Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:16][CH3:17]>>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:21]2[CH2:22][CH2:23][N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCCN1CCNCC1
Agent: Br
Product: CCCN1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-N-propylpiperazine dihydrobromide, which is commercially available from, for example, Sigma-Aldrich Corporation. m/z (ES+) M+1=273.2; HPLC tR=1.49 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J=7.6 Hz, 2H), 7.20-7.15 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.70-3.55 (m, 4H), 2.49-2.35 (m, 5H), 2.33-2.27 (m, 2H), 1.99-1.91 (m, 1H), 1.65 (dt, J=9.2, 4.7 Hz, 1H), 1.50 (sextet, J=7.5 Hz, 2H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][NH:2]1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][N:2]=1
Reactant: O=c1[nH]ncc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nncc2ccccc12
Temperature: 80 °C
Yield: 85 %

Procedure:
One mole equivalent (250 g) of 1 (2H)-phthalazinone and 3.8 mole equivalents (775 g) of phosphorus oxychloride were charged into a 3-L, 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 80° C., maintained at that temperature for 30 minutes, and then the heat source was removed. Thin layer chromatographic analysis indicated that conversion to 1-chlorophthalazine was complete. The mixture was allowed to cool to room temperature, and 1.6 L of hexanes was added. The resulting slurry was stirred for several minutes, and the hexane layer was decanted. Addition of hexanes and decantation was repeated two more times. Then 1.6 L of tetrahydrofuran was added; as the solution was stirred, an off-white precipitate formed. The solid was isolated by filtration and washed with 250 mL of cold tetrahydrofuran to afford an 85-100% yield of 1-chlorophthalazine, the desired product, as an off-white powder that could be dried and characterized.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][CH:18]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=3)=[CH:26][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl.CSC.B(F)(F)F.CCOCC>O>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][CH:18]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[CH:26][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1
Reactant: COC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(OCc2ccccc2)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)C(Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)SCCc1ccc(O)cc1
Yield: 64.5 %

Procedure:
To a solution of methyl 2-({2-[4-(benzyloxy)phenyl]ethyl}thio)-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate (477 mg, 0.8 mmol) and 15 ml dichlormethane, dimethyl sulfide (239 mg, 3.8 mol) and boron trifluoride etherate (545 mg, 3.8 mmol) were added. After 18 hours of stirring water was added to the reaction. The phases were separated and the aqueous phase was extracted twice with dichlormethane. The organic phases were pooled, dried (MgSO4) and evaporated under reduced pressure. 274 mg of the desired product (yield 67%) was obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5]=2[NH:4][N:3]=1.Br[CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:3]([CH2:24][CH2:25][Cl:26])[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][CH2:13][CH3:14])[C:7](=[O:15])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCCBr
Reactant: CCCn1c(=O)c2c(N)n[nH]c2n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(N)n(CCCl)nc2n(Cc2ccccc2)c1=O
Yield: 60.2 %

Procedure:
A mixture of 3-amino-7-benzyl-5-propylpyrazolo[3,4 -d]pyrimidine-4,6(5H,7H)-dione (11 g), 1-bromo-2-chloroethane (8.0 g) and potassium carbonate (7.0 g) was stirred in DMF (120 ml) at 50°-60° C. for 12 hours. The reaction mixture was concentrated to dryness, then the concentrate was extracted with chloroform/water. The chloroform layer was washed with water, dried and concentrated. The resultant brown syrup was purified by flash chromatography (silica gel 100 g, chloroform). The resultant syrup was crystallized from isopropylether to afford colorless needles (8.0 g, 60%), m.p. 126° to 128° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>O1CCCC1>[CH3:14][C:12]1[C:11](=[O:15])[NH:9][C:5]2[C:4]([N:10]=1)=[CH:3][C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=2
Reactant: Cc1cc(N)c(N)cc1C
Reactant: CCOC(=O)C(C)=O
Solvent: C1CCOC1
Product: Cc1cc2nc(C)c(=O)[nH]c2cc1C
Temperature: 25 °C

