Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][N:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].C(Cl)Cl.O>[CH:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[N:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CN(C)C=O
Reactant: CC(C)OCc1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: CC(C)OCc1ccc(C#N)nc1
Temperature: 180 °C

Procedure:
In a microwave reaction tube was placed 2-chloro-5-isopropoxymethyl-pyridine (0.12 g, 0.66 mmol), Zn(CN)2 (0.077 g, 0.66 mmol), tetrakis(triphenylphosphino)dipalladium (76 mg, 0.066 mmol), DMF (2 mL). The reaction mixture was heated at 180° C. for 5 minutes. The resulted mixture was worked up by CH2Cl2/H2O. The CH2Cl2 layer was dried and concentrated to give the crude product. The crude was purified by column chromatography by using 30% EtOAc/Hexane. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 3.73 (m, 1H), 4.59 (s, 2H), 7.68 (d, 1H), 7.85 (m, 1H), 8.67 (s, 1H). Exact mass calculated for C10H12N2O 176.09, found 177.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(Cl)Cl.Cl[Si](C)(C)C>C(OC(=O)C)C>[C:11]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1)([CH:10]=[CH2:9])=[O:12]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CC(=O)Nc1ccc(CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
4-(4-aminophenyl)butyric acid (6 g, 3.36 mmol) was added to a 200 mL three-mouthed round flask, and methylene chloride (100 mL) was added and dissolved under the nitrogen atmosphere at 40° C. To the solution was added chlorotrimethyl silane (6.0 mL). The solution was refluxed and agitated for 2 hours and, after reaction, cooled down to the room temperature. While kept at 0 to 5° C. on an ice bath under the nitrogen atmosphere, an acid eliminator (in an excess amount by 10% in concentration relative to the reactant) was added dropwise through a funnel for 10 minutes, where the acid eliminator contained imidazole and tetraethyl amine mixed at the same mole fraction. In the same manner, a solution containing acryloyl chloride (2.8 mL) in methylene chloride (30 mL) was added dropwise for 20 minutes, and the solution was kept for 30 minutes of reaction and then warmed up to the room temperature for 2 more hours of reaction. After the solvent was removed, 2M sodium hydroxide solution (200 mL) was added, and the solution was stirred for 2 hours. The aqueous solution was weak-acidified (pH 5˜6) with a 2M hydrogen chloride solution to form an aqueous solution containing a white precipitate. This solution was added to a separatory funnel along with ethylacetate (200 mL) and shaken up to cause phase separation into aqueous and ethylacetate layers. The solvent in the ethylacetate layer where the product is dissolved was removed on an evaporator, and the residual solid was dried out in a vacuum oven for 24 hours to yield a white 4-(4-acrylaminophenyl)butyric acid (APB) solid (yield 92%). The melting point of the solid was 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:10]=3[CH2:9][CH2:8][C:4]=2[CH:3]=1
Reactant: COc1ccc(C(=O)O)c(CCc2cccc(Cl)c2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O

Procedure:
For the synthesis of the title compound, 16.6 g (0.057 mol) of [2-(3-chlorophenyl-ethyl]-4-methoxybenzoic acid, 7.25 g (0.06 mol) of SOCl2, 250 ml of methylene chloride and 10 g of AlCl3 (0.075 mol) are employed in method K. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%). C16H13ClO2(Mr=272.73)
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1C=C[CH:21]=[CH:22][N:23]=1)=[O:16].CC1ON=C(NC(C2N(C)[S:41](=O)(=O)C3C=CC=CC=3C=2O)=O)C=1>>[OH:14][C:4]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=1[C:15]([NH:17][C:18]1[S:41][CH:21]=[CH:22][N:23]=1)=[O:16]
Reactant: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2ccccc2S1(=O)=O

