Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:12])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol -5-yloxy]-propyl ester (1.02 g, 1.89 mmol) in 2.0 M dimethylamine in THF (20 mL, 40 mmol) was stirred for 16 hours at 70° C. in a sealed tube. After cooling to ambient temperature, the reaction mixture was concentrated and partitioned in chloroform and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 0.5% ammonium hydroxide/5.0% methanol in chloroform. Dimethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine was obtained as a light yellow solid (0.453 g, 58.5%). Methanol and ethereal hydrochloride were then added to this compound. The resulting solution was concentrated and dried for 14 hours at 84° C. in vacuo. Dimethyl-{3-[3-(naphthalene -1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride as a very light yellow solid (0.455 g) was obtained: MP: 264-5° C.; Mass Spectrum (−EI, [M−H]−) m/z 408.
Reaction SMILES: Cl[Sn]Cl.[Cl:4][C:5]1[C:6]([C:11]2[CH:12]=[C:13]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.C([O-])(O)=O.[Na+]>CCO>[Cl:4][C:5]1[C:6]([C:11]2[CH:16]=[C:15]([CH:14]=[C:13]([C:20]3[NH:28][C:23]4=[N:24][CH:25]=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:12]=2)[NH2:17])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(-c2nc3cccnc3[nH]2)cc(-c2ncccc2Cl)c1
Temperature: 100 °C
Yield: 69.9 %

Procedure:
SnCl2 (450 mg, 2.0 mmol) was added to a solution of Example 182 (140 mg, 0.4 mmol) in EtOH (5 mL) and the resulting suspension was heated at 100° C. for 3 h. The mixture was cooled to rt and saturated NaHCO3 solution (500 mL) was slowly added. The resulting milky white suspension was extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by LCMS (acetonitrile-water gradient) to give the title compound (90 mg, 70%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31 (t, J=5.21 Hz, 1 H) 7.43 (dd, J=7.21, 4.42, Hz, 1 H) 7.55 (dd, J=5.27, 3.48 Hz, 1 H) 7.69 (t, J=5.11 Hz, 1 H) 7.86 (t, J=5.11 Hz, 1 H) 7.98 (dd, J=9.21, 5.42, Hz, 1 H) 8.56 (d, J=5.91 Hz, 1 H) 8.62 (d, J=5.91 Hz, 1 H). MS (ES) [M+H] calculated for C17H13ClN5, 322.01; found 321.98.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[Br:14][C:15]1[CH:24]=[CH:23][C:18]([C:19](=O)[CH2:20]Br)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:20]=2)=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(Br)cc3)cs2)cc1
Yield: 73 %

Procedure:
In the same manner as in Example 74, methyl 4-thiocarbamoylbenzoate was reacted with 4-bromophenacyl bromide to obtain methyl 4-[4-(4-bromophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 73%. Colorless prisms. Melting point: 206 to 207° C.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][NH:14][C:15](=[O:16])[CH:10]2[CH2:9]1)C1C=CC=CC=1>C(O)C.C(#N)C.[Pd]>[C:15]1(=[O:16])[CH:10]2[CH2:9][NH:8][CH2:12][CH:11]2[CH2:13][NH:14]1
Reactant: O=C1NCC2CN(Cc3ccccc3)CC12
Agent: [Pd]
Solvent: CC#N
Solvent: CCO
Product: O=C1NCC2CNCC12
Reaction time: 16 h