Procedure:
4,5-Dimethyl-o-phenylenediamine (10.0 g., 0.073 mol.) was dissolved in tetrahydrofuran (200 ml.) and ethyl pyruvate (12.75 g., 0.11 mol.) added. The reaction mixture was stirred at room temperature for eighteen hours, during which time a white solid precipitated and was collected by filtration (13.35 g.). Recrystallization from methanol-chloroform gave fine white needles. (12.65 g., m.p. 306°-308°, 92%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:26])[CH:6]=[C:7]([CH2:24][CH3:25])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]([Cl:38])=[CH:35][CH2:36]Cl>CN(C)C=O>[CH2:24]([C:7]1[CH:6]=[C:5]([O:26][CH2:36][CH:35]=[C:34]([Cl:38])[Cl:33])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][N:15]=1)[CH3:25]
Reactant: ClCC=C(Cl)Cl
Reactant: CCc1cc(O)cc(CC)c1OCCCOc1ccc(C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCOc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 0.45 g of 3,5-diethyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]phenol and 0.17 g of potassium carbonate, to which a solution of 0.18 g of 1,1,3-trichloropropene dissolved in 5 ml of N,N-dimethylformamide was added dropwise, while stirring at room temperature. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice-water, and extracted twice with 100 ml of diethyl ether. The combined diethyl ether was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude produce was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-diethyl-4-[3-(5-trifluoromethyl-2-pyridyloxy)propyloxy]-1-(3,3-dichloro-2-propenyloxy)benzene (60% yield), nD20.0 1.5192.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.[OH-].[K+].[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14]1>O.C(O)C>[O:13]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:3][C:2](=[O:1])[CH3:10])[CH2:14]1
Reactant: O=CC1CCOC1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)C=CC1CCOC1

Procedure:
Dimethyl (2-oxopropyl)phosphonate (32.06 g, 193 mmol) is added to a chilled (ice-bath) solution of potassium hydroxide (10.83 g, 193 mmol) in water (30 ml) and ethanol (170 ml) and the mixture is stirred. Tetrahydrofuran-3-carboxaldehyde (50% wt. % solution in water, 25 ml, 138 mmol) is added dropwise and the reaction mixture is stirred at 5° C. for 10 minutes. The cooling bath is removed and the mixture is stirred at room temperature for 7 hours. Most of the solvent is removed in vacuo, water (100 ml) and diethyl ether (200 ml) are added, the mixture is poured into a separating funnel and the organic phase collected. The aqueous phase is extracted three times with diethyl ether, and the organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and the filtrate is evaporated in vacuo. The residue is further purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to give 4-(tetrahydrofuran-3-yl)-3-buten-2-one as a pale yellow liquid.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[NH:14][N:15]=[CH:16][C:8]=2[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[Br:5][C:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[N:14]([CH:24]([CH3:26])[CH3:25])[N:15]=[CH:16][C:8]=2[CH:7]=1
Reactant: CC(C)I
Reactant: Cn1c(=O)c(Br)cc2cn[nH]c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1ncc2cc(Br)c(=O)n(C)c21
Yield: 46.5 %

Procedure:
At RT, to a solution of 5-bromo-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one acetic acid adduct (202 mg, 0.701 mmol) in THF (10 mL) was treated with potassium carbonate (290 mg, 2.10 mmol) and 2-iodopropane (0.50 mL, 5.0 mmol). It was heated to reflux for 48 h. The reaction mixture was then treated with water and extracted 2×20 mL EtOAc, dried over MgSO4, filtered and concentrated in vacuo (rotovap). The crude residue was purified on the ISCO (12 g column, 25-90% EtOAc:Hexanes) affording the title compound (88 mg) as a white amorphous solid in >95% purity. MS (ESI, pos.ion) m/z: 270.0/272.0 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:19]1([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:24][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Fc1cccc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1nccc2nc(-c3c(F)cccc3Cl)sc12)C1CC1
Yield: 30.4 %

