Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][OH:7])[N:3]=[CH:2]1.CCN(CC)CC.[Si:15](OS(C(F)(F)F)(=O)=O)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl.CCOC(C)=O>[Si:15]([O:7][CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OCc1cscn1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cscn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-thiazol-4-ylmethanol (311.4 mg, 2.7 mmol) in CH2Cl2 (15 mL) was added Et3N (1.9 mL, 13.6 mmol). The solution was cooled to −78° C. and TBSOTf (776 μL, 3.38 mmol) was added. The reaction was warmed to room temperature and stirred for 1 hour. Next, the reaction was diluted with EtOAc (75 mL) and washed with saturated NaHCO3, brine, 1N HCl, and brine (20 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 15% EtOAc/hexanes) to afford 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazole. Rf=0.28 (15% EtOAc/hexanes). LCMS=230.1 (M+1)+. 1H NMR (CDCl3, 600 MHz) δ 8.77 (d, J=2.0 Hz, 1H), 7.25 (m, 1H), 4.93 (d, J=1.1 Hz, 2H), 0.95 (s, 9H), 0.12 (s, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH:3](O)[CH2:4][N+:5]([O-:7])=[O:6].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][CH:3]([CH:2]([CH3:1])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:4][N+:5]([O-:7])=[O:6]
Reactant: CC(C)CC(C)C(O)C[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)CC(C)C(Cl)C[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 67.9 %

Procedure:
After dissolving 2.0 g of 3,5-dimethyl-1-nitro-2-hexanol in 15 ml of toluene, 4.1 g of thionyl chloride and two drops of N,N-dimethylformamide were added thereto, and the solution was stirred for 2.5 hours at 80° C. The solution was cooled to room temperature and concentrated, and then purified by silica gel chromatography (hexane/ethyl acetate=8/1), thereby obtaining 1.5 g of 2-chloro-3,5-dimethyl-1-nitrohexane (yield: 72.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:15]([CH3:18])([O-:17])=[O:16].Cl.CN.C([O-])(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1/[CH:5]=[CH:18]/[N+:15]([O-:17])=[O:16]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C(F)(F)F)ccc1C=O
Agent: CC(=O)[O-]
Agent: CN
Agent: Cl
Product: COc1cc(C(F)(F)F)ccc1/C=C/[N+](=O)[O-]
Reaction time: 12 h
Yield: 65.4 %

Procedure:
A portion of 2-methoxy-4-(trifluoromethyl)benzaldehyde (3.78 g, 18.5 mmol) was diluted with nitromethane (7.02 ml, 130 mmol) followed by the addition of methylamine hydrochloride (0.750 g, 11.1 mmol) and sodium acetate (0.911 g, 11.1 mmol). After stirring for 12 hours, the reaction was loaded directly onto a biotage 40 cartridge and eluted with 5% ethyl acetate/hexanes to 20% ethyl acetate hexanes to yield (E)-2-methoxy-1-(2-nitrovinyl)-4-(trifluoromethyl)benzene (3.0 g, 12.1 mmol, 65.6% yield).
Reaction SMILES: OC1C=CC(C2SC3C=C(OC)C=CC=3C=2OC2C=CC(/C=C/C(OC)=O)=CC=2)=CC=1.[OH:32][C:33]1[CH:34]=[CH:35][C:36]2[C:40]([O:41][C:42]3[CH:47]=[CH:46][C:45](/[CH:48]=[CH:49]/[C:50]([O:52]C)=[O:51])=[CH:44][CH:43]=3)=[C:39]([C:54]3[CH:59]=[CH:58][C:57]([O:60][CH3:61])=[CH:56][CH:55]=3)[S:38][C:37]=2[CH:62]=1.O.[Li+].[OH-]>C1COCC1.CO.C(Cl)Cl>[OH:32][C:33]1[CH:34]=[CH:35][C:36]2[C:40]([O:41][C:42]3[CH:43]=[CH:44][C:45](/[CH:48]=[CH:49]/[C:50]([OH:52])=[O:51])=[CH:46][CH:47]=3)=[C:39]([C:54]3[CH:55]=[CH:56][C:57]([O:60][CH3:61])=[CH:58][CH:59]=3)[S:38][C:37]=2[CH:62]=1
Reactant: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(OC)cc3)sc3cc(O)ccc23)cc1
Agent: COC(=O)/C=C/c1ccc(Oc2c(-c3ccc(O)cc3)sc3cc(OC)ccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(O)ccc3c2Oc2ccc(/C=C/C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a 30 mL vial containing a mixture of (E)-methyl 3-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate and (E)-methyl 3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (32 mg, 0.07 mmol) in THF (3 mL), MeOH (1 mL), and H2O (2 mL) was added LiOH (9.14 mg, 0.38 mmol). The reaction mixture was stirred for 60 min at room temperature and then concentrated in vacuo, diluted with water, and acidified to pH 2 with 6 M HCl causing a precipitate to form. The mixture was diluted with 20 mL DCM and 2 mL MeOH. The organic layer was collected (phase separator) and concentrated in vacuo to afford the crude product. The sample was purified by supercritical fluid chromatography (CHIRALCEL® OJ-H column, 45% MeOH in CO2) to afford (E)-3-(4-((6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (17 mg, 0.04 mmol, 53% yield) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ ppm=7.64 (d, J=8.59 Hz, 2H), 7.55-7.62 (m, 2H), 7.51 (d, J=16.17 Hz, 1H), 7.30 (d, J=2.02 Hz, 1H), 7.13 (d, J=8.59 Hz, 1H), 6.90-7.04 (m, 4H), 6.83 (dd, J=2.02, 8.59 Hz, 1H), 6.38 (d, J=16.17 Hz, 1H), 3.75 (s, 3H). LC/MS (m/z, M-H): 417.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][CH:15]([N:29]3[CH2:28][CH2:27][N:26]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:31][CH2:30]3)[CH2:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(C2=CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C2=CCC(N3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc1[N+](=O)[O-]
Reaction time: 24 h
Yield: 76.9 %