Procedure:
A solution of 5-benzylhexahydropyrrolo[3,4-c]pyrrole-1-one, (7.2 g; 33 mmol) in absolute ethanol (100 ml) is placed in a 250 ml autoclave and palladium-on-charcoal at 5% (1.5 g) is then added. After having purged with nitrogen, the autoclave is placed under 56 bar of hydrogen at 70° C. for 16 hours. After returning to 20° C., the catalyst is filtered off and the filtrate is evaporated under reduced pressure. The compound obtained is taken up in acetonitrile (15 ml) at reflux, filtered, under hot conditions, through paper and then crystallized. After crystallization, the solid obtained is filtered off, washed with acetonitrile (3 ml) and then with diethyl ether (20 ml) and, finally, dried under reduced pressure at constant weight. Hexahydropyrrolo[3,4-c]pyrrole-1-one, (1.3 g; 31%) is isolated, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]=[C:6]([NH2:11])[CH2:7][CH:8]1[CH2:10][CH2:9]1)[CH3:2].[F:13][C:14]([F:32])([F:31])/[C:15](/O)=[CH:16]/[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[C:15]([C:14]([F:13])([F:32])[F:31])=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:21][CH:20]=2)=[N:11][C:6]=1[CH2:7][CH:8]1[CH2:9][CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C(N)CC1CC1
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1CC1CC1
Yield: 41 %

Procedure:
3-Amino-4-cyclopropyl-but-2-enoic acid ethyl ester (231 mg, 1.4 mmol) was added to a solution of (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one (819 mg, 2.7 mmol; example 16 a]) in acetonitrile (2.7 ml). The mixture was heated under reflux conditions for 12 h, the solvent was removed under reduced pressure and the residue purified by flash chromatography (silica gel, heptane/AcOEt) to give 242 mg (0.56 mmol, 41%) of the title compound as yellow oil.
Reaction SMILES: [H-].[Na+].C1CCCCC1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[O:21])[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].[C:22](O)(=[O:24])[CH3:23]>C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[O:21])[CH2:20][C:22](=[O:24])[CH3:23])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: CC(=O)O
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CC(C)=O)cc1OC

Procedure:
3.9 g of sodium hydride were initially introduced into 150 ml of cyclohexane, and a solution of 15 g of 1-(3,4-dimethoxyphenyl)ethanone in 16.3 ml of ethyl acetate was added. The reaction solution was boiled at 80° C. for 1 h, after which acetic acid was added and the whole was extracted with MTB-ether. The MTB-ether phase was dried over magnesium sulfate and subjected to rotary evaporation. The residue was chromatographed through silica gel (ethyl acetate/heptane 1/6). The following was obtained: 41 C12H14O4 (222.24); MS (ESI) 223 (M+H)
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]3[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=3[N:12]=[CH:13][N:14]=2)[NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][Si](C)(C)CCOCN1C2N=CN=C(CN)C=2C=C1.Cl>COC(OC)N(C)C.C(OCC)(=O)C>[CH:1]1([C:7]2[N:8]=[CH:26][N:14]3[C:9]=2[C:10]2[CH:17]=[CH:16][N:15]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[N:12]=[CH:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(C(N)C3CCCCC3)ncnc21
Reactant: C[Si](C)(C)CCOCn1ccc2c(CN)ncnc21
Agent: COC(OC)N(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c1ncn1cnc(C3CCCCC3)c21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 302.6 %

Procedure:
Cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)methanamine (10 mg. 0.028 mmol) in N,N-dimethylformamide dimethyl acetal (0.7 mL) was stirred at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in 1,3-dimethylimidazolidin-2-one (1.0 mL) and stirred at 230° C. for 1.5 hours under microwave irradiation. Separately, cyclohexyl(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-ylmethanamine (89 mg, 0.25 mmol) in N,N-dimethylformamide dimethyl acetal (1 mL) was stirred at 170° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in 1,3-dimethylimidazolidin-2-one (4.5 mL) and stirred at 230° C. for 1.5 hours under microwave irradiation. The reaction mixture and the previously obtained reaction mixture were combined, diluted with ethyl acetate, acidified with 1 M hydrochloric acid and washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (hexane/ethyl acetate=2/1→1/1→1/2 (v/v)) to give the title compound as a pale yellow oil (31.4 mg, yield 30%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([F:11])[F:10].CN(C)[CH:14]=[O:15].Cl>C1COCC1>[F:10][CH:9]([F:11])[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[CH:14]=[O:15]
Reactant: CN(C)C=O
Reactant: Fc1ccc(C(F)F)c(Br)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cc(F)ccc1C(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 36.8 %

