Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[C:48]([Cl:49])=[CH:47][CH:46]=[CH:45][C:44]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(Cl)c3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 45.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, 0.0607 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 2,3-dichlorobenzenesulfonyl chloride (0.0479 g, 0.195 mmol) to obtain 4-(2,3-dichlorobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0186 g, yield 37%).
Reaction SMILES: [N:1]1([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][N:4]([C:37](=[O:39])[CH3:38])[CH2:5][CH2:6]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)Cl
Reactant: c1ccc2nc(N3CCC(Oc4nccnc4N4CCNCC4)CC3)ccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 2-(4-((3-(piperazin-1-yl)pyrazin-2-yl)oxy)piperidin-1-yl)quinoline (130 mg, 0.33 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and acetyl chloride (80 mg, 0.66 mmol) was added dropped to the reaction mixture. 1 hour later, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give 1-(4-(3-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyrazin-2-yl)piperazin-1-yl)ethanone (108 mg, 0.25 mmol, 78% yield) as a white solid. ESI-MS (M+1): 433 calc. for C24H28N6O2 432.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[C:34]([NH:35]C(=O)OCC3C=CC=CC=3)=[CH:33][C:32]3[C:27](=[CH:28][C:29]([N:46]4[CH2:51][CH2:50][CH2:49][CH2:48][C:47]4=[O:52])=[CH:30][CH:31]=3)[N:26]=2)=[O:24])[CH2:10]1)=O)(C)(C)C>Br.CC(O)=O>[NH2:35][C:34]1[C:25]([C:23]([NH:22][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][C:16]=2[N:11]2[CH2:12][C@H:13]([CH3:15])[CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:24])=[N:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[C:29]([N:46]1[CH2:51][CH2:50][CH2:49][CH2:48][C:47]1=[O:52])[CH:28]=2
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H](N)CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl [2-{[(4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-(2-oxopiperidin-1-yl)quinolin-3-yl]carbamate (0.005 g, 0.007 mmol) in 2 mL of 33% HBr in AcOH was stirred at room temperature for 2 h. The mixture was evaporated to dryness under reduced pressure. The resulting residue was dissolved in 4 mL of MeOH and treated with 0.5 mL of NH4OH solution. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H32N7O2 [M+H]: m/z=474.3. found: 474.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.O>O1CCCC1.C(=O)([O-])O.[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cn2)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1
Yield: 60.5 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyridin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (486 mg) synthesized in Example 100-1 and 4-fluorophenylboric acid (297 mg) were dissolved in tetrahydrofuran (10 mL) and sodium hydrogen carbonate (1 mol/l, 10 mL), tetrakis(triphenylphosphine)palladium (245 mg) was added, and the mixture was refluxed for 4.5 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (304 mg) as a pale-yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([NH:2][CH2:3][CH2:4][C:5]([NH:7][NH:8][C:9]([N:11]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[O:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]1=2)=[O:10])=[O:6])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Product: CS(=O)(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[-3-[(methylsulfonyl)amino]-1-oxopropyl]hydrazide (11) was prepared from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9), prepared as described above in Example 9, and methanesulfonyl chloride, in the manner described in Example 10 above, on a 2-mmol scale to yield 0.46 g (52%) of product.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[N:3]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])=[C:11]([CH3:22])[CH:10]=1.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(#N)C>[CH2:25]([O:1][CH:2]1[CH2:6][N:5]([CH3:7])[C:4](=[O:8])[N:3]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:21])([F:20])[CH:17]([F:18])[F:19])=[C:11]([CH3:22])[CH:10]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cc(N2C(=O)N(C)CC2O)ccc1OC(F)(F)C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(N2C(=O)N(C)CC2OCc2ccccc2)ccc1OC(F)(F)C(F)F
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
16.1 g (0.05 mol) of 4-hydroxy-1-methyl-3-[3-methyl-4-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazolidin-2-one are dissolved in 150 ml of acetonitrile, and 1.50 g of sodium hydride (80% strength in white oil) are added at 5° C. The mixture is stirred for 10 minutes at 5° C., and 6.40 g (0.05 mol) of benzyl chloride are subsequently added dropwise at 5° C. The mixture is stirred for 5 hours at 50°and poured into 400 ml of ice-water. The mixture is extracted twice with 100 ml of methylene chloride in each case, and the combined methylene chloride phases are washed with 100 ml of water and dried over sodium sulfate. After removing the solvent by distillation, 19.4 g (94% of theory) of 4-benzyloxy-1-methyl-3-[3-methyl-4-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazolidin-2-one are obtained in the form of a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:3]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cccnc1-c1cccc(N)c1
Yield: 100 %

