Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:25])[CH:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:26]([O:30]C)(=[O:29])[CH:27]=[CH2:28]>CO.C(COC)OC>[CH2:12]([C:11]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:10](=[O:25])[CH:9]=[CH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:28][CH2:27][C:26]([OH:30])=[O:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C=Cc1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1
Reactant: C=CC(=O)OC
Solvent: COCCOC
Solvent: CO
Product: O=C(O)CCC(Cc1ccccc1)(C(=O)C=Cc1ccc(Cl)cc1)c1ccccc1
Reaction time: 96 h

Procedure:
Triton B (2 ml., 40% in MeOH) is added to a stirred solution of 1-(p-chlorophenyl)-4,5-diphenyl-1-penten-3-one (17.33 g., 0.05 mole) in glyme (200 ml.) followed by addition of methyl acrylate (4.73 g., 0.055 mole) in glyme (50 ml.). The solution is stirred for 96 hours and the solvent is removed under reduces pressure. The residue is dissolved in methanol (500 ml.) and a 20% sodium hydroxide solution (25 ml.) is added. After an additional 24 hours, the methanol is evaporated in vacuo and the residue is dissolved in water. Extraction with ether removes unreacted ketone. Acidification produces 16.18 g., m.p. 160°-170°C. when collected and air-dried. Recrystallization from butyl chloride gives material with m.p. 173°-176°C.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C1C(=O)N([Br:21])C(=O)C1.O>CN(C=O)C>[Br:21][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[S:2]([F:10])([F:11])([F:12])([F:13])[F:1]
Reactant: Nc1cccc(S(F)(F)(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Br)c(S(F)(F)(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
To a solution of 3-(pentafluoro-λ6-sulfanyl)aniline (13.46 g, 61.4 mmol) in DMF (123 ml) stirred in a 500 mL round-bottomed flask in an ice bath under a nitrogen atmosphere, NBS (12.02 g, 67.6 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 4 hr. The reaction was worked up by the addition of H2O and extracted with EtOAc (2×100 mL). The combined organic layer was washed with H2O and brine. The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by CombiFlash Rf system eluted with a gradient up to 20% EtOAC/hexanes of EtOAc on a 120 g column to afford the desired 4-bromo-3-(pentafluoro-λ6-sulfanyl)aniline (11 g, 36.9 mmol, 60.1% yield).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:18]=[C:17]2[C:13]([CH2:14][CH2:15][C:16]2=O)=[CH:12][CH:11]=1>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[CH3:1][C:2]([S@:5]([N:7]=[C:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([C:9]([F:8])([F:20])[F:21])[CH:18]=2)[CH2:14][CH2:15]1)=[O:6])([CH3:4])[CH3:3]
Reactant: O=C1CCc2ccc(C(F)(F)F)cc21
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N=C1CCc2ccc(C(F)(F)F)cc21
Temperature: 75 °C

Procedure:
To a stirred solution of (R)-2-methylpropane-2-sulfinamide (578 mg, 4.77 mmol) and 6-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (1000 mg, 5.00 mmol) in THF (4 mL) at rt was added tetraethoxytitanium (1.88 mL, 9.08 mmol). The reaction mixture was heated at 75° C. overnight. The reaction mixture was allowed to cool and used directly in the next step. LC-MS (ESI) 304.0 (M+H), RT=2.20 minutes (Method B).
Reaction SMILES: [Pt+2:1].Cl[C:3]1[C:4](=O)[C:5]([C:13]#[N:14])=[C:6]([C:11]#N)[C:7](=O)[C:8]=1Cl.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO.C(Cl)(Cl)Cl>[C:16]1([C:22]2[C:13]3[C:5]4[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=4[C:11]([N:14]=3)=[C:13]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=3)[C:11]3[NH:14][C:13]([C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:11]4[N:14]=[C:13]([C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[C:11]5[NH:14][C:13]=2[C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][C:6]5=2)[C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][C:6]4=2)=[C:5]2[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=32)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Pt+:1]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: [Pt+2]
Reactant: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: [Pt+]
Product: c1ccc(-c2c3nc(c(-c4ccccc4)c4[nH]c(c(-c5ccccc5)c5nc(c(-c6ccccc6)c6[nH]c2c2ccccc62)-c2ccccc2-5)c2ccccc42)-c2ccccc2-3)cc1
Yield: 71 %