Procedure:
Isopropylmagnesium chloride-lithium chloride complex (1M, 21.46 mL, 21.46 mmol) was added to 2-bromo-1-(difluoromethyl)-4-fluorobenzene (4.39 g, 19.51 mmol) in THF (120 mL) cooled to −20° C. under nitrogen. The resulting solution was stirred at −20° C. for 1 hour. N,N-Dimethylformamide (1.813 mL, 23.41 mmol) was added, and the mixture stirred for a further 1 hour, maintaining the temperature in the range −15 to −20° C. The mixture was allowed to warm to ambient temperature, then 2M hydrochloric acid (100 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic layer was washed with saturated sodium bicarbonate (120 mL) and concentrated to yield crude product. The crude product was purified by flash silica chromatography, elution gradient 5 to 10% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 2-(difluoromethyl)-5-fluorobenzaldehyde (1.250 g, 36.8%) as a colourless liquid.
Reaction SMILES: C(NC(C1SC(N2CCN(CC3C=C(C=CC=3)C(OCC)=O)C2=O)=NC=1C)=O)C1C=CC=CC=1.[CH:35]1([CH2:38][N:39]2[CH2:43][CH2:42][N:41]([C:44]3[S:45][C:46]([C:49]([O:51]C)=[O:50])=[CH:47][N:48]=3)[C:40]2=[O:53])[CH2:37][CH2:36]1>>[CH:35]1([CH2:38][N:39]2[CH2:43][CH2:42][N:41]([C:44]3[S:45][C:46]([C:49]([OH:51])=[O:50])=[CH:47][N:48]=3)[C:40]2=[O:53])[CH2:37][CH2:36]1
Reactant: COC(=O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Agent: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Product: O=C(O)c1cnc(N2CCN(CC3CC3)C2=O)s1
Yield: 93 %

Procedure:
Following the procedure as described in Example 25, making variations as required to replace ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate with methyl 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 93% yield: mp 250-252 (water); 1H NMR (300 MHz, DMSO-d6) δ 12.97 (s, 1H), 7.93 (s, 1H), 4.03-3.96 (m, 2H), 3.66-3.61 (m, 2H), 3.08 (d, J=7.1 Hz, 2H), 0.96-0.87 (m, 1H), 0.49-0.43 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 163.3, 162.8, 155.0, 145.2, 122.4, 48.2, 42.5, 42.4, 9.27, 3.62; MS (ES+) m/z 268.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:19][C:3]2[CH:4]=[CH:5][C:6]([N:8]3[CH2:12][CH2:11][C@H:10]([N:13]4[CH2:17][CH2:16][CH2:15][C@@H:14]4[CH3:18])[CH2:9]3)=[CH:7][C:2]=2[CH3:1])=[O:26])=[CH:23][CH:22]=1
Reactant: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: Cc1cc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1NC(=O)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-(2-(S)-methyl-[1,3′(S)]bipyrrolidinyl-1′-yl)-phenylamine with 4-chloro-benzoyl chloride. LCMS: RT=3.96 minutes, MS: 398 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[Cl:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CCCCCC.O.O1CCCC1>[Cl:22][C:23]1[CH:37]=[CH:36][C:26]([C:27]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)([C:5]2[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)[OH:28])=[CH:25][CH:24]=1
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COCn1ccnc1C(O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 11.2 g. (0.1 mol) of 1-(methoxymethyl)-imidazole and 13.9 g. (0.12 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml. of anhydrous tetrahydrofuran 51 ml. (0.12 mol) of n-butyllithium solution in hexane was added with stirring over a period of about one hour and at a temperature of -60° C. Stirring was continued for another 2 hours at -60° C. Cooling was discontinued and 25.1 g. (0.1 mol) of 4,4'-dichlorobenzophenone in 150 ml. of anhydrous tetrahydrofuran was added drop-wise. The mixture was stirred for 6 hours at room temperature and decomposed by addition of 15 ml. of water. Lithium hydroxide was removed by filtration and the filtrate was concentrated. A 2 N hydrochloric acid solution was added and the mixture was extracted with liberal amounts of diethyl ether. The acidic aqueous solution was made alkaline by addition of potassium carbonate and extracted with diethyl ether, toluene and ethyl acetate. The organic solvent solutions were combined, dried and concentrated. The solid was purified by crystallisation from toluene; its melting point was 145°-146° C.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)(=O)=O.[C:15]1(O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[Na+]>C(O)(C)C>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][CH2:6][O:5][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]=1
Reactant: Cc1cccc(CCOS(C)(=O)=O)n1
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cccc(CCOc2ccccc2)n1
Temperature: 90 °C
Yield: 26 %

