Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].ClCCl.CCN(C(C)C)C(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[O:8])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13]
Reactant: CN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc(N)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a suspension of 4-amino-3-(trifluoromethoxy)benzoic acid (900 mg, 4 mmol) in dichloromethane (60 ml) TBTU (1.9 g, 6 mmol) and DIPEA (1.04 ml, 6 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Then 1-methylpiperidin-4-amine (513 mg, 4.5 mmol) was added and the reaction was stirred for an additional 3 h. The solution was washed with water and the organic phase was dried over anhydrous Na2SO4. The crude was purified by flash chromatography (DCM/MeOH/NH3aq, 9:1:0.5), to give the title compound (900 mg, 71%), as an orange solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CC(C)([O-])C.[K+].Br[CH2:24][C:25]#[N:26].Cl>CS(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH2:24][C:25]#[N:26])=[O:8]
Reactant: N#CCBr
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OCC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene-2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:959 (1992)] in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by bromoacetonitrile (878 μL, 12.58 mmol). The mixture is stirred at room temperature for 1.5 hours, then poured into ethyl acetate and 1N HCl. The organic layer is washed with 1N HCl, followed by several portions of brine, and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 413 mg. additional crop of 112 mg can be obtained from the mother liquor, mp 159.5°-160° C.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C12BC(CCC1)CCC2.O1CCCC1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C@H:31]([O:33][CH2:34][C@H:35]1[CH2:37][O:36]1)[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.ClCCl.O1CCCC1>[O:36]1[CH2:37][C@@H:35]1[CH2:34][O:33][C@@H:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])[CH3:32]
Reactant: C[C@@H](OC[C@H]1CO1)c1ccccc1Br
Reactant: C=CCCCC(=O)OC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CCCCCc1ccccc1[C@@H](C)OC[C@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To methyl 5-hexenoate (608 mg) was added 0.5 M 9-bora bicyclo[3.3.1]nonane-tetrahydrofuran solution (9.5 ml) under ice-cooling and the mixture was stirred overnight at room temperature. The reaction mixture was added dropwise to a suspension of tetrahydrofuran (10 ml), (2R)-2-[[(1R)-1-(2-bromophenyl)ethoxy]methyl]oxirane (1.06 g) obtained in Example 1, Step 1, tri-potassium phosphate (1.32 g), [bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (170 mg) and the mixture was heated under reflux for 7 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1) to give the title compound (621 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (20 mg, 0.042 mmol), 3-fluoro benzyl bromide (5.5 μL, 0.045 mmol, 1.1 equiv), and potassium carbonate (11.7 mg, 0.09 mmol) in dimethylformamide (0.6 mL) was stirred at room temperature for 16 h. The solvents were removed in vacuo and the residue purified by column chromatography to afford 15.2 mg (63%). Mass spec.: 580.04 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1/[CH:21]=[CH:22]\[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:10])[C:2]1C=CC=C[CH:3]=1.Cl.[H][H]>[Pd].CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:10])[CH:2]=[CH2:3]
Reactant: [H][H]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](/C=C\c2cccnc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1cccnc1
Yield: 93.5 %

Procedure:
A solution of (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(Z)-2-(pyridin-3-yl)vinyl]pyrrolidine (4.13 g), conc. hydrochloric acid (1.71 ml), 10% palladium on carbon (50% wet) (2.0 g) in methanol (80 ml) was stirred for 4 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was evaporated in vacuo. The resulting residue was dissolved in a mixture of tetrahydrofuran (40 ml) and water (40 ml). To the solution was added dropwise a solution of allyl chloroformate (1.52 ml) in tetrahydrofuran (5 ml) with stirring, while keeping the pH to 8~10 with 4N aqueous sodium hydroxide under ice-cooling. The mixture was stirred at the same condition for 1 hour. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (200 ml). The organic layer was washed with saturated sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[2-(pyridin-3-yl)ethyl]pyrrolidine (3.40 g).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CN(C)C=O>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: C1COCCN1
Reactant: Clc1nccnc1Cl
Solvent: CN(C)C=O
Product: Clc1nccnc1N1CCOCC1