Procedure:
The oxicams may be combined with the special 1,2-diacyl-glycero-3-phosphocholines in a molar ratio of 1:1 to 1:20, preferably in a molar ratio of 1:1 to 1:10. A unit dose for the therapeutic application to humans amounts to 5-300 mg oxicam combined with 10-500 mg 1,2-diacyl-glycerol-3-phosphocholine per day, preferably 10-20 mg for piroxicam and 100-300 mg for isoxicam combined with 50-250 mg 1,1-diacyl-glycero-3-phosphocholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:12]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([N:22]2[CH2:21][CH2:20][N:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)C(c1cccc(Cl)c1)C1(O)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Cl)c2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A solution of (3-chlorophenyl)(1-hydroxycyclohexyl)acetic acid (Reference Example 1-a) (5.4 g, 20.1 mmol), benzotriazol-1-yloxytris(dimethylaminop)phosphonium hexafluorophosphate (14.22 g, 32.15 mmol), and tert-butyl 1-piperazinecarboxylate (5.99 g, 32.15 mmol) in methylene chloride (20 mL) was treated with triethylamine (8.4 mL, 60.3 mmol). The reaction was stirred at 25° C. for 16 h, after which time the solvent was removed in vacuo and the product was purified via Biotage Horizon (FLASH 40 M, silica, gradient from 0% EtOAc/hexane to 30% EtOAc/hexane) to yield 7.10 g (81%) tert-butyl 4-[(3-chlorophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate as a white foam. HRMS: calcd for C23H33ClN2O4, 436.2129; found (ESI_FT), 437.21996.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)=[O:5])C.[OH-].[Na+].Cl.O>C(O)C>[N+:11]([C:10]1[C:6]([C:4]([OH:5])=[O:3])=[N:7][N:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=1)([O-:13])=[O:12]
Reactant: CCOC(=O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nn(-c2ccccc2)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a stirred suspension of 4-nitro-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester (240 mg, 0.92 mmol) at rt in ethanol (3 ml) under an argon atmosphere was added 1 N NaOH (1.8 ml). The mixture was stirred for 2 hrs. 3 N HCl was added until pH˜2 was reached. Upon addition of H2O (˜2 ml), the product precipitated out. It was collected by filtration, washed with H2O and dried. Off-white solid (184 mg, 86%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:21])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1>C(OCC)(=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([NH:29][C:2]2[N:3]=[C:4]([O:11][C:12]3[C:19]([CH3:20])=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[CH3:21])[C:5]3[CH:10]=[CH:9][S:8][C:6]=3[N:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Cl)nc2sccc12
Reactant: N#Cc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2sccc12
Temperature: 90 °C
Reaction time: 48 h
Yield: 14.5 %

Procedure:
To a solution of 4-(2-chlorothieno[2,3-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (188 mg, 0.59 mmol), TFA (0.37 mL, 4.75 mmol) in TFE (2.5 mL) was added 4-aminobenzonitrile (280 mg, 2.37 mmol) in a scaled tube. The reaction was stirred at 90° C. for 2 d. Reaction-mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC afforded the product as white solid (34 mg, 14%):
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[O-:10])[CH:5]=[N:6][CH:7]=1>C(O)(=O)C.[Rh].[Pt](=O)=O>[CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([NH:8][C:9](=[O:10])[O:11][C:2]([CH3:3])([CH3:7])[CH3:1])[CH2:3]1
Reactant: Cc1cncc(NC(=O)[O-])c1
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CC(=O)O
Product: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
To a solution of 5-methylpyridin-3-ylcarbamate (3 g, 14 mmol) in glacial acetic Acid (50 mL) was added 5% Rhodium on active carbon (0.5 g) and Platinum(IV) oxide (0.5 g) in the hydrogenation steel bomb. The mixture was sealed and hydrogenated at 200 psi and 70° C. for 48 hours. The mixture was filtered through Celite and concentrated to give cis-(+/−)-tert-butyl 5-methylpiperidin-3-ylcarbamate. LCMS (m/z): 215.1 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([Br:13])[N:3]=1.[CH3:14][O-:15].[Na+].O>CO>[Br:13][C:4]1[C:5]([N+:10]([O-:12])=[O:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:15][CH3:14])[N:3]=1
Reactant: C[O-]
Reactant: COc1cc([N+](=O)[O-])c(Br)nc1Br
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(Br)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 g of 2,6-dibromo-3-methoxy-5-nitropyridine (example E3) were dissolved in 550 ml of anhydrous methanol at 30-40° C. 4.6 g sodium methoxide dissolved in 30 ml anhydrous methanol were added to this solution. The reaction mixture was stirred for one hour at room temperature, poured into 700 ml of water and stored in the refrigerator overnight. The precipitate was filtered, washed with ice cold water and dried under vacuum to yield the title compound.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[OH-].[Na+].O.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[CH3:19][C:20](/[CH:22]=[CH:7]/[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)=[O:21]
Reactant: CC(C)=O
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)/C=C/c1ccc2c(c1)OCO2

Procedure:
A solution of 100 g piperonal in 900 ml acetone was stirred at room temperature with 15 ml of 10% aqueous sodium hydroxide and 30 ml of water. After 3 hours 5 ml of acetic acid was added and the reaction mixture was evaporated. The residue was recrystallized from methanol and dried in vacuo to yield 60 g of piperonalacetone, m.p. 104°-105° C. (EtoAc).
Reaction SMILES: [C:1]1([S:7]([NH:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][C:12]2=[S:17])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.CC([O-])=O.[Na+]>CO>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:14]2[S:13][C:12](=[S:17])[N:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:15]2=[O:16])=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CSC(=S)N1NS(=O)(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1C(=Cc2ccc(F)cc2)SC(=S)N1NS(=O)(=O)c1ccccc1
Reaction time: 5 h
Yield: 9.8 %

