Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26]CCC)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].O.[C:32]1(C)C=CC(S(O)(=O)=O)=C[CH:33]=1>C(O)(=O)C>[CH3:26][N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:32]=[CH2:33])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: O
Product: C=CC1CN(c2ncc(C(=O)N(C)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 2 h
Yield: 90.5 %

Procedure:
A mixture of 2.84 g (7 mmol) of the same compound II as in Example 70, 1.05 g of p-toluenesulfonic acid monohydrate and 5 ml of glacial acetic acid was stirred at 70° for 2 hours and then worked up as. in Example 5. 2.03 g (=71.5% yield) of pure 4-amino-2-(4-vinyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl)amide were obtained, melting point 203°-204°.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[C:20]=3[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:31][CH:30]=3)=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+:49]>CO>[Na+:49].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[C:20]=3[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:33][CH:34]=3)=[CH:15][C:10]=2[C:11]([O-:13])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCN1CCCC1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from methyl 2-[2-(1-pyrrolidinyl)ethoxy]-5-[3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]benzoate (Part C) by saponification of a stirred solution (about 10% w/v) in 1:1 THF:MeOH with 1 N NaOH (1 equivalent) at room temperature (about 22 h). The reaction mixture was evaporated under reduced pressure and dried in a vacuum oven over P2O5 to provide the acid salt.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:15]([CH3:24])=[C:16]([CH3:23])[C:17]2[N:18]([N:20]=[CH:21][N:22]=2)[N:19]=1.Cl>CN(C)C=O.O>[CH3:24][C:15]1[C:14]([O:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])=[N:19][N:18]2[N:20]=[CH:21][N:22]=[C:17]2[C:16]=1[CH3:23]
Reactant: CC(C)(CO)CS(N)(=O)=O
Reactant: Cc1c(Cl)nn2ncnc2c1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCC(C)(C)CS(N)(=O)=O)nn2ncnc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.3 %

Procedure:
In 30 ml of dimethylformamide was suspended 1.38 g of 60% sodium hydride in oil, followed by addition of 2.51 g of 3-hydroxy-2,2-dimethyl-1-propanesulfonamide and the mixture was stirred under reduced pressure at room temperature for 1 hour. To this was added 2.56 g of 6-chloro-7,8-dimethyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was stirred at room temperature for 3 hours. Following addition of 100 ml of iced water, the reaction mixture was adjusted to pH 6 with 5N-hydrochloric acid and extracted with 3 portions of ethyl acetate-tetrahydrofuran (2:1). The extract was washed with 20 ml of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, elution being carried out with dichloromethane-methanol (30:1). The fractions containing the desired product were pooled and concentrated to provide 0.63 g of the title compound. m.p. 175°-177° C.
Reaction SMILES: CC(CCC[C@H:7]([C@@H:9]1[C@:27]2(C)[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2(C)[C:16](C[C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])C.C1C(NCCN)=C2C(C3C=CN=CC=3C(=O)C2=C(NCCN)C=1)=[O:40]>>[CH3:8][CH2:7][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:27]\[CH2:26]/[CH:25]=[CH:24]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:22][CH2:21][CH2:20][C:18]([OH:19])=[O:40]
Reactant: NCCNc1ccc(NCCN)c2c1C(=O)c1ccncc1C2=O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O

Procedure:
Therefore, the invention provides a liposome formulation of compound BBR 2778 consisting of liposomes comprising phosphatidylcholine, cholesterol and BBR 2778, in a cholesterol/phospholipide 1:2 to 1:7 weight ratio and in a BBR 2778/phospholipide 1:4 to 1:25 weight ratio. Phosphatidylcholine preferably includes residues of fatty acids selected from palmitic, oleic, linoleic, gamma-linoleic, linolenic and stearic acids, and the liposome is formed by a mixture of hydrogenated and non-hydrogenated phosphatidylcholines, having the fatty acids composition indicated, in a 1:2 to 2:1 ratio, more preferably said mixture consists of hydrogenated phosphatidylcholine having melting point of 120° C. and crystallization point of 90° C., and non-hydrogenated phosphatidylcholine having a thermogram as reported in FIG. 5. The hydrogenated and non-hydrogenated phosphatidylcholines, having the above-indicated composition, are commercially available respectively under the name PHOSPHOLIPON® 90 H and PHOSPHOLIPON® 90.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:17]#[N:18])[C:12](=[CH:15][CH:16]=2)[C:13]#[N:14])=[N:5]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=2)[CH:20]=1>>[C:17]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][CH2:2][NH:1][C:30]([C:28]3[NH:27][N:26]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH:29]=3)=[O:31])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14])#[N:18]
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1C#N
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]1
Product: N#Cc1ccc(-c2ccn(CCNC(=O)c3cc(-c4cccnc4)n[nH]3)n2)cc1C#N

