Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[C:14]1[NH:15][C:16]([CH3:24])=[C:17]2[C:22]=1[CH:21]=[N:20][NH:19][C:18]2=[O:23].[H][H]>[Pd].C(OCC)(=O)C>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:3]2[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:2]=2[F:1])=[C:6]([C:14]2[NH:15][C:16]([CH3:24])=[C:17]3[C:22]=2[CH:21]=[N:20][NH:19][C:18]3=[O:23])[CH:7]=1
Reactant: Cc1[nH]c(-c2cc([N+](=O)[O-])ccc2Oc2ccc(F)cc2F)c2cn[nH]c(=O)c12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1[nH]c(-c2cc(N)ccc2Oc2ccc(F)cc2F)c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 73302.5 %

Procedure:
A mixture of Example 78b (80 mg, 0.20 mmol) and 10% palladium on carbon (42.7 mg, 0.040 mmol) in ethyl acetate (20 mL) was treated with a balloon of hydrogen gas. The reaction mixture was stirred at ambient temperature for 16 hours. The solid was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, 2-6% methanol in dichloromethane) to afford the title compound (54 g, 73%). 1 H NMR (300 MHz, DMSO-d6) δ 12.35 (s, 1 H) 11.34 (s, 1 H) 8.00 (s, 1 H) 7.20-7.37 (m, 1 H) 6.85-6.97 (m, 1 H) 6.71-6.83 (m, 3 H) 6.59 (dd, J=8.73, 2.78 Hz, 1 H) 5.18 (s, 2 H) 2.56 (s, 3 H). MS (ESI+) m/z 369 (M+H)+.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH:14]1([C:17]2[CH:22]=[N+:21]([O-])[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=2)[CH2:16][CH2:15]1.O>CN(C)C=O>[CH:14]1([C:17]2[CH:18]=[CH:19][C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:21][C:22]=2[OH:4])[CH2:16][CH2:15]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1ccc(C2CC2)c[n+]1[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(C2CC2)c(O)n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Trifluoroacetic anhydride (23 mL) was added to a solution of ethyl 5-cyclopropylpyridine-2-carboxylate 1-oxide (15.4 g) in N,N-dimethylformamide (45 mL), and the mixture was stirred at 50° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give ethyl 5-cyclopropyl-6-hydroxypyridine-2-carboxylate (12.4 g, 78%) as a colorless powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].[I-:16].[K+].[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[I-:16].[CH3:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][P+:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COCCOCCOCCOCCCCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCOCCOCCOCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -20 °C

Procedure:
To a solution of 1-chloro-3-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}propane (2.4 g) in dry acetonitrile (30 ml) was added potassium iodide (1.66 g), and triphenylphosphine (2.63 g) and the suspension heated at reflux for 24 hours. The cooled solution was filtered and the filtrate evaporated under reduced pressure to give a colourless oil which on cooling to -20° C. gave a white oily solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:18]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N+:11]2([O-])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([CH:18]([S:27]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)(=[O:28])=[O:29])[C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:4][C:5]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCC[N+]2([O-])CCOCC2)ncc1Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NCCN2CCOCC2)ncc1Cl
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
The 4-[2-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]aminoethyl]morpholine-N-oxide (78 mg, 0.14 mmol) obtained in Example 349 was dissolved in a mixed solvent of acetic acid (2.0 ml) and water (2.0 ml). The resulting mixture was heated to 60° C. Iron powder (40 mg, 0.72 mmol) was added and the mixture was stirred for 30 minutes. After cooling, the reaction mixture was poured into a saturated aqueous solution of potassium carbonate, followed by extraction with ethyl acetate (60 ml). The solution was washed with brine, dried and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% methanol/chloroform solution), whereby the title compound (30 mg, 40%) was obtained.
Reaction SMILES: [CH:1]12[CH2:8][C:7](=[O:9])[CH:6]1[CH2:5][CH2:4][CH:3]=[CH:2]2.[CH2:10](O)[CH2:11][OH:12].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[O:9]1[CH2:10][CH2:11][O:12][C:7]21[CH2:8][CH:1]1[CH:6]2[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C1CC2C=CCCC12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C1=CC2CC3(OCCO3)C2CC1