Procedure:
3-(Benzenesulfonylamino)-4-oxo-2-thionothiazolidine 624 mg (2.17 mmol, 1.0 equiv) was combined with 349 μL 4-fluorobenzaldehyde (3.26 mmol, 1.5 equiv) and 18 mg NaOAc (0.217 mmol, 0.1 equiv) in 8 mL MeOH. The solution was allowed to stir for 5 h, at which time the resulting yellow solid was removed via filtration. The solid was washed (4×MeOH) and dried under vacuum to give the product as a yellow solid 83.5 mg (0.212 mmol, 10%). 1H NMR (DMSO, 400 MHz) δ 7.90-9.86 (m, 3 H), 7.77-7.70 (m, 3 H), 7.61 (t, J=8.8 Hz, 2 H), 7.42 (t, J=8.8 Hz, 2 H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23](Cl)=[O:24])[CH:16]=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:26][O:27][C:28]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH3+:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)=[O:29].[Cl-]>C(Cl)Cl>[CH3:26][O:27][C:28](=[O:29])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:43]=[CH:42][C:41]([CH2:44][NH:45][C:23]([C:17]3[CH:16]=[N:15][N:14]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[C:18]=3[C:19]([F:22])([F:21])[F:20])=[O:24])=[CH:40][CH:39]=2)=[CH:36][CH:37]=1
Reactant: O=C(Cl)c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: COC(=O)COc1ccc(-c2ccc(C[NH3+])cc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)COc1ccc(-c2ccc(CNC(=O)c3cnn(-c4ccccc4)c3C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 100 %

Procedure:
Triethylamine (275 μL, 1.97 mmol) was added under nitrogen to a mixture of 1-phenyl-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (272 mg, 0.992 mmol) and 4′-methoxycarbonylmethoxy-biphenyl-4-ylmethyl-ammonium; chloride (304 mg, 0.986 mmol), prepared in the previous step, in 20 mL of methylene chloride at room temperature. The reaction was stirred at room temperature for 6 h. The reaction was extracted with water, 5% NaHCO3, dried (MgSO4) and the solvent removed under reduced pressure to give methyl({4′-[({[1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]carbonyl}amino)methyl][1,1′-biphenyl]-4-yl}oxy)acetate (508 mg, 100%) as a white solid, mp 174-176° C. Elemental Analysis for C27H22F3N3O4+0.07 CH2Cl2. Calc'd C, 63.08; H, 4.33; N, 8.15. Found: C, 63.01; H, 4.17; N, 8.16.
Reaction SMILES: [CH:1]([CH:3]1[O:8][C:6](=O)[CH2:5][CH2:4]1)=[CH2:2].[CH3:9][NH2:10]>>[CH:1]([CH:3]1[N:10]([CH3:9])[C:6](=[O:8])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC(=O)O1
Reactant: CN
Product: C=CC1CCC(=O)N1C
Yield: 46 %

Procedure:
21 g (179 mmol) of gamma-vinylbutyrolactone prepared as in Example 1 were stirred with 125 g of 40% strength aqueous methylamine in an autoclave at 280° C. for two hours. After cooling, the reaction mixture was concentrated at 50° C./20 mbar. The residue (22.7 g) was distilled using a spinning band column to yield 10.3 g (46%) of 5-vinyl-N-methylpyrrolidone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2].[S:23]([O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35]OS(=O)(=O)C)(=[O:26])(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][S:23]([CH3:24])(=[O:25])=[O:26])[C:10]=1[CH2:19][CH2:20][CH3:21])[CH3:2]
Reactant: CS(=O)(=O)OCCOCCOCCOS(C)(=O)=O
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCOCCOCCOS(C)(=O)=O
Yield: 44.6 %

Procedure:
A mixture of 4.0 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butanoic acid ethyl ester, 19.9 g of triethylene glycol dimesylate and 3.6 g of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 40 ml of anhydrous dimethylformamide was stirred at reflux for 23 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was purified by high pressure liquid chromatography using 30% ethyl acetate-toluene to give 3.0 g (45% yield) of 4-[4-acetyl-3-[2-[2-[2-[(methylsulfonyl)oxy]ethoxy]ethoxy]ethoxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]([F:28])([F:27])[C:16]1[CH:17]=[C:18]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[NH2:19]>>[F:14][C:15]([F:27])([F:28])[C:16]1[CH:17]=[C:18]([NH:19][C:9](=[O:11])[C:8]2[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[OH:13])[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[CH:22]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc([N+](=O)[O-])ccc1O
Yield: 57.2 %

