mL) and cooled to 0° C. 60% Sodium hydride (0.035 g, 0.64 mmol) was added portionwise and the reaction was stirred at 0° C. for 1 h, then rt overnight. The reaction was quenched with 1N HCl, extracted with ethyl acetate and washed with saturated ammonium chloride solution. Organic layer was dried (MgSO4) and concentrated and purified by flash column chromatography (silica gel, 0 to 40% ethyl acetate/hexane) to give a white solid (0.027 g, 18%). 1H NMR (300 MHz, CDCl3): δ 7.80 (s, 2H), 7.39 (s, 1H), 4.01 (s, 3H), 3.93 (s, 3H), 2.37 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H). Mass spectrum: 342.3 (M+H)+.