Procedure:
A mixture of 4-chloro-2-(2-chloro-6-fluoro-phenyl)-thiazolo[5,4-c]pyridine (0.050 g, 0.17 mmol), cyclopropanecarboxamide (0.016 g, 0.18 mmol), Pd2(dba)3 (0.008 g, 0.009 mmol), XantPhos (0.010 g, 0.017 mmol) and cesium carbonate (0.139 g, 0.43 mmol) in dioxane (1.7 mL) was degassed with nitrogen then subjected to microwave irradiation at 170° C. for 60 minutes. Further cyclopropanecarboxamide (0.006 g, 0.08 mmol), Pd2(dba)3 (0.010 g, 0.010 mmol) and XantPhos (0.012 g, 0.021 mmol) were added. The mixture was degassed with nitrogen then subjected to microwave irradiation at 200° C. for 90 minutes. Water and DCM were added and the resulting mixture was filtered through Celite®. The layers of the filtrate were separated via a phase separator and the organic phase concentrated under reduced pressure. The residue was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were combined, concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography (0-30% EtOAc in DCM) to give the desired compound as an off-white solid (0.018 g, 30% yield). 1H NMR (300 MHz, DMSO-d6): δ 11.40 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 7.92 (d, J=5.6 Hz, 1H), 7.69 (dd, J=8.3, 6.1 Hz, 1H), 7.59-7.58 (m, 1H), 7.52-7.49 (m, 1H), 2.13-2.03 (s, 1H), 0.91-0.90 (m, 4H). LCMS (Method D): RT=3.36 min, m/z: 348 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[C:40]1([CH:46]2[CH2:48][CH:47]2[NH2:49])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CN(C=O)C>[C:40]1([CH:46]2[CH2:48][CH:47]2[NH:49][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:20])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: NC1CC1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CC4c4ccccc4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (21.8 mg, 0.0617 mmol) in dichloromethane (1 ml) with a drop of DMF was added oxalyl chloride (2M in dichloromethane) (0.0370 ml, 0.0740 mmol). Gas evolution was observed. The mixture was stirred for 0.5 hours at ambient temperature. Triethylamine (0.0430 ml, 0.3085 mmol) and 2-phenylcyclopropanamine, hemisulfate (28.11 mg, 0.1542 mmol) were added sequentially to the mixture. The mixture was stirred for 17 hours at ambient temperature. The crude mixture was purified on silica gel (MeOH in dichloromethane gradient) to provide 25.9 mg of the title compound as a thin film (90%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:12][O-:13].[Na+]>O1CCOCC1.CO.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([O:13][CH3:12])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(Cl)c(C(=O)O)n1
Temperature: 85 °C
Reaction time: 14 h

Procedure:
To a solution of 3,6-dichloropyridine-2-carboxylic acid (7.10 mmol 1.36 g) in dioxane (15 mL) was added sodium methoxide (21.31 mmol 1.15 g) in methanol dropwise. The mixture was stirred at 85° C. for 14 h, cooled to rt, and diluted with ethyl acetate and aqueous HCl. The organic layer was washed with water and brine, and dried (MgSO4). Removal of the solvent provided 3-chloro-6-methoxypyridine-2-carboxylic acid which was used in the next step without further purification.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:14])[CH:11](Br)[CH3:12])[CH:8]=[CH:9][C:2]1=2.C(O)C.[C:18]1([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:14])[CH:11]([NH:28][CH2:27][CH2:26][CH2:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:12])[CH:8]=[CH:9][C:2]1=2
Reactant: NCCCCc1ccccc1
Reactant: CC(Br)C(O)c1ccc2c(c1)CCS2
Solvent: CCOCC
Solvent: CCO
Product: CC(NCCCCc1ccccc1)C(O)c1ccc2c(c1)CCS2

Procedure:
4 gr of 1-(2,3-dihydro-5-benzo[b]thienyl-2-bromo-1-propanol, 100 ml of ethanol and 20 gr of 4-phenylbutylamine are refluxed for 5 hours. The solvent and excess amine are evaporated in vacuo and the residue obtained is treated with ether. The solid is recrystallized from a mixture of methanol and ether, and the corresponding free base is obtained by treatment with a diluted NaOH solution and recrystallized from acetone. 1.05 gr of final product are so obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.C1C2CCC3C=CC=CC=3SC=2C=C(C(O)=O)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([CH2:16][OH:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C=C2
Agent: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2
Product: OCc1ccc2c(c1)Sc1ccc(F)cc1C=C2

Procedure:
Repeat the process of Example 1, substituting an equivalent quantity of 8-fluorodibenzo[b,f]thiepin-3-carboxylic acid for the 10,11-dihydrodibenzo[b,f]thiepin-3-carboxylic acid, to obtain the title product (m.p., 123°-125° C.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([O:24][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31][O:26]3)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:13]=2)[CH:5]=1
Reactant: CCCCCC(O)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCCCCC(OC1CCCCO1)c1cccc(OCc2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 67 %