Procedure:
2.0 g (2 mmol) of platinum(II) tetraphenylcyclohexenoporphyrin according to Example B2 are mixed with 4.5 g (20 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 400 ml of toluene, and the mixture is heated at reflux for one hour. After cooling, the reaction mixture is taken up in methanol and filtered. There are obtained 1.8 g of crude product, which is dissolved in chloroform and then subjected to flash chromatography on silica gel. The green eluates are combined and the chloroform is removed in vacuo at 60° C. 1.4 g (71%) of a microcrystalline green powder are obtained.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:13][O:14][C:15]=2[CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Li+]>O1CCCC1.CO.O>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:13][O:14][C:15]=2[CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(OCc2onc(-c3ccccc3)c2-c2ccc(S(N)(=O)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccccc3)noc2COc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Methyl 4-[[4-[4-(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]methoxy]benzoate (Example 50) (65.0 mg, 0.14 mmol) was dissolved in tetrahydrofuran/methanol/water (5.0 mL 7:2:1) and lithium hydroxide (10 mg, 0.250 mmol) was added. The solution was heated to reflux for 4 hours and cooled to room temperature. The solvent was removed in vacuo and the crude product was purified by preparative high pressure liquid chromatography using a C18 reverse phase column. The appropriate factions were combined and concentrated to afford pure 4-[[4-[4(aminosulfonyl)phenyl]-3-phenylisoxazol-5-yl]methoxy]benozoic acid as a white crystalline material (38 mg, 60%): mp 206.4°-207.9° C. 1H NMR CD3OD 5.29 (S, 2H), 7.01 (d, 2H, 8.4 Hz), 7.25-7.45 (m, 7H), 7.84-7.97 (m, 4H). Mass spectrum calc'd. for C23H18N2O6S: 450. Found: 451 (m+H+).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[N-:7]=[N+:8]=[N-:9].[Na+].[Cl-].[NH4+]>CO>[N:7]([C@@H:6]1[CH2:5][O:4][CH2:3][C@H:2]1[OH:1])=[N+:8]=[N-:9]
Reactant: [N-]=[N+]=[N-]
Reactant: C1OCC2OC12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1COC[C@H]1O
Temperature: 75 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
3,4-Epoxytetrahydrofuran (9 g, 105 mmol) was added to a stirred solution of sodium azide (27 g, 415 mmol) and ammonium chloride (9 g, 159 mmol) in aqueous methanol (95%, 200 ml). The reaction was heated to 75° C. and stirred for 20 hours. The reaction was cooled, filtered and evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate, dried and evaporated under reduced pressure to afford the title compound as a colourless oil, 10 g, 74% yield.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:7][CH2:6][CH2:5][CH2:4]1.[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[C:28]=3[C:36]([C:38]3[CH:43]=[CH:42][C:41](F)=[CH:40][CH:39]=3)=[O:37])=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH2:45].CN([CH:49]=[O:50])C>>[OH2:12].[C:49]([OH:50])(=[O:20])[C:11]([OH:12])=[O:45].[C:49]([OH:50])(=[O:12])[C:19]([OH:20])=[O:45].[N:13]1([CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[S:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[C:28]=3[C:36]([C:38]3[CH:43]=[CH:42][C:41]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:40][CH:39]=3)=[O:37])=[CH:25][CH:26]=2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: OCCCCN1CCCC1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=O)O
Product: O=C(c1ccc(OCCCCN2CCCC2)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reaction time: 0.25 h
Yield: 66 %