Procedure:
A mixture of 2,3-dichloropyrazine (5 g., 0.034 mmole), morpholine (5.8 g., 0.067 mmole), and 50 ml. of dimethylformamide are heated at 90°-120° C. for 6-14 hours, in an atmosphere of nitrogen. The reaction mixture is cooled and evaporated to dryness at a water-bath temperature of 55° C. A chloroform solution of the residue is extracted twice with 0.1 M sodium hydroxide, dried over magnesium sulfate and evaporated to leave the product.
Reaction SMILES: [I:1][C:2]1[C:6]([CH2:7]O)=[CH:5][N:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.P(Br)(Br)[Br:13]>ClCCl>[Br:13][CH2:7][C:6]1[C:2]([I:1])=[N:3][N:4]([CH:9]([CH3:11])[CH3:10])[CH:5]=1
Reactant: CC(C)n1cc(CO)c(I)n1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(C)n1cc(CBr)c(I)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A solution of (3-iodo-1-isopropyl-1H-pyrazol-4-yl)methanol (0.63 g, 2.37 mmol) in 20 mL dichloromethane was cooled to 0° C. Phosphorus(III)bromide (0.67 mL, 7.10 mmol) was added to the solution and the mixture was stirred 30 minutes at 0° C., 1 hour at room temperature, and then quenched with 50 mL water and stirred 15 minutes at room temperature. The mixture was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (10-80% ethyl acetate/heptanes, 25 g silica gel) to yield 400 mg of 4-(bromomethyl)-3-iodo-1-isopropyl-1H-pyrazole as a colorless solid. +APCI (M+H) 329.0; 1H NMR (400 MHz, CDCl3, δ): 7.42 (s, 1H), 4.47 (spt, J=6.7 Hz, 1H), 4.35 (s, 2H), 1.50 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.O1CCCOB1[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[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.O1CCOCC1>[Cl:8][C:6]1[CH:7]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: c1cncc(B2OCCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Clc1cc(-c2cccnc2)c2nccn2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A microwave vial was charged with a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (1.06 g, 4.56 mmol), 3-(1,3,2-dioxaborinan-2-yl)pyridine (0.743 g, 4.56 mmol), dioxane (14 mL), and tetrakis(triphenylphosphine)palladium(0) (0.527 g, 0.456 mmol), and K3PO4 (2.90 g, 13.68 mmol) (2.0 M water solution) was stirred at room temperature for 5 min. under nitrogen. The resulting mixture was heated to 100° C. for 8 h in microwave. The reaction mixture was cooled to room temperature, quenched with water, and diluted with EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by BIOTAGE® (20-60% EtOAc/hex, 1.5 L) to the product (0.39 g, 37%). LC/MS: Rt=1.07 min. LC/MS (Condition A): 231.09/233.09.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][N:22]3C(=O)C4=CC=CC=C4C3=O)[CH2:16][CH2:15]2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=1.O.NN>>[NH2:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][N:14]([CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCN(C(c2ccccc2)c2cccnc2)CC1
Agent: NN
Solvent: O
Product: NCCN1CCN(C(c2ccccc2)c2cccnc2)CC1
Yield: 98 %