Procedure:
MsCl (6.7 mmol, 0.52 mL) was added to a solution of 6-methyl-2-pyridineethanol (6.7 mmol, 0.92 g) and triethyl amine (13.4 mmol, 1.88 mL) in toluene (6 mL) at 0° C. dropwise. The resulting mixture was stirred at 0° C. for 30 min. The precipitate generated from reaction was filtered off. The filtrate was concentrated in vacuo to give crude 2-(6-methylpyridin-2-yl)ethyl methanesulfonate which was used for next step without further purification. A mixture of above described 2-(6-methylpyridin-2-yl)ethyl methanesulfonate, PhOH (13.4 mmol, 1.26 g) and NaOH (13.4 mmol, 0.54 g) in isopropanol (20 mL) was refluxed at 90° C. for 3 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc which was washed with water. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography to give desired 2-methyl-6-(2-phenoxyethyl)pyridine as a colorless oil in 26% yield.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[F:51][C:52]([F:67])([F:66])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[S:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[O:18]=[C:16]([N:63]1[CH2:62][CH2:61][CH:60]([S:59][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=2[C:52]([F:66])([F:51])[F:67])[CH2:65][CH2:64]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:11][N:10]=1)=[O:13]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: FC(F)(F)c1ccccc1SC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Sc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a stirred solution of [(5-Phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.05 g, 0.00018 mol) in DMF (1 mL) was added DIPEA (0.0689 g, 0.00053 mol), HOBt (0.028 g, 0.00021 mol) and EDCI.HCl (0.0407 g, 0.00021 mol) at ambient temperature. After 2 minutes 4-(2-trifluoromethyl-phenylsulfanyl)-piperidine hydrochloride (0.063 g, 0.00021 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.068 g (78%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylsulfanyl)-piperidin-1-yl]-ethyl}-amide. LCMS: 489.15 (M+1)+, 94.5%, 1H NMR (DMSO-d6): δ 13.8 (s, 1H), 8.0 (s, 1H), 7.8 (m, 4H), 7.65 (t, 1H), 7.5-7.3 (m, 4H), 7.1 (s, 1H), 4.3-4.05 (m, 3H), 3.9-3.6 (m, 2H), 3.2 (m, 1H), 2.9 (m, 1H), 1.9 (m, 2H), 1.6 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[CH:7]=[C:6]([Cl:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:30])C=1.O.[OH-].[Na+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[O:21][CH:2]([CH2:3][OH:30])[CH2:1][C:4]=2[C:12]2[O:11][N:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:8]=2[CH:7]=1
Reactant: C=CCc1c(O)c(Cl)cc2c(-c3ccccc3Cl)noc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4Cl)noc23)O1
Temperature: 0 °C
Yield: 97.4 %

Procedure:
To the ice-cooled solution of 7-allyl-5-chloro-3-(2-chlorophenyl)-6-hydroxy-1,2-benzisoxazole (4.5 g) in methylene chloride (200 ml), 6.6 g of m-chloroperbenzoic acid was added in small portions under agitation, and the mixture was subsequently refluxed for 4 hours. After cooling the mixture, water and 50 ml of an aqueous solution of 2N sodium hydroxide were added and the mixture was extracted with methylene chloride. The methylene chloride layer was washed with water and dried. By distilling off the solvent, 4.6 g of 5-chloro-3-(2-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-methanol was obtained. m.p. 162°-163° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 335.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:12]=1[C:13](O)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:27](CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].O>[NH:1]([C:8]1[S:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][C:12]=1[C:13]([NH2:27])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccccc2)sc1Nc1ccccc1
Reaction time: 15 h