Procedure:
Sodium hydride (49 mg of 60% NaH in mineral oil; 1.23 mmol) was suspended in 3 mL of dry DMF in a flame-dried, argon-filled flask. After stirring for 15 min, a solution of 4-(1-pyrrolidinyl)butanol (Part B) in 1 mL of dry DMF was added. After stirring for 15 min and gas evolution had ceased, 4-fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxyl]phenyl]benzo[b]thiophen-3-yl ketone (Part A) (0.2 g; 0.49 mmol) in 1 mL of dry DMF was added. The mixture was stirred at room temperature for 5 h, then poured into 25 mL of water. Extraction was carried out with Etoac (4×25 mL). The combined organics were washed with brine and dried by passage through sodium sulfate. The title compound (0.18 g; 66% yield) was isolated as a colorless oil by flash chromatography on silica gel, eluting with a gradient of EtOAc(100-85%)/Et3N(0-5%)/MeOH(0-10%). Conversion to the dioxalate was effected as in Example 137, Part E.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]([OH:28])=O)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH3:11].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:35]N(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][C:3]=1[OH:9])[O:6][CH:35]=[C:25]([C:22]1[CH:21]=[CH:20][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)=[CH:24][CH:23]=1)[C:26]2=[O:28]
Reactant: CN(C)C=O
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: CCOc1cccc(-c2ccc(CC(=O)O)cc2)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1cccc(-c2ccc(-c3coc4cc(O)c(Cl)cc4c3=O)cc2)c1

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.26 g, 1.8 mmol), (3′-Ethoxybiphenyl-4-yl)-acetic acid (0.44 g, 1.8 mmol), BF3Et2O (5 ml), PCl5 (0.56 g, 2.69 mmol), DMF (8 ml and 5 ml). The crude oil product (0.39 g, 55.2%) was taken onto the next stage. Rf 0.8 ethyl acetate/hexane (70/30)].
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([O-])=O.C1CCCCC=1>C(O)C.[Pd]>[NH2:1][C:4]1[C:5]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:6]([CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(C(F)(F)F)cc([N+](=O)[O-])c1N1CCCCC1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: CCOC(=O)c1cc(C(F)(F)F)cc(N)c1N1CCCCC1
Yield: 48 %

Procedure:
To a solution of ethyl 3-nitro-2-piperid-1-yl-5-trifluoromethylbenzoate (4.9 g; 1 eq.) in ethanol (50 ml) are added cyclohexene (10.5 ml; 7.5 eq.) and 10% Pd/C (0.6 g), and the mixture is stirred at reflux for 5 hours. After removing the catalyst by filtration and concentrating to dryness, the pasty solid is purified by chromatography on silica (eluent: 4/1 pentane/ether). 2.15 g of ethyl 3-amino-2-piperid-1-yl-5-trifluoromethylbenzoate are obtained in the form of a reddish oil.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:37])[CH2:6][NH:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH2:24][C:23]([C:29]3[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=3)([C:25]([F:28])([F:27])[F:26])[O:22][N:21]=2)=[CH:12][CH:11]=1)=[O:9]>O1CCCC1.O>[Cl:36][C:31]1[CH:30]=[C:29]([C:23]2([C:25]([F:27])([F:26])[F:28])[O:22][N:21]=[C:20]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:10]([C:8]([NH:7][CH2:6][C:5]([OH:37])=[O:4])=[O:9])=[CH:11][CH:12]=3)[CH2:24]2)[CH:34]=[C:33]([Cl:35])[CH:32]=1
Reactant: COC(=O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aqueous solution of LiOH (300 mg, in 5 mL of H2O) was added to a stirred solution of N-[[4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-1-naphthalenyl]carbonyl]glycine methyl ester (i.e. the product of Step C, 620 mg) in tetrahydrofuran (5 mL). After stirring at room temperature for 1 h, the reaction mixture was diluted with water and extracted with hexane. The aqueous layer was acidified with 6.0 N HCl to pH 2, and a white precipitate formed. The aqueous mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to provide the title compound (600 mg) as a white solid. 1H NMR (Me2S(O)-d6): δ 9.02 (t, 1H), 8.81 (d, 1H), 8.37 (d, 1H), 7.92 (d, 1H), 7.83 (t, 1H), 7.65-7.74 (m, 5H), 4.58 (d, 1H), 4.54 (d, 1H), 4.02 (d, 2H).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.[NH2:40][C:41]1[CH:42]=[C:43]([C:47]2[N:48]=[N:49][N:50]([CH3:52])[N:51]=2)[CH:44]=[CH:45][CH:46]=1>CN(C)C=O>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([C:47]4[N:48]=[N:49][N:50]([CH3:52])[N:51]=4)[CH:42]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: Cn1nnc(-c2cccc(N)c2)n1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)Nc2cccc(-c3nnn(C)n3)c2)(C2CCCCC2)N=Cc2ccccc21
Temperature: 50 °C
Yield: 80.9 %