Procedure:
A solution of 4-[3-(methyloxy)-4-nitrophenyl]-3-cyclohexen-1-one (514 mg, 2.08 mmol) and 1-BOC-piperazine (430 mg, 2.28 mmol) were stirred in DCE (8 mL) at rt under N2. To this mixture was added sodium triacetoxyborohydride (610 mg, 2.89 mmol) and HOAc (125 mg, 2.08 mmol). The reaction was stirred for approximately 24 h. The reaction was diluted with DCM and aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried over MgSO4, filtered, then concentrated and purified by silica gel chromatography to give the title compound of step E (669 mg, 1.60 mmol, 77%) as a tan solid. MS (ESI): 418 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])/[C:5](/[O:30][CH2:31][CH3:32])=[CH:6]/[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[C:9]([CH3:29])[CH:8]=1)C.CC1C=C(C=C(C)C=1OCCC1N=C(C2C=CC=CC=2)OC=1C)C=O.[Cl-].C(OC([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C(OCC)=O)C>>[CH3:13][C:11]1[CH:12]=[C:7](/[CH:6]=[C:5](\[O:30][CH2:31][CH3:32])/[C:4]([OH:33])=[O:3])[CH:8]=[C:9]([CH3:29])[C:10]=1[O:14][CH2:15][CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:20][C:21]=1[CH3:22]
Reactant: CCOC(=O)/C(=C/c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1)OCC
Agent: CCOC(=O)C(OCC)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C=O)cc(C)c1OCCc1nc(-c2ccccc2)oc1C
Agent: [Cl-]
Product: CCO/C(=C\c1cc(C)c(OCCc2nc(-c3ccccc3)oc2C)c(C)c1)C(=O)O

Procedure:
In analogy to the procedure described in example 120 f], 3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2Z-ethoxy-acrylic acid ethyl ester {prepared from 3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 117) and (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride (K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556) in analogy to the procedure described in example 114 c]} was saponified to yield 3-{3,5-dimethyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2Z-ethoxy-acrylic acid as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[CH:43]=[CH:42][NH:41][C:38]3=[N:39][CH:40]=2)O1>>[CH3:20][S:17]([C:13]1[CH:12]=[C:11]([C:9]2[S:8][C:6]3[N:7]=[C:2]([C:35]4[CH:36]=[C:37]5[CH:43]=[CH:42][NH:41][C:38]5=[N:39][CH:40]=4)[N:3]=[C:4]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[C:5]=3[N:10]=2)[CH:16]=[CH:15][CH:14]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Product: CS(=O)(=O)c1cccc(-c2nc3c(N4CCOCC4)nc(-c4cnc5[nH]ccc5c4)nc3s2)c1
Yield: 43.6 %