Procedure:
Using 5-nitrosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[S:11])[CH2:10][CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[CH:6][CH:7]=1
Reactant: CC(=S)Nc1ccc(Cl)cc1
Reactant: CC(C)=CCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCCCC(=S)Nc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
In a dehydrated tetrahydrofuran (35 ml) solution of N-(4-chloro-phenyl)-thioacetamide (3.3 g), 27 ml of n-butyllithium (1.59 mol/l, n-hexane solution) was added dropwise at 0° C. under a nitrogen atmosphere. After stirring at 0° C. for 1 hour, the mixture was cooled to −78° C. A tetrahydrofuran (35 ml) solution of 5-bromo-2-methyl-2-pentene (2.9 g) was added dropwise thereto. After raising the temperature to room temperature and further stirring for 30 minutes, an aqueous saturated ammonium chloride solution was added and then the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.0 g of the target compound.
Reaction SMILES: CS([Cl:5])(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19]O)[N:16]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=4[F:41])[N:29]=[CH:28][C:27]=3[C:26]([CH3:43])([CH3:42])[CH2:25]2)=[O:23])[CH2:15][C@H:14]1[CH3:44])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[CH2:18][C@H:17]([CH2:19][Cl:5])[N:16]([CH2:21][C:22]([N:24]2[C:32]3[CH:31]=[C:30]([CH2:33][C:34]4[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=4[F:41])[N:29]=[CH:28][C:27]=3[C:26]([CH3:43])([CH3:42])[CH2:25]2)=[O:23])[CH2:15][C@H:14]1[CH3:44])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3cnc(Cc4ccc(F)cc4F)cc32)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.8 %

Procedure:
Chloroacetyl chloride (0.995 mL, 12.0 mmol) was added dropwise to a stirred solution of 6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine hydrochloride (3.10 g, 10.0 mmol) and triethylamine (4.6 mL, 33.0 mmol) in anhydrous DCM (50 mL) and the mixture was stirred at room temperature for 16 hours. (2R,5R)-5-Hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.76 g, 12.0 mmol) was added and the mixture was stirred at room temperature for a further 16 hours. Further triethylamine (1 mL) and (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (700 mg) were added and the mixture stirred for a further 16 hours. The mixture was diluted with DCM, washed with water, the organic layer separated and the solvent removed in vacuo. Chromatography (silica, elution with 30-100% ethyl acetate in petroleum ether) afforded (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 80%) as a pale tan foam. MS: [M+H]+ 545. Methanesulfonyl chloride (0.78 mL, 10.0 mmol) was added dropwise to a stirred solution of (2R,5R)-4-{2-[6-(2,4-difluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridin-1-yl]-2-oxo-ethyl}-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (4.36 g, 8.0 mmol) and triethylamine (1.67 mL, 12.0 mmol) in anhydrous DCM (40 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM, washed successively with saturated aqueous sodium hydrogen carbonate and then water. The organic layer was separated and the solvent removed in vacuo to afford the title compound (4.0 g, 71%) as a pale yellow foam. MS: [M+H]+=563, 565.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=2)[NH:13][C:12]1=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)=[O:35])[CH3:32].O>CN(C=O)C>[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:4](=[C:11]2\[C:12](=[O:30])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:42][CH:43]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc(NS(=O)(=O)c3ccccc3)cc21)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
0.84 g (2 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone and 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in 10 ml of DMF. The mixture is heated to 140° C. for 5 hours. Then water is added while the mixture is cooled with ice and stirred for 1 hour at ambient temperature. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].CCOCC>O1CCOCC1>[ClH:23].[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[O:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)ccc2F)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(F)c(OC2CCNCC2)c1
Yield: 65 %

Procedure:
To a stirred solution of 2,5-difluorophenol (1.0 g, 0.0076 mole) in DMF (20 mL) was added cesium carbonate (12.4 g, 0.038 mole) followed by 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 0.076 mole). The reaction mixture was heated at 80° C. overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate, and concentrated. The resulting residue was purified by column chromatography using silica gel 60-120 mesh (10% ethyl acetate in hexane) to afford 1.5 g (63.0%) of 4-(2,5-Difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. LCMS: 356.08 (M+1)+, 85%. 1H NMR (CDCl3): δ 7.0 (m, 1H), 6.6 (m, 1H), 6.5 (m, 1H), 4.5 (m, 1H), 3.7 (m, 2H), 3.4 (m, 4H), 2 (m, 2H), 1.9 (m, 2H). 1.5 (s, 9H). A solution of 4-(2,5-difluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.0047 mole) in dioxane.HCl (2 mL) was stirred at ambient temperature for 1 hour. Ether was then added, and the resulting precipitate was isolated by filtration and dried to afford 0.65 g (65%) of 4-(2,5-difluoro-phenoxy)-piperidine hydrochloride. LCMS: 214.1 (M+1)+, 100%. 1H NMR (CDCl3): δ 9.2 (bs, 2H), 7.4 (m, 2H), 6.9 (m, 1H), 4.8 (m, 1H), 3.2 (m, 2), 3.0 (m, 2H), 2.2 (m, 2H), 1.9 (m, 2H).