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-phthalonitrile (50 mg) and 3-(pyridin-3-yl)-1H-pyrazole-5-carboxylic acid (42 mg) using the method of Example 34(d). Yield 39 mg. 1H-NMR (400 MHz; d6-DMSO): δ 3.73 (q, 2H), 4.40 (t, 2H), 7.02 (d, 1H), 7.21 (s, 1H), 7.49 (m, 1H), 7.88 (s, 1H), 8.11-8.16 (m, 2H), 8.30 (dd, 1H), 8.40-8.58 (m, 1H), 8.48 (d, 1H), 8.56 (d, 1H), 8.99 (s, 1H), 13.78 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:24]([O-])=O)=[C:4]2[C:9]3=[C:10]([O:13][CH2:14][C:15]4([CH2:19][CH2:18][CH2:17][CH2:16]4)[N:8]3[CH:7]=[C:6]([C:20]([NH2:22])=[O:21])[C:5]2=[O:23])[C:11]=1[F:12].S(S([O-])=O)([O-])=O.[Na+].[Na+].O>O.CO>[NH2:24][C:3]1[C:2]([F:1])=[C:11]([F:12])[C:10]2[O:13][CH2:14][C:15]3([CH2:16][CH2:17][CH2:18][CH2:19]3)[N:8]3[C:9]=2[C:4]=1[C:5](=[O:23])[C:6]([C:20]([NH2:22])=[O:21])=[CH:7]3
Reactant: NC(=O)c1cn2c3c(c(F)c(F)c([N+](=O)[O-])c3c1=O)OCC21CCCC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OCC21CCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a suspension of 9,10-difluoro-8-nitro-7-oxo-2,7-dihydrospiro[[1,4]oxazino[2,3,4-ij]quinoline-3,1′-cyclopentane]-6-carboxamide (1 g, 2.7 mmol) in a mixture of water/methanol (1:1 v/v, 30 mL) was added sodium hydrosulfite (Na2S2O4, 3.75 g, 22 mmol). The suspension was refluxed for 5 h until all starting material had disappeared. Upon completion, the reaction mixture was cooled to room temperature and 50 ml of water were added. After 20 minutes, a light yellow solid was collected by filtration and washed with water. The solid was dried under vacuo to give 660 mg (73% yield) of the title compound that was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.Cl.O1CCOCC1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
In 3.5 ml of methanol were dissolved 253 mg of (2R,3R)-2-(2,4-difluorophenyl)-3-[[trans-2-phenyl-1,3-dioxan-5-yl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Example 40, and 0.35 ml of a 4N HCl-dioxane solution were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. To the reaction mixture were added 250 mg of a NAHCO3 powder, and the mixture was stirred for 10 minutes, followed by filtration of the reaction mixture and concentration of the filtrate under reduced pressure. The thus obtained oil was subjected to column chromatography using 5 g of silica gel and eluted with 10% methanol-ethyl acetate to obtain 179 mg (yield: 88%) of the title compound as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1)([CH3:26])[CH3:25]
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: CC(C)N
Product: CC(C)Nc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and isopropylamine (43 mg, 0.73 mmol; 5.0 eq.) as a white solid (8 mg, 15%). HPLC, Rt: 3.09 min. (purity 87.7%). LC/MS, M+(ESI): 365.0, M−(ESI): 363.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:25]([C:21]2[CH:20]=[C:19]([C:12]3[CH:11]=[C:10]4[C:15]([CH2:16][CH:17]([CH3:18])[N:8]([C:6]5[CH:5]=[C:4]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)[N:3]=[C:2]([NH2:1])[N:7]=5)[CH2:9]4)=[CH:14][CH:13]=3)[CH:24]=[CH:23][N:22]=2)=[O:26])[CH2:39][CH2:38][CH2:37]1
Reactant: C1CNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CCC4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61B starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61B, Step 2) and azetidine hydrochloride (Aldrich, Cat. No. 414336). LCMS (M+H)+: m/z=499.2.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[CH3:12][CH2:13][OH:14]>>[CH2:13]([O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5])[CH3:12]
Reactant: COc1cccc(F)c1C=O
Reactant: CCO
Product: CCOc1cccc(OC)c1C=O
Temperature: 55 °C