Procedure:
5-Chloro-2-(3-methanesulfonyl-phenyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (80 mg) was reacted with 54 mg of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine via General Procedure A. The product was purified by reverse phase HPLC to yield 41.8 mg of 109. MS (Q1) 493.2 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li]>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1Cl
Reactant: [Li]c1ccccc1OC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)c1ccc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2,6-Dichloro-N-methoxy-N-methyl-nicotinamide (503.3 mg, 2.141 mmol, Example 1) in anhydrous tetrahydrofuran (8 mL) was added a solution of freshly prepared 2-methoxyphenyl lithium (3-5 equiv, from above) and the reaction was stirred at −78° C. for 30-60 mins until the complete consumption of starting material. The resulting mixture was quenched with aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was purified on silica gel with hexanes/ethyl acetate to give (2,6-Dichloro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone as a light brown waxy solid (314.3 mg, 52% yield). HRMS, observed: 281.0023, Calcd for M+: 281.0010.
Reaction SMILES: OO.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[C:13]3[C:14](=[CH:25][N:26]([CH2:29][C:30]([NH2:32])=[O:31])[C:27]=3[CH3:28])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1.S(=O)(O)[O-:36].[Na+]>C(O)(=O)C>[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[C:13]3[CH:27]([CH3:28])[N:26]([CH2:29][C:30]([NH2:32])=[O:31])[C:25](=[O:36])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: Cc1c2c(cn1CC(N)=O)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Reactant: O=S([O-])O
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1C2=C(CN=C(c3ccccc3Cl)c3cc(Cl)ccc32)C(=O)N1CC(N)=O
Reaction time: 1 h

Procedure:
In one portion, 0.7 ml (6.2 mmol) of 30% hydrogen peroxide was added to a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 1.7 g (4.2 mmol) of 8-chloro-6-(2-chlorophenyl)-1-methyl-2H,4H-pyrrolo[3,4-d][2]benzazepine-2-acetamide were added, and the resulting solution was stirred for 30 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The residue was crystallized from ethyl acetate to give 8-chloro-6-(2-chlorophenyl)-1,4-dihydro-1-methyl-3-oxo-2H-pyrrolo[3,4-d][2]benzazepine-2-acetamide as colorless prisms, mp 221°-222° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)[CH3:8].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[O:27][CH3:28].[Cl-].[Al+3].[Cl-].[Cl-]>CN(C)C=O.C(Cl)(Cl)Cl.O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:7][CH3:8])=[CH:18][CH:17]=2)=[O:16])[C:21]=1[O:27][CH3:28]
Reactant: COc1cc(Cl)ccc1Br
Reactant: CCOc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOc1ccc(C(=O)c2c(Cl)ccc(Br)c2OC)cc1
Reaction time: 5 h
Yield: 31.1 %