Procedure:
The title compound was prepared in a yield of 98% in a similar manner to that described in Preparation 15' by reacting 4-[α-(3-pyridyl)benzyl]-1-(2-phthalimidoethyl)piperazine (prepared as described in Preparation 49') and hydrazine hydrate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[C:3]=1[CH2:17]O.S(Cl)([Cl:21])=O>>[Cl:21][CH2:17][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CO
Product: Cc1onc(-c2ccc(C(F)(F)F)cc2)c1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 5-methyl-3-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (1.75 g) and thionyl chloride (5.0 ml) was stirred at 0° C. for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated to give 4-chloromethyl-5-methyl-3-(4-trifluoromethylphenyl)isoxazole (1.50 g, yield 80%). The crystals were recrystallized from diisopropyl ether. melting point: 91–92° C.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17]([CH2:20][C:21]5[CH:22]=[C:23]6[C:28](=[CH:29][CH:30]=5)[N:27]=[CH:26][CH:25]=[CH:24]6)=[CH:18][N:19]=4)[N:16]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[N:27]1[C:28]2[C:23](=[CH:22][C:21]([CH2:20][C:17]3[N:15]4[N:16]=[C:11]([N:8]5[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]5)[CH:12]=[CH:13][C:14]4=[N:19][CH:18]=3)=[CH:30][CH:29]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: c1cnc2ccc(Cc3cnc4ccc(N5CCC6(CC5)OCCO6)nn34)cc2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCN(c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
6-[6-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-imidazo[1,2-b]pyridazin-3-yl methyl]-quinoline (Example 110, 132 mg, 0.329 mmol) was dissolved in THF (493 μL). A 2 M HCl solution (493 μL) was then added and the RM was stirred at rt for 22 h and then at 40° C. for 3 h. A basic work up (KHCO3) followed by a crystallization in Et2O/isopropanol afforded the title compound as white crystals (tR 1.33/1.48 min (conditions 6), MH+=358.1, 1H-NMR in DMSO-d6: 8.84 (m, 1H); 8.29 (m, 1H); 7.90 (m, 3H); 7.72 (m, 1H); 7.49 (m, 2H); 7.22 (d, 1H); 4.42 (s, 2H); 3.85 (m, 4H); 2.35 (m, 4H)).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][CH:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C1CCC(Nc2cccc3cnccc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: c1cc(NC2CCC(NC3CC3)CC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.7 %

Procedure:
4-(5-Isoquinolylamino)-1-cyclohexanone (intermediate 4) (60 mg) and cyclopropylamine (30 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was. stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile]. A saturated aqueous sodium hydrogencarbonate solution (2 ml) was then added to fractions containing respective compounds, followed by extraction with chloroform-propanol (3/1). The organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure to give an anti-form compound (11 mg) and a syn-form compound (12 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1C=CC(S([CH2:28][N+:29]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+]>COCCOC.CCO>[CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH:11]([C:28]#[N:29])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CC2CC(O)C(C1)N2Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1CC2CC(O)C(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a mixture of 8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octan-3-one (1.2 g) and TosMIC (1.95 g) in a mixture of 20 mL of DME and 0.5 mL of absolute EtOH was added t-BuOK (3.5 g) portionwise while keeping the temperature between 5 and 10° C. The resulting mixture was stirred at room temperature 30 min, and then warmed to 35-40° C. for another 30 minutes. The suspension thus obtained was cooled to room temperature, and the precipitate (TosK) was removed and extracted with DME. The combined DME solutions were concentrated to 3 mL and purified by silica gel chromatography to give 8-benzyl-6-hydroxy-8-azabicyclo[3.2.1]octane-3-carbonitrile 150b (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][C:17]([O:29][CH3:30])=[N:16]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:14])[F:13])=[O:39])=[CH:4][C:3]=1[N:15]1[C:19]([O:20][CH2:21][C:22]([F:27])([F:28])[C:23]([F:25])([F:26])[F:24])=[CH:18][C:17]([O:29][CH3:30])=[N:16]1
Reactant: COc1cc(OCC(F)(F)C(F)(F)F)n(-c2cc(SCC(F)(F)F)c(C)cc2F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OCC(F)(F)C(F)(F)F)n(-c2cc(S(=O)CC(F)(F)F)c(C)cc2F)n1
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
0.16 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.079 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous potassium carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.13 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-methoxy-5-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([C:7]1[N:8]=[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:10][CH:11]=1)C.[OH-].[K+].Cl>C(O)C.C(OCC)(=O)C>[CH2:12]([C:9]1[S:10][CH:11]=[C:7]([CH2:2][C:1]([OH:4])=[O:3])[N:8]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)O
Reactant: CCCCCCCCCCCCCc1nc(CC)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCc1nc(CC(=O)O)cs1