Procedure:
A mixture of commercially available 2-fluoro-6-methoxybenzaldehyde (3.372 g; 21.90 mmol) and sodium hydroxide NaOH (10.208 g; 255.00 mmol) in EtOH (525 ml) was heated to 55° C. for 1 h. After cooling to rt, the reaction mixture was concentrated under reduced pressure. Water and DCM were added, and the aq. layer was further extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-ethoxy-6-methoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 181.13 g/mol.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH:2]=[CH2:3].[CH2:6]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17]I)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1.CSC.[Cu]Br>[CH2:6]([O:13][C:14](=[O:20])[NH:15][C@H:16]([CH3:19])[CH2:17][CH2:3][CH:2]=[CH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C=CC[Mg]Cl
Reactant: C[C@H](CI)NC(=O)OCc1ccccc1
Agent: [Cu]Br
Solvent: C1CCOC1
Solvent: CSC
Product: C=CCC[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Copper (I) bromide-dimethyl sulfide (1.93 g, 9.4 mmol) was dissolved in distilled THF (24 ml), then was cooled to −78 degrees C. A solution of allyl magnesium chloride (9.4 ml, 2M in THF, Aldrich) was added dropwise, then the solution was stirred for 30 minutes. ((R)-2-Iodo-1-methyl-ethyl)-carbamic acid benzyl ester (1.5 g, 4.7 mmol) in distilled TBF (3 ml) was added dropwise, then the reaction was warmed to −40 degrees C. and was stirred for 2.5 h. The reaction mixture was quenched with aq. sat. NH4Cl (4 ml) at −40 degrees C., warmed to RT and the gray reaction mixture turned sky blue. THF was removed in vacuo. Then, Et2O was added and the reaction mixture was filtered to remove precipitated solids. The solids were washed with additional Et2O. The combined organics were extracted with 10% NH4OH (3×), then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo, then filtered through a plug of silica gel washing with 20% EtOAc/hexanes (100 ml). The solution was concentrated in vacuo, then the resultant colorless oil was used in the next reaction without further purification (0.8 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=C(F)C=3)([CH3:26])[NH:23][C:24](=O)[C:3]=12.C(N(CC)CC)C.Cl.[CH3:42][O:43][NH2:44]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][N:14]=2)[C:5](=[O:21])[N:4]2[C:22]3([CH2:26][CH2:30][CH2:31][CH2:32][CH2:27]3)[NH:23][C:24](=[N:44][O:43][CH3:42])[C:3]=12
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Reactant: CON
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ccncn1)c2=O
Temperature: 25 °C

Procedure:
To a solution of 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 1 g, 2.89 mmol) in chloroform (30 mL) was added triethylamine (1.21 mL, 8.67 mmol) and O-methylhydroxylamine hydrochloride (241 mg, 2.89 mmol). The reaction was stirred at reflux overnight. The resulting mixture was cooled to room temperature and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude was purified via flash column chromatography to afford 8′-chloro-1′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one (Cpd. No. 132).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([N:20]1[C:24]([CH:25]=O)=[CH:23][C:22]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([N:20]1[C:24]([CH2:25][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[CH:23][C:22]([CH2:27][CH:28]([CH3:30])[CH3:29])=[N:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)Cc1cc(C=O)n(C(C)(C)C)n1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3)CC2)n(C(C)(C)C)n1
Yield: 50.1 %