Procedure:
To a solution of 2-anilino-5-phenylthiophene-3-carboxylic acid (47.3 mg, 0.160 mmol), ammonium chloride (17.12 mg, 0.320 mmol), and N,N-diisopropylethylamine (0.084 ml, 0.480 mmol) in N,N-dimethylformamide (1 mL) was added 1-hydroxybenzotriazole hydrate (32.4 mg, 0.240 mmol) and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (46.0 mg, 0.240 mmol). After being stirred for 15 hours, the reaction mixture was diluted with ethyl acetate (20 mL), saturated aqueous sodium bicarbonate solution (10 mL), and water (2 mL). The layers were separated and the organic layer was washed with water (2×5 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The crude reaction mixture was purified by silica gel chromatography (50% ethyl acetate/hexanes) to afford 2-anilino-5-phenylthiophene-3-carboxamide.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][S:8](Cl)(=[O:10])=[O:9])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[O:21]1[CH2:22][CH2:23][N:18]([S:8]([CH2:7][CH2:6][N:5]2[C:4](=[O:12])[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:1]2=[O:17])(=[O:10])=[O:9])[CH2:19][CH2:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: C1COCCN1
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)N1CCOCC1

Procedure:
Prepared according to general method A from 2-phthalimidoethanesulfonyl chloride (2.0 g) and morpholine (2.14 ml). Yield: 1.28 g (48%). 1H-NMR (CDCl3) δ (ppm) 7.94-7.84 (m, 4H), 3.99 (t, J=6.8 Hz, 2H), 3.62 (t, J=4.7 Hz, 4H), 3.45 (t, J=6.8 Hz, 4H), 3.15 (t, J=4.6 Hz, 4H).
Reaction SMILES: [C:1]([CH:5]([N:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[CH2:15])[C:8]1=[O:16])[CH3:6])([O:3][CH3:4])=[O:2].C1(C)C=CC=CC=1.[C:24]([OH:27])(=[S:26])[CH3:25]>>[C:1]([CH:5]([N:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:15][S:26][C:24](=[O:27])[CH3:25])[C:8]1=[O:16])[CH3:6])([O:3][CH3:4])=[O:2]
Reactant: CC(O)=S
Reactant: C=C1CCCCCN(C(C)C(=O)OC)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)N1CCCCCC(CSC(C)=O)C1=O

Procedure:
A solution of 50 mg of 1-(1-carbomethoxyethyl)-3-methyleneperhydroazocin-2-one in thioacetic acid (0.5 ml) is kept at room temperature for 18 hours. Toluene (5 ml) is added and the mixture is concentrated to dryness under reduced pressure. The product is purified by preparative tlc on silica gel (system 5% acetone in chloroform) to yield the title compound (62 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17]O)=[CH:12][CH:11]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OCCc1ccc(F)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a stirred solution of 4-bromophenol (81.7 g, 472 mmol), 2-(4-fluorophenyl)ethanol (79 g, 567 mmol) and Ph3P (149 g, 567 mmol) in THF (100 mL) cooled in an ice-water bath was added drop wise DEAD (93 ml, 590 mmol) over 20 min. Note: The reaction is exothermic and efficient cooling is highly recommended before initiating large scale reaction. After 1 h, cold bath was removed and stirred overnight (17 h) at rt. Then, the reaction mixture was concentrated, the resulting residue triturated with hexanes, filtered and the filter cake washed with 10% ether/hexanes (2-lit). The filtrate was concentrated and purified by flash chromatography (silica gel column 3″×11″) using 4-lit hexanes and 2-lit 2% EtOAc/Hex to afford 1-bromo-4-(4-fluorophenethoxy)benzene (142 g, 469 mmol, 99% yield) as colorless liquid (contaminated with ˜2.5% Ph3P by 1HNMR). 1H NMR (500 MHz, CDCl3) δ 7.41-7.36 (m, 2H), 7.28-7.22 (m, 2H), 7.05-6.99 (m, 2H), 6.82-6.76 (m, 2H), 4.14 (t, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H).