Procedure:
To a solution of methyl-3-[[3-(1-hydroxyhexyl)phenoxy]methyl]benzoate (2.2 g), dihydropyran (2.3 ml) and ethyl ether was added a catalytic amount of para-toluene sulfonic acid. The reaction was stirred at room temperature for four days. The ethyl ether was removed in vacuo and the remaining oil was purified by HPLC on silica gel using 7:93 ratio of ethyl acetate/hexanes as an eluent (1.8 g., 67% yield).
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)([OH:15])[CH2:10]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[ClH:1].[F:25][C:22]([F:23])([F:24])[C:18]1[CH:17]=[C:16]([C:11]2([OH:15])[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH:21]=[CH:20][CH:19]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: OC1(c2cccc(C(F)(F)F)c2)CCCNC1
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of gaseous hydrogen chloride in ethyl acetate was added dropwise to a solution of 64 g of 1-benzyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-ol in 100 ml of ethyl acetate until the pH was acidic and the mixture was vacuum filtered. The recovered product was washed with ethyl acetate and was dried under reduced pressure to obtain 62.5 g of 1-benzyl-3-(3-trifluoromethyl-phenyl)-piperidine-3-ol hydrochloride which sublimed towards 240° C. A suspension of 60 g of the said hydrochloride in 2.4 liters of ethanol was admixed with 12 g of activated carbon containing 10% by weight of palladium hydroxide and 4.2 liters of hydrogen was bubbled therethrough at 20° C. in 2 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was crystallized from 100 ml of methanol and the mixture was vacuum filtered at 5° C. The recovered product was washed with iced methanol and dried at 35° C. to obtain 43.6 g of 3-(3-trifluoromethyl-phenyl)-piperidine-3-ol hydrochloride melting at 210° C.
Reaction SMILES: [CH3:1][CH:2]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][CH:2]([N:8]([CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[S:23]([CH3:22])(=[O:25])=[O:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCC(C)NCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCCC(C)N(Cc1cccnc1)S(C)(=O)=O

Procedure:
A 3.1 g. portion of 3-(1-methylhexylaminomethyl)pyridine was dissolved in dichloromethane with stirring, and to it were added 2.1 g. of potassium carbonate and 1.16 ml. of methanesulfonyl chloride with cooling in an ice bath. The mixture was stirred at ambient temperature for 4 days. The reaction mixture was then extracted twice with 15 ml. portions of water, and the organic layer was dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was dissolved in ethyl acetate and purified by chromatography over silica gel in ethyl acetate. The product-containing fractions were combined to obtain 1.7 g. of the desired product. Elemental analysis:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([NH:19][NH:20][C:21](=[O:34])[CH:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:24][CH2:25][Cl:26])=O)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1>P(Cl)(Cl)(Cl)=O>[Cl:26][CH2:25][CH2:24][CH2:23][CH:22]([C:21]1[O:34][C:17](/[CH:16]=[CH:15]/[C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:19][N:20]=1)[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1
Reactant: COc1cc(/C=C/C(=O)NNC(=O)C(CCCCl)c2ccc(Cl)cc2)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(/C=C/c2nnc(C(CCCCl)c3ccc(Cl)cc3)o2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 5-chloro-2-(4-chlorophenyl)pentanoic acid N′-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazide (4.67 g) in phosphorus oxychloride (15 mL) was stirred at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and saturated sodium bicarbonate water were added to the resulting residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate) to obtain 1.90 g of the title compound. The property value of the compound is as follows. ESI-MS; m/z 483 [M++H].
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])O.[Na+].[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]#[N:24])=[CH:12][N:11]=1>C(O)C.O>[NH2:9][C:10]1[N:15]=[C:14]([NH2:16])[C:13]([O:17][C:18]2[C:19]([CH:28]([CH3:30])[CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[C:23]([NH:2][OH:3])=[NH:24])=[CH:12][N:11]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C#N
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(=N)NO
Yield: 82.8 %

Procedure:
The benzamidination carried out in this step follows the procedure reported by Meyer et al., Synthesis 2003, 6, pp. 899-905. To a stirred mixture of hydroxylamine hydrochloride (0.099 g, 1.43 mmol) and sodium hydrogen carbonate (0.119 g, 1.42 mmol) in ethanol (1.4 ml) and water (0.3 ml) was added 5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.385 g, 1.29 mmol) and the mixture heated at reflux for 5 hours. A second portion of hydroxylamine hydrochloride (0.049 g, 0.71 mmol) and sodium hydrogen carbonate (0.060 g, 0.71 mmol) was added. After a further 2 hours the mixture was cooled, concentrated in vacuo, then diluted with water (10 ml) and extracted with ethyl acetate. The combined organic extracts were washed with brine then dried (MgSO4), filtered and concentrated in vacuo to yield 5-(2,4-diamino-pyrimidin-5-yloxy)-N-hydroxy4-isopropyl-2-methoxy-benzamidine (355 mg) as a yellow foam. This material was used directly without further purification.