Procedure:
To a stirred solution of 5-cyclohexyl-1,3-dihydro-1-methyl-3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (150 mg, 0.34 mmol) [Example 11, Step 3], in anhydrous dimethylformamide (3 ml) was added triethylamine (48 μl, 0.34 mmol). After 5 min a solution of 5-(3-aminophenyl)-2methyltetrazole (65 mg, 0.37 mmol) in anhydrous dimethylformamide (3m]) was added, and the solution heated at 50° C. for 2 h. After this time the solution was cooled to ambient temperature and evaporated in vacuo. The residue was dissolved in ethyl acetate (5 ml) and on standing a solid precipitated. This was recrystallised from ethyl acetate to afford the urea (65 mg, 40%) as a colourless solid. mp 195°-196° C. 1H NMR (360 MHz, CDCl3) δ 1.05-2.06 (10H, m), 2.79 (1H, m), 3.45 (3H, s), 4.36 (3H, s), 5.42 (1H, d, J=8 Hz), 6.75 (1H, d, J=8 Hz), 7.15-7.60 (7H, m), 7.77 (1H, d, J=8 Hz), 8.06 (1H, s).
Reaction SMILES: C[Si](Cl)(C)C.[N:6]1([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[C:18](=[O:20])=O.S(Cl)([Cl:23])=O>C(Cl)Cl>[Cl:23][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:13][CH2:14]1)=[O:20]
Reactant: O=S(Cl)Cl
Reactant: O=C=O
Reactant: C1CCN(C2CCNCC2)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCC(N2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
In 300 ml of methylene chloride, 20 ml (158 mmol) of trimethylsilyl chloride were dissolved. While the resulting solution was stirred under ice cooling in a nitrogen atmosphere, a solution of 22 g (131 mmol) of 4-piperidinopiperidine (1-1) dissolved in 100 ml of methylene chloride was gradually added dropwise over one hour. The resulting mixture was stirred at room temperature for one hour, whereby a solution containing 4-piperidinopiperidinyl trimethylsilyl (1-2) was obtained. While stirring the resulting solution, 5.9 liter (262 mmol) of a carbon dioxide gas of 1 atomic pressure were blown into the solution over two hours, whereby a solution containing 4-piperidinopiperidinyl trimethylsilyl carbamate derivative (1-3) was obtained. To the resulting solution, 11.5 ml (158 mmol) of thionyl chloride were added dropwise over 10 minutes under ice cooling and nitrogen atmosphere, followed by stirring at room temperature for 18 hours, whereby a solution containing 1-chlorocarbonyl-4-peridinopiperidine hydrochloride (1-4) was obtained. The solution was filtered and 8.8 g (33%) of 4-piperidinopiperidine hydrochloride were recovered as a residue. Under ice cooling, the filtrate was added to 330 ml of a 10% aqueous solution of sodium hydroxide. Then the organic layer obtained by separation was washed with water, dried over anhydrous magnesium sulfate and then concentrated under a low pressure. Isopropyl ether (50 ml) was added to the concentrate to dissolve the latter in the former, followed by cooling at 0° C. for 2 hours. The precipitate was then removed by filtration and the residue was concentrated under reduced pressure. The concentrate so obtained was recrystallized from 50 ml of n-hexane, whereby 15 g of the title compound (1-5) were obtained. The compound so obtained has the following physical properties:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)[CH2:19][CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:18]([C:21]1[CH:26]=[CH:25][C:24]([O:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:23][CH:22]=1)[CH2:19][CH3:20]
Reactant: CCOc1ccc(O)cc1
Reactant: OCCCN1CCN(c2ccc(Cl)nn2)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOc1ccc(OCCCN2CCN(c3ccc(Cl)nn3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
3-[4-(6-chloropyridazin-3-yl)piperazin-1-yl]propan-1-ol (0.77 g, 3 mmol), p-ethoxylphenol (0.41 g, 3 mmol), triphenylphosphine (0.79 g, 3 mmol) and anhydrous THF (20 mL) were placed in a 100 mL three-necked bottle, and DEAD (0.52 g, 3 mmol) was added slowly in dropwise within 10 min under an ice-bath condition. The mixture was stirred at room temperature overnight, subjected to a column chromatography (eluting agent: petroleum/ethyl acetate, v/v 3: 2) to obtain a white solid, 0.27 g, yield 23.9%. mp: 125-127° C.; 1H-NMR (400 MHz, CDCl3, δppm) δ1.39(t, 3H, J=7.2 Hz), 2.00(m, 2H), 2.61(br, 6H), 3.67(br, 4H), 3.98 (m, 4H), 6.83(s, 4H), 6.90(d, 1H, J=9.6 Hz), 7.21(d, 1H, J=9.6 Hz); EI-MS(m/z): 376.2[M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16]I)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C([O-])([O-])=O.[K+].[K+].[N:28]1[CH:33]=[C:32]([CH2:34][C:35]2[C:36](=[O:42])[NH:37][C:38](=[S:41])[NH:39][CH:40]=2)[CH:31]=[N:30][CH:29]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:41][C:38]3[NH:39][CH:40]=[C:35]([CH2:34][C:32]4[CH:31]=[N:30][CH:29]=[N:28][CH:33]=4)[C:36](=[O:42])[N:37]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1nc(SCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Temperature: 60 °C
Yield: 24.7 %