Procedure:
A suspension of 2-bromo-5-chlorophenol (2.85 g, 13.7 mmol; synthesized in reference to International Patent Publication WO0109122), potassium carbonate (1.89 g, 13.7 mmol), n-Bu4NI (50 mg, 0.137 mmol), methyl iodide (1.28 mL, 20.6 mmol) and N,N-dimethylformamide (8.0 mL) was stirred for two hours. An iced water was added and the obtained mixture was extracted with ethyl acetate twice. The combined organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain colorless oily 2-bromo-5-chloroanisole (2.94 g, 97%). Then, oxalyl chloride (1.23 mL, 15.1 mmol) and N,N-dimethylformamide (2 drops) were added to 4-ethoxybenzoic acid (2.28 g, 13.7 mmol) in chloroform (8 mL) and stirred for five hours. The yellow oil obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (5 mL). To this solution, a chloroform solution (10 mL) of 2-bromo-5-chloroanisole (2.94 g, 13.3 mmol) was added and then aluminum chloride (2.07 g, 15.5 mmol) was added portion wise at −10° C. over five minutes. After stirred at 5° C. for one hour, the reaction mixture was to room temperature and stirred for 13 hours. The reaction mixture was poured into an iced water and extracted with chloroform three times. After washed with 1 M hydrochloric acid, water, brine, the combined organic layer was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by NH type silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain (5-bromo-2-chloro-6-methoxyphenyl)(4-ethoxyphenyl)methanone (1.53 g, 31%) as a colorless crystal.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:24][C:25]([CH3:27])=[CH2:26])([CH2:15][CH2:16][O:17]C2CCCCO2)[C:12](=[O:14])[N:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[S:10][C:11]([CH2:15][CH2:16][OH:17])([CH2:24][C:25]([CH3:27])=[CH2:26])[C:12](=[O:14])[N:13]=1
Reactant: C=C(C)CC1(CCOC2CCCCO2)SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: C=C(C)CC1(CCO)SC(N[C@H]2C[C@@H]3CC[C@H]2C3)=NC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The mixture of 2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-(2-methylallyl)-5-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)thiazol-4(5H)-one (420 mg, 1.07 mmol) and p-toluenesulfonic acid (100 mg) in MeOH (5.0 mL) was stirred for 16 h at room temperature. The reaction mixture was then concentrated in vacuo, and sat'd NaH2PO4 was added. The mixture was then extracted with EtOAc, and the organic layer was washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (4:1; Hexane:EtOAc) to give the title compound as solid. MS (ES+): 309 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[C:17](=[O:23])[CH2:16][CH2:15]4)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:24](Cl)(=[O:26])[CH3:25]>>[CH3:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([C:7]3[C:6]4[CH2:5][CH2:4][CH2:3][C@@H:2]([NH:1][C:24](=[O:26])[CH3:25])[C:11]=4[CH:10]=[N:9][CH:8]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:23]
Reactant: CC(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc4c3CCC[C@H]4N)ccc21
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc4c(c3)CCC(=O)N4C)cncc21

Procedure:
In analogy to the procedure described for the preparation of intermediate B-1, reaction of (R)-6-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one (example 61) with acetyl chloride gave the title compound as colorless amorphous solid. MS: 350.5 (M+H+).
Reaction SMILES: COC1N=CC(N2CCC(N3CC[C@@H](NC(=O)C[NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)C3)CC2)=CC=1.COC1N=CC(N)=CC=1>>[F:32][C:31]([F:33])([F:34])[C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH2:23])=[O:35]
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N)cn1
Product: NC(=O)c1cccc(C(F)(F)F)c1

Procedure:
N-[2-({3R)-1-[1-(3-ethoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, substituting 3-ethoxyaniline for 6-methoxypyridin-3-amine. The crude product was purified by preparative HPLC. MS m/z: 519 (M+1).
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:4]2[C:3](=[O:26])[C:2]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:5]2(=[O:14])=[O:13])=[CH:17][CH:18]=1
Reactant: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(Cc3ccc(OC(F)F)cc3)C2=O)cc1

Procedure:
The title compound was prepared from 4-chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-methoxyaniline in a similar manner as described for e.g. Examples 14 and 30. H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 4.86 (s, 2H), 6.48-6.52 (m, 2H), 6.50 (t, J=74 Hz, 1H), 6.60-6.64 (m, 2H), 7.09-7.14 (m, 7H), 7.52-7.56 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 42.8, 55.5, 109.9, 113.6, 115.8 (t, J=259 Hz), 119.6, 123.8, 124.6, 128.0, 128.7, 129.0, 129.3, 130.6, 131.3, 131.4, 151.2, 157.3, 159.3; Mass Spectrum: M−H+ 485.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>>[C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([Cl:16])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccccc1C(=O)O
Product: CC(=O)Oc1ccccc1C(=O)Cl
Temperature: 80 °C