Procedure:
A mixture of 6.4 g bicyclo[4.2.0]oct-2-en-7-one (III), (Tetrahedron, 27, 615 (1971)), 18.62 g ethylene glycol, 100 ml benzene, and 25 mg p-toluenesulfonic acid is heated at reflux for 4 hr using a Dean-Stark trap to effect continuous removal of water. The cooled reaction mixture is poured onto 100 ml saturated sodium bicarbonate solution and the resulting mixture is extracted with three 75 ml portions of diethyl ether. The combined organic extract is washed with 100 ml saturated sodium chloride solution and is then dried over sodium sulfate. The solvent is removed under vacuum and the residue is distilled under vacuum to give 7.12 g of spiro[bicyclo[4.2.0]oct-2-ene-7,2'-[1.3]dioxolan] (IV).
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])[C:6]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:5][N:4]=1.[Cl:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][OH:32])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[N:30]=[CH:29][C:28]([CH2:31][O:32][C:3]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=3[Cl:16])[C:6]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:5][N:4]=2)=[CH:27][CH:26]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: OCc1ccc(Cl)nc1
Product: Clc1ccc(-c2cnc(OCc3ccc(Cl)nc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted 6-chloro-3-pyridinemethanol according to the procedure described in Example 59 to afford 2-(6-chloro-3-pyridylmethoxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=476 (M++1); Rt=4.45 min; 1H-NMR 400 MHz (CDCl3): δ 5.51 (s, 2H), 7.05 (d, J=9 Hz, 2H), 7.20 (d, J=9Hz, 1H), 7.25-7.30 (m, 4H), 7.38-7.40 (m, 1H), 7.85 (m, 1H), 8.55 (d, J=2 Hz, 1H), 8.60 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[I:8].C([Sn](CCCC)(CCCC)[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1)CCC.C(OCC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Brc1ccccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: Ic1ccccc1-c1cnccn1
Temperature: 90 °C
Reaction time: 22 h
Yield: 16.2 %

Procedure:
1-Bromo-2-iodobenzene (0.32 mL, 2.4 mmol), copper(I) iodide (50 mg, 0.26 mmol) and bis(triphenylphosphine)palladium(II) chloride (88 mg, 0.12 mmol) were added to a degassed solution of 2-tributylstannylpyrazine (1.0 g, 2.4 mmol) in tetrahydrofuran (10 mL) and stirred at 90° C. under nitrogen for 22 hours. Diethyl ether was added to the cooled mixture, filtered through ‘Hyflo’ silica and concentrated in vacuo. Purification by flash column chromatography eluting with a 10-100% diethyl ether/isohexane gradient gave a pale yellow oil of 2-(2-iodophenyl)pyrazine (0.11 g, 16%) which contained some 2-(2-bromophenyl)pyrazine. 1H NMR (500 MHz, CDCl3) δ 8.85 (1H, d, J=1.4 Hz), 8.71-8.65 (1H, m), 8.59 (1H, d, J=2.5 Hz), 8.00 (1H, d, J=7.9 Hz), 7.49-7.46 (2H, m), 7.19-7.11 (1H, m); m/z (ES+) 283 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][C@@:8]2([CH3:34])[N:12]3[C:13]([S:16]([NH:19][C@@H:20]([CH3:24])[C:21]([OH:23])=O)(=[O:18])=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:9]2=[O:33])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.[NH2:60][C@@H:61]([C:63]([NH2:65])=[O:64])[CH3:62].C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[C:63]([C@H:61]([NH:60][C:21](=[O:23])[C@@H:20]([NH:19][S:16]([C:13]1[N:12]2[C@@:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:36][CH:35]=3)([CH3:34])[C:9](=[O:33])[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[C:11]2=[N:15][CH:14]=1)(=[O:17])=[O:18])[CH3:24])[CH3:62])(=[O:64])[NH2:65]
Reactant: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: C[C@@H](N)C(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NS(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)N[C@H](C)C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.2 %