Procedure:
A mixture of 1-chloro-4-{[4-(2-iodoethyl)phenyl]oxy}-2-(trifluoromethyl)benzene (50 mg, 0.117 mmol), K2CO3 (32.4 mg, 0.234 mmol), and 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (26 mg, 0.118 mmol) in DMF (1 mL) was heated with a microwave reactor at 60° C. for 0.5 h. Purification via MDAP then afforded the title compound (15 mg, 24.66% yield). LCMS: rt=3.62 min, [M+H+]=519
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62](O)=[O:63]>>[CH3:56][O:57][CH2:58][CH2:59][O:60][CH2:61][C:62]([N:21]1[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20]1)=[O:63]
Reactant: COCCOCC(=O)O
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Product: COCCOCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 4.1 %

Procedure:
The crude product obtain using Compound 18 (200 mg, 0.602 mmol), N-methylmorpholine (0.132 mL, 1.20 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (161 mg, 0.842 mmol), 1-hydroxybenzotriazole monohydrate (106 mg, 0.783 mmol) and 2-methoxyethoxyacetic acid (0.0674 mL, 0.722 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (chloroform/methanol=80/20) to obtain Compound 127 (0.011 g, 4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1)=[O:9].C(N(CC)CC)C.C(Cl)Cl.[C:40](Cl)(=[O:42])[CH3:41]>O>[C:40]([NH:1][C:2]1[CH:3]=[C:4]([N:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=2)[CH2:14][CH2:15]1)=[O:9])(=[O:42])[CH3:41]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N)CC2)c(C)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cc(N2CCOC2=O)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Reaction time: 8 h

Procedure:
To a mixture of 3-{3-amino-4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (80 mg) described in Example 133, triethylamine (0.1 mL) and methylene chloride (2 mL) was added acetyl chloride (0.03 mL), and the mixture was stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (55.3 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].S(=O)(=O)(O)O.O.[CH2:21](O)[CH3:22]>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
To a slight suspension of 4-methyl-3-(trifluoromethyl)benzoic acid (2.18 g, 10.7 mmol, ABCR) in ethanol (30 ml) was added concentrated sulphuric acid specific gravity 1.84 (0.5 ml, 9.38 mmol). The resulting solution was heated to reflux overnight under nitrogen. The solution was diluted with DCM (100 ml) and then water (100 ml). The phases were separated and the organic extract washed with saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a mobile pale yellow oil (2.27 g); LCMS: (System 4) MH+=233, tRET=3.29 min.