Procedure:
Ethyl-2-tridecyl-thiazole acetate (2.13 g, 6.35 mmol) and potassium hydroxide (0.39 g, 6.98 mmol) were refluxed overnight in ethanol (200 mL). The mixture was then acidified with 1M HCl and the precipitate filtered to give a solid which was dissolved in ethyl acetate and washed with brine, dried (MgSO4), filtered concentrated, and triturated with hexanes. The solid was filtered and air dried to yield 0.75 g, 37%. % C,H,N(found): C, 66.16; H, 9.50; N 3.99.
Reaction SMILES: CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1.Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].C(OCC)(=O)C.O>[CH2:21]([N:23]([CH2:24][CH3:25])[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH3:22]
Reactant: CCNCC
Reactant: Brc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccnc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a mixture of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene (521 mg, 0.90 mmol), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (311 mg, 0.30 mmol), sodium t-butoxide (2.16 g, 23 mmol) and anhydrous toluene (37 ml) were added 3-bromopyridine (1.5 ml, 15 mmol) and diethylamine (1.9 ml, 18.0 mmol). The mixture was heated to 70° C., and the mixture was stirred for 3 hrs and at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The mixture was stirred, stood still and partitioned. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1→2:1) to give N,N-diethylpyridin-3-amine (820 mg, yield 36%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[N:11][C:12]([N:16]2C(C)=CC=C2C)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.O.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[C:10]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[N:11][C:12]([NH2:16])=[N:13][C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCCCCCCCCc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCc1nc(N)nc(C)c1OCc1ccccc1

Procedure:
To stirred solution containing 269 mg (0.52 mmol) of 5-(benzyloxy)-2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-hexadecyl-6-methylpyrimidine in 10 mL of ethanol were added 723 mg (10.40 mmol) of hydroxylamine hydrochloride. The reaction mixture was then stirred at reflux during 5 h. The reaction mixture was then poured into 70 mL of water and then basified to a pH 9-10 with a 1N NaOH aqueous solution. The mixture was extracted with two 70-mL portions of ethyl acetate. The combined organic layer was washed with a 70-mL portion of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 3:2 hexanes-ethyl acetate afforded the expected product as a colorless oil: yield 231 mg (100%); silica gel TLC Rf 0.25 (1:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 0.85 (t, 3H, J=6.8 Hz), 1.26 (m, 26H), 1.61 (quint, 2H, J=7.2 Hz), 2.28 (s, 3H), 2.56 (dd, 2H, J=7.6, 7.6 Hz), 4.72 (s, 2H), 5.03 (br s, 2H) and 7.35-7.40 (m, 5H); 13C NMR (CDCl3) δ 14.08, 18.91, 22.66, 28.42, 29.33, 29.41, 29.52, 29.63, 29.63, 29.63, 29.63, 29.67, 29.67, 29.67, 29.67, 29.73, 31.90, 75.88, 127, 88, 128.24, 128.24, 128.58, 128.58, 136.79, 142.87, 158.79, 161.12 and 164.87; mass spectrum (APCI), m/z 440.3646 (M+H)+ (C28H46N3O requires 440.3641).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH:18]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:20][C:21]1([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][N:24]2[CH2:25][CH2:26][C:21]([OH:20])([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:22][CH2:23]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccsc1
Product: OC1(CCCc2ccccc2)CCN(CC2CN(Cc3ccccc3)CC2c2ccsc2)CC1

Procedure:
The title compound was prepared from 1-benzyl-3-(SR)-formyl-4-(SR)-thiophen-3-ylpyrrolidine and 4-hydroxy-4-(3-phenylpropyl)piperidine by procedures described in Example 1.