Procedure:
(S)-2-[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H -imidazo[1,2-α]imidazole-3-sulfonylamino]-propionic acid (see Example 14) (0.05 g, 0.091 mmol) was dissolved in anhydrous DMF (2 mL) and TBTU (0.044 g, 0.137 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 10 min and D-alaninamide hydrochloride (0.017 g, 0.137 mmol) was added to the mixture followed by N,N-diisopropylethylamine (0.039 mL, 0.227 mmol). The reaction mixture was stirred at room temperature for another 15 min. The mixture was then diluted with EtOAc (10 mL) and washed with water, 1 N HCl, saturated NaHCO3 and then water. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography to afford 0.035 g of the title compound as a white foam (M+1, 618.2).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:16])[CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[CH3:17][N:18]([CH2:22][CH2:23]Cl)[CH2:19][CH2:20]Cl.Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[CH3:17][N:18]1[CH2:22][CH2:23][N:16]([C:6]2[CH:7]=[CH:8][C:9]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:20][CH2:19]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1ccc(N2CCCCC2)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2ccc(N3CCCCC3)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
To a solution of 512 mg g (2.31 mmol) of 3-nitro-4-piperidin-1-yl-phenylamine (as prepared in the previous step) and 404 mg (2.10 mmol) of mechlorethamine hydrochloride in 15 mL of EtOH was added 1.45 g (10.5 mmol) of anh K2CO3 and the mixture heated to reflux under Ar for 48 h. The mixture was cooled to RT, concentrated in vacuo, extracted with EtOAc (3×20 mL) and the combined extracts filtered (Celite), and concentrated to a dark oil. Chromatography of the resulting residue on a 70-g silica SPE column with a gradient of 0-3% MeOH-dichloromethane afforded 456 mg (71%) of the title compound as a dark red solid: Mass spectrum (ESI, m/z): Calcd. for C16H24N4O2, 305.2 (M+H), found 305.1.
Reaction SMILES: [N+](C(C)C)([O-])=[O:2].C(O)C.[O-]CC.[Na+].[Br:14][C:15]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=2[C:16]=1[CH2:33]Br>C(O)C>[Br:14][C:15]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:18]2[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=2[C:16]=1[CH:33]=[O:2]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C[Si](C)(C)CCOCn1c(Br)c(CBr)c2c(=O)[nH]ncc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(Br)c(C=O)c2c(=O)[nH]ncc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
To 370 mg (4.2 mmol) of 2-nitropropane were added 10 ml of dehydrated ethanol and 1.43 g (4.2 mmol) of 20% sodium ethoxide ethanol solution, then, 500 mg (0.84 mmol) of 2-bromo-3-bromomethyl-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 24-(f) was added to the mixture at 5° C., and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=1:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 167 mg of the title compound as a white solid. (Yield: 32%)
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[C:10]#[CH:11].C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[C:20]1([S:26]([O:8][C:5]2[CH:6]=[CH:7][C:2]([S:1][CH2:11][C:10]#[CH:9])=[CH:3][CH:4]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Oc1ccc(S)cc1
Reactant: C#CCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCSc1ccc(OS(=O)(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 109.6 %

Procedure:
4-Mercaptophenol (1) (37.85 g, 300 mmol) and propargyl bromide (42.82 g, 360 mmol) were dissolved in ethyl acetate (757 ml). To the solution was added dropwise triethylamine (42.5 g, 420 mmol) over 25 minutes with stirring and under ice-cooling. After stirring for another 1.5 hours at the same temperature, triethylamine (42.5 g, 420 mmol) was added in one portion, and benzenesulfonyl chloride (63.58 g, 360 mmol) was added dropwise over 20 minutes. After keeping 1 hour at the same temperature, the cooling bath was removed and the mixture was stirred for 30 minutes at room temperature and partitioned into two layers by adding ice-water (500 ml) and 2N hydrochloric acid (110 ml). The aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to provide 100.04 g of the title compound (2) as oil. Crude yield: 109%.
Reaction SMILES: C(O[CH2:5][C:6]1[C@H:7]2[CH2:20][CH2:19][C@@H:18]([CH3:21])[C@H:8]2[C@H:9]([O:12][CH:13]([O:15][CH2:16][CH3:17])[CH3:14])[O:10][CH:11]=1)(=O)C.N1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:16]([O:15][CH:13]([O:12][C@H:9]1[C@@H:8]2[C@H:18]([CH3:21])[CH2:19][CH2:20][C@@H:7]2[C:6]([CH3:5])=[CH:11][O:10]1)[CH3:14])[CH3:17]
Reactant: [H][H]
Reactant: CCOC(C)O[C@@H]1OC=C(COC(C)=O)[C@H]2CC[C@@H](C)[C@@H]12
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(C)O[C@@H]1OC=C(C)[C@H]2CC[C@@H](C)[C@@H]12
Yield: 74.5 %