Procedure:
Acetyl salicylic acid (1.0 g) was mixed with thionyl chloride (1.0 mL) and mixture was heated in a 50 mL round bottom flask under nitrogen at 80° C. for 1 hour. The excess thionyl chloride was removed by distillation, dried in high vacuum to get acetyl salicyloyl chloride as a viscous liquid, ˜1.1 g. Used for next step with out further purification. Curcumin (0.50 g) was taken in 10 mL of DMF in a 50 mL round bottom flask under nitrogen and pyridine was added. Acetyl salicyloyl chloride (˜1.1 g) was taken in 5 mL of DMF and was added drop wise from a pressure equalizing separating funnel. The solution turned darker in color. The mixture was heated at 90° C. for 1 hour and then at room temperature overnight. To the reaction mixture 100 mL of water was added. A solid formed which was filtered, the solid was stirred with 30 mL of NaHCO3 solution. The solid was filtered, washed with water, dried under high vacuum to yield 1.10 g of the product, curcumin acetyl salicylate or curcumin-aspirin, NMR was consistent with the structure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[Cl:15][CH:16]([C:21]1[O:26][C:25](=[O:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:31]([C:32]([F:35])([F:34])[F:33])[C:23]=2[N:22]=1)[C:17]([CH3:20])([CH3:19])[CH3:18]>>[Cl:15][CH:16]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:21]([NH:22][C:23]1[C:31]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](=[O:27])[CH:8]([C:7]([NH:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:26]
Reactant: CCOC(=O)CC(=O)Nc1nccs1
Reactant: CC(C)(C)C(Cl)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Product: CCOC(=O)C(C(=O)Nc1nccs1)C(=O)c1cccc(C(F)(F)F)c1NC(=O)C(Cl)C(C)(C)C
Yield: 88.5 %

Procedure:
Using the procedure of Step A of Example 4, 7.7 g of ethyl 3-(2-thiazolylamino)-3-oxo-propanoate and 10.55 g of 2-(1-chloro-2,2-dimethylpropyl)-8-trifluoromethyl-4H-3,1-benzoxazine-4-one [prepared according to the process described in the European Pat. No. 0040573] were reacted to obtain 15.6 g of ethyl 2-[(2-chloro-1-oxo-3,3-dimethylbutyl)-amino]-β-oxo-α-[(2-thiazolylamino)-carbonyl]-3-(trifluoromethyl)-benzene-propanoate melting at 180° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10].[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:12]=[N:13][C:14]([S:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[O:8][C:9]=1[CH3:10]
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)nc2)oc1C
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1nc(-c2ccc(Sc3ccccc3)nc2)oc1C
Yield: 73.4 %

Procedure:
[2-(6-Chloro-pyridin-3-yl)-5-methyl-oxazol-4-yl]-acetic acid methyl ester (4.8 g, 17.98 mmol) is dissolved in anhydrous dimethylformamide (100 mL) and allowed to stir under nitrogen. Benzenethiol (2.78 mL, 27 mmol) is added by syringe, followed by anhydrous cesium carbonate (12.6 g, 36 mmol). The mixture is allowed to stir under nitrogen 50° C. and monitored by HPLC. After complete consumption of strating material, the solution is quenched with 1N sodium hydroxide solution, diluted with ethyl acetate, and then enough water added to dissolve the solids. The two phases are separated and the organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure [5-Methyl-2-(6-phenylsulfanyl-pyridin-3-yl)-oxazol-4-yl]-acetic acid methyl ester (4.51 g, 13.2 mmol) is isolated in 74% yield after column chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[H-].[Na+].FS([C:18](C(O)=O)([F:20])[F:19])(=O)=O.O>CC#N>[F:19][CH:18]([F:20])[O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Reactant: COC(=O)c1ccc(O)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(OC(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of commercially available methyl 6-hydroxynicotinate (3.000 g; 19.59 mmol) in anh. MeCN (320 ml) was treated portionwise with NaH (60% dispersion in mineral oil; 2.115 g; 52.89 mmol), and stirring at rt, under nitrogen, was continued for 20 min. FSO2CF2CO2H (5.931 g; 33.30 mmol) was then added dropwise, and the resulting heterogeneous mixture was further stirred at rt, under nitrogen, for 30 min. Water (10 ml) was slowly added, and acetonitrile was removed under reduced pressure. Water (150 ml) and AcOEt (150 ml) were added, and the separated aq. layer was further extracted with AcOEt (2×100 ml). The mixed organic layers were washed with brine (100 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM) afforded methyl 6-(difluoromethoxy)nicotinate as a beige solid. LC-MS (conditions D): tR=0.93 min.; no ionisation.