Procedure:
Compound 6 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 2-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C@@H:1]12[O:9][CH2:8][C@@H:6]([O:7]1)[CH:5]=[CH:4][C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33](O)=[O:34].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([Cl:39])[CH:38]=1)[C:33]([O:3][C@@H:2]1[CH:4]=[CH:5][C@H:6]2[CH2:8][O:9][C@@H:1]1[O:7]2)=[O:34]
Reactant: O[C@H]1C=C[C@H]2CO[C@@H]1O2
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1C=C[C@H]2CO[C@@H]1O2)c1cc(Cl)cc(Cl)c1
Yield: 77.7 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-3,4-dideoxy-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.80 g (20.0 mmol) of 3,5-dichlorobenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.48 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 41 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=6:1) to obtain 2.34 g (yield: 77.7%) of 1,6-anhydro-2-O-(3,5-dichlorobenzoyl)-3,4-dideoxy-β-D-erythro-hex-3-enopyranose. This product was recrystallized from a solvent mixture of hexane, diethyl ether, and chloroform.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH3:12]>>[NH2:12][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Product: Nc1nc(Cl)ccc1C(=O)O
Temperature: 135 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A mixture of 2,6-dichloro-nicotinic acid (31 g, 0.14 mol) and 28% aqueous ammonia solution (200 mL) was stirred in a sealed tube for 10 hours at 135° C. This reaction solution was cooled to room temperature, and the excess ammonia gas was removed under a reduced pressure. Water was added to the residue to a total of 1000 mL, the mixture was cooled to 0° C., and citric acid was added to a pH being about 6. The precipitated solids were filtered out to obtain the title compound (12 g, 49%).
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1.CCOCC>[CH:21]1([C:4]([CH:6]2[CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:13])=[O:14])[CH2:10][CH2:11]2)=[O:5])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: Br[Mg]C1CCCCC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(C1CCCCC1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 25.1 g (0.085 mole) of 1-(phenylsulfonyl)-4-piperidinecarboxylic acid ethyl ester in 500 ml of dry tetrahydrofuran cooled to 0° C. and under an atmosphere of nitrogen, was added 95 ml of a 2 molar solution (0.19 mole) of cyclohexylmagnesium bromide in ether. The mixture was stirred for 2 hr at ambient temperature and then was quenched on an icy solution of ammonium chloride. The mixture was extracted with methylene chloride. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a semisolid material. This was recrystallized from ethanol to give 8.50 g (29.8% yield) of title compound as a white, crystalline solid, mp 141°-143° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([OH:16])=O)[CH2:13][CH2:12]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:29].[Br-].[NH3+:31][CH2:32][CH2:33][CH2:34][P+:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O.C(Cl)Cl>[Br-:29].[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1([C:14]([NH:31][CH2:32][CH2:33][CH2:34][P+:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:16])[CH2:12][CH2:13]1)[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [NH3+]CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CC1(C(=O)O)CC1)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(CC1(C(=O)NCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
1-{[(tert-butoxycarbonyl)(methyl)amino]methyl}cyclopropanecarboxylic acid (680 mg, 3.0 mmol) was dissolved in N,N-dimethylformamide (6.8 mL) and treated with N,N-carbonyldiimidazole (571 mg, 3.52 mmol). The mixture was stirred at room temperature for 30 minutes. To the solution was added (3-ammoniopropyl)(triphenyl)phosphonium dibromide (1.93 g, 4.00 mmol). The mixture was stirred overnight at room temperature and then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude title compound. The crude product was purified on a silica gel column eluting with a gradient of 0-20% methanol with methylene chloride to isolate the title compound (810 mg, 40%, 91% pure).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].[CH:24](OCC)(OCC)[O:25][CH2:26][CH3:27]>>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([N:1]=[CH:24][O:25][CH2:26][CH3:27])=[C:3]([S:21]([CH3:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CCOC(OCC)OCC
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Product: CCOC=Nc1c(S(C)=O)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.92 g) in triethyl orthoformate (100 ml) was heated under reflux for two hours, then stirred at 20° C. for 16 hours and evaporated. Trituration with boiling hexane gave 1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-5-[(ethoxymethylene)amino]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (4.05 g), m.p. 93-95° C. By proceeding in a similar manner the following compound was prepared:
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH2:14][C:13]([C:10]1[CH:9]=[CH:8][C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[CH:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1ccc(C2CCCCC2)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(C2CCCCC2)cc1
Temperature: 0 °C

Procedure:
50 Parts of 4′-cyclohexylacetophenone was dissolved in 250 parts of chloroform, After cooled to 0° C., 40 parts of bromine was added dropwise thereto. After the reaction, the mixture was washed with 5% aqueous NaHSO3 solution, with 2% aqueous K2CO3 solution and with water, organic layer obtained was concentrated to obtain 60 parts of 2-bromo-4′-cyclohexylacetophenone.