Procedure:
(1S, 4aS, 7R, 7aR)-4-(acetoxymethyl)-1-[1(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta[c] pyran (65 mg, 0.00024 mol) obtained in Example 26 was dissolved in 3 ml of ethyl acetate, and 0.05 ml of pyridine and 10% palladium carbon (3 mg) were added. The reaction mixture was stirred for 24 hours in a hydrogen gas atmosphere of 1 atm. After the catalyst was removed by celite filtration, concentration was effected. The residual matter was purified by chromatography using silica gel, and the solvent of the fraction obtained from hexane:ether=8:2 eluent was distilled off. A colorless oily substance was thus obtained, i.e., (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-4, 7-dimethylcyclopenta[c]pyran (43 mg, yield=82%). This (1S, 4aS, 7R, 7aR)-1-[1-(ethoxy)ethoxy]-1,4a,5,6,7,7a-hexahydro-4,7-dimethylcyclopenta[c]pyran had the following physicochemical properties:
Reaction SMILES: [C:1]12([OH:12])C[CH:5]([C:6]1(C)[CH3:7])[CH2:4][CH2:3][C:2]2(O)[CH3:10].C[C@@H](CCC)[C@@H](B([O-])[O-])CC.OO>CCCCCC>[CH3:10][C@@H:2]([CH2:3][CH2:4][CH3:5])[C@@H:1]([OH:12])[CH2:6][CH3:7]
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Agent: CCC[C@H](C)[C@H](CC)B([O-])[O-]
Agent: OO
Solvent: CCCCCC
Product: CCC[C@H](C)[C@@H](O)CC

Procedure:
As disclosed in Pearce et al., J. Chem. Ecol., 1, p 115 (1975), this compound is known to be a component of the pheromone of the European elm bark beetle, Scolytus multistriatus. The present synthesis began with (+)-pinanediol propane-1-boronate, which was converted to (+)-pinanediol (1S)-1-chlorobutane-1-boronate by the procedure outlined in Example 1. This compound was then treated with methylmagnesium bromide (stoichiometric amounts of reactants were used, with 60 ml of tetrahydrofuran solvent for 24 mmol), and kept at 20° C. overnight. The isomeric purity of the (+)-pinanediol (2S)-pentane-2-boronate was confirmed by oxidation with alkaline hydrogen peroxide to (S)-2-pentanol, rotation [α]25 589 +12.86° (c 1.5%, ethanol), which corresponds to 98.2% enantiomeric excess, 99.1% diastereomeric purity of the precursor. (+)-Pinanediol (2S)-pentane-2-boronate was converted to (+)-pinanediol (1S,2S)-1-chloro-2-methylpentane-1-boronate by the procedure outlined in Example 1. This compound was then treated with ethylmagnesium bromide as described above to yield (+)-pinanediol (3S,4S)-4-methylheptane-3-boronate. This material which was chromatographed on silica with 20% ethyl acetate in hexane and distilled in a short path apparatus under high vacuum, and which was prepared in a yield of 86.5% (based on the pentane-2-boronate), was oxidized with alkaline hydrogen peroxide to yield (3S,4S)-4-methyl-3 -heptanol, bp 102°-104° C. (95 torr), [α]24 589°-19.84° (c 4.4%, hexane). Attempts to detect any diastereomer by standard NMR methods failed. Properties reported for this compound in Mori, Tetrahedron, 33, pp 289-294 (1977) are bp 105°-108° C. (102 torr), [α]22D -21.7° (c 0.57%, hexane).
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].C(COC)OC.COCCOCCOC.[CH:24]1[CH:29]=[C:28]2C=[CH:31][C:32]3[C:37]([C:38](=[O:39])[C:27]2=[CH:26][CH:25]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3>O>[F:6][C:2]1([F:7])[CH:31]2[CH:3]1[C:28]1[CH:29]=[CH:24][CH:25]=[CH:26][C:27]=1[C:38](=[O:39])[C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Solvent: COCCOC
Product: O=C1c2ccccc2C2C(c3ccccc31)C2(F)F

Procedure:
A solution of an alkali halodifluoroacetate such as sodium chlorodifluoroacetate in a solvent (for example, glyme, diglyme) is added over a period of 4 to 8 hours (preferably 6 hours) to a solution of dibenzosuberenone (for example in diglyme) with stirring and under nitrogen, maintaining the reaction temperature at 160°-165° C. Other reaction temperatures may be employed depending upon the reactants used, as described in Ciganek et al., “Imine Analogues of Tricyclic Antidepressants,” J. Med. Chem., 1981, 24,336-41; or in Coyne and Cusic, “Aminoalkyldibenzo[a,e]cyclopropa[c]cycloheptene Derivatives. A Series of Potent Antidepressants,” J. Med. Chem., 1974, Vol. 17, No. 1, 72-75. The reaction mixture is brought to room temperature, then poured into water and extracted (e.g., with diethylether or pentane). The 1,1-difluoro-1a,10b-dihydrodibenzo[a,e]cyclopropa[c]cyclohepten-6(1H)-one is isolated and purified by conventional means, for example, the organic phase is washed with water, dried (e.g., over Na2SO4), evaporated, and the residue is recrystallized (e.g., from ethanol, and optionally recrystallized again, e.g., from acetone/hexane).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[C:16]([Br:24])=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH2:26])=[C:17]3[C:16]([Br:24])=[N:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: Clc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(Br)nn2C1CCN(Cc2ccccc2)CC1
Temperature: 120 °C

Procedure:
1-(1-benzyl-4-piperidinyl)-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate C) (9 g, 61% purity) was mixed with dioxane (100 ml) and ammonium hydroxide (100 ml) in a pressure vessel. The mixture was heated to 120° C. overnight. Solvent was removed and the residue was purified via flash column chromatography using ethyl acetate as the mobile phase to give 1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (CDCl3) 1.94(d, J=11.23 Hz, 2H), 2.21 (m, 2H), 2.35 (m, 2H), 3.04(d, J=11.48 Hz), 3.57(s, 2H), 4.71(m, 1H), 5.98(s, 2H), 7.34(m, 5H), 8.33(s, 1H); LC/MS (MH+=389).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:21])=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([CH2:15][C:16]#N)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O>C(O)C.[Pt](=O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][C:10]=1[Cl:21])[NH:18][CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cc(OCc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Clc1cc2[nH]ccc2cc1OCc1ccccc1
Reaction time: 12 h
Yield: 17.7 %

Procedure:
To a solution of (5-benzyloxy-4-chloro-2-nitrophenyl)acetonitrile (4.170 g) in ethanol (70 mL) was added platinum (IV) oxide (0.344 g) at room temperature and this mixture was stirred under a hydrogen atmosphere (30-35 psi) for 12 hours. To this reaction mixture were added acetic acid (7 mL) and water (7 mL), and this mixture was stirred under same condition for 24 hours. After this reaction mixture was replaced under argon atmosphere, the insoluble material was removed by filtration. To this filtrate was added water and this resulting mixture was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0.629 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH:21]([OH:28])[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:29](O)[CH:30]([OH:32])[CH3:31]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]3([CH3:2])[O:32][CH:30]([CH3:31])[CH2:29][O:3]3)=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[C:15]([C:21]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)=[O:28])[CH:16]=1
Reactant: CC(O)CO
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(O)c2ccncc2)cc1
Product: CC1COC(C)(c2ccc(S(=O)(=O)Nc3ccc(Cl)cc3C(=O)c3ccncc3)cc2)O1

Procedure:
The title compound was prepared using 4-Acetyl-N-[4-chloro-2-(hydroxy-pyridin-4-yl-methyl)-phenyl]-benzenesulfonamide and propane-1,2-diol following the procedure described in the preceding example. MS: m/z 473 M++1).