Procedure:
A suspension of 3-(3-methylpyridin-2-yl)nitrobenzene (214 mg) in ethanol (5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 50 mg) under a hydrogen atmosphere for 2 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(3-methylpyridin-2-yl)aniline (184 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:10](=[O:12])[NH:9][C:8]3[CH:13]=[CH:14][CH:15]=[N:16][C:7]=3[NH:6][C:5]=2[C:4]([CH3:17])=[N:3]1.[H-].[Na+].[CH3:20]I.O>CN(C)C=O>[CH3:1][N:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:20])[C:8]3[CH:13]=[CH:14][CH:15]=[N:16][C:7]=3[NH:6][C:5]=2[C:4]([CH3:17])=[N:3]1
Reactant: CI
Reactant: Cc1nn(C)c2c1Nc1ncccc1NC2=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nn(C)c2c1Nc1ncccc1N(C)C2=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
An amount of 5.25 gm (0.025 mol) of 1,3-dimethyl-1,4,9,10-tetrahydro-pyrazolo[4,3-e]pyrido[3,2-b][1,4]diazepin-10-one was dissolved in 25 ml of N,N-dimethylformamide and mixed with 1.2 gm of a 55% sodium hydride dispersion in mineral oil. After stirring for 2 hours at 60° C., the solution was cooled to 40° C., and 2.2 ml of methyl iodide were added dropwise. Subsequently the mixture was stirred for 3 hours at 40° C., and after addition of 50 ml of water and cooling in the ice-bath, the desired compound was obtained in crystals. The crystals were recovered by suction filtration, and the mineral oil was washed out by means of petroleum ether.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)[C:8]2[N:13]=[N:12][N:11](CC3C=CC(OC)=CC=3)[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C.[C:36](O)([C:38]([F:41])([F:40])[F:39])=[O:37]>>[C:1]([C:5]1[N:6]=[C:7]([N:23]2[CH2:27][CH2:26][C@H:25]([O:28][C:36](=[O:37])[C:38]([F:41])([F:40])[F:39])[CH2:24]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cn2nnc3c(N4CC[C@H](O)C4)nc(C(C)(C)C)nc32)cc1
Agent: CC[SiH](CC)CC
Product: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Temperature: 70 °C

Procedure:
A mixture of (S)-1-[5-tert-Butyl-3-(4-methoxy-benzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol and triethylsilane in TFA was heated to 70° C. for 22 h and evaporated to dryness. The residue was used without further purification in the consecutive step.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=1.[OH-].[K+].C(O)C.Cl>O>[CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCCCCCCCCCC(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1

Procedure:
A solution of 3.5 g. of ethyl 4-(15-methylhexadecyl)aminobenzoate and 1.7 g. of 85% potassium hydroxide in 50 ml. of 95% ethanol is heated at reflux for 5 hours. The warm solution is diluted with 100 ml. water and adjusted to pH5 with 37% hydrochloric acid. The precipitate is collected, dried, and crystallized from acetic acid to yield the title compound as an amorphous, cream-colored solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.[CH2:16]([NH:18][CH2:19]C)C>S(Cl)(Cl)=O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:16])=[O:5]
Reactant: Nc1ccccc1C(=O)O
Reactant: CCNCC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1ccccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-aminobenzoic acid (1.0 g, 7.3 mmol) in thionyl chloride (20 mL) was refluxed for 3 hours. Excess of thionyl chloride was removed. And the residue was treated with toluene (3×10 mL) to remove the excess thionyl chloride. To the crude product obtained was added THF (20 mL) and the resulting solution was cooled to 0° C. Diethyl amine (3.78 mL, 36 mmol) was added and the resulting solution was stirred for 2 hrs at room temperature. The solvent was removed under reduced pressure and residue was taken into dichloromethane (20 mL), washed with saturated sodium bicarbonate solution (3×20 mL), water (20 mL), dried over sodium sulfate and concentrated to provide the desired product as brown oil. This crude product was used in Step 2 without further purification.
Reaction SMILES: [F:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29]OS(C)(=O)=O>C1COCC1>[Cl:22][C:23]1[CH:24]=[C:25]([O:36][S:37]([C:40]([F:42])([F:43])[F:41])(=[O:39])=[O:38])[CH:26]=[C:27]([Cl:35])[C:28]=1[CH2:29][CH:10]1[CH2:11][CH2:12][N:8]([C@H:5]2[CH2:6][CH2:7][C@H:2]([F:1])[CH2:3][CH2:4]2)[C:9]1=[O:13]
Reactant: CS(=O)(=O)OCc1c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc1Cl
Reactant: O=C1CCCN1[C@H]1CC[C@H](F)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1C(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCN1[C@H]1CC[C@H](F)CC1
Reaction time: 8 h

Procedure:
To a solution of trans-1-(4-fluoro-cyclohexyl)-pyrrolidin-2-one (252 mg, 1.36 mmol) in 13 mL dry THF, add 1.09 mL of 2M LDA (1.2 eq.) in THF dropwise at −78° C. Then, add 821 mg of trifluoro-methanesulfonic acid 3,5-dichloro-4-methanesulfonyloxymethyl-phenyl ester (1.5 eq) at −78° C. Allow the resulting solution to stand at room temp for overnight. Quench the mixture with saturated aqueous NH4Cl and extract with CH2Cl2. Wash the organic layer with water, then brine, and dry over Na2SO4, filter and concentrate. Purify the crude material by chromatography to afford the title compound: mass spectrum (m/z): 358 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=c1[nH]cncc1Br
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2cncc(Br)c2=O)cc1
Reaction time: 0.5 h

Procedure:
5-Bromopyrimidin-4(3H)-one (459 mg) was dissolved in N,N-dimethylformamide (13 mL), then with cooling with ice, sodium hydride (55%, 137 mg) was added, followed by stirring at the same temperature for 30 minutes. Then, 1-(chloromethyl)-4-methoxybenzene (392 μL) was added, followed by stirring at room temperature for 15 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain 5-bromo-3-(4-methoxybenzyl)pyrimidin-4(3H)-one (382 mg) as a white solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[C:13]([C:29]#[N:30])=[C:14]([CH:26]=[CH:27][CH:28]=1)[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:22]([C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:26]=[CH:27][CH:28]=[C:12]([Cl:11])[C:13]=3[C:29]#[N:30])=[CH:21][CH:20]=2)(=[O:23])=[O:24])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)c1sc(N)nc1C
Product: CC(=O)c1sc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)nc1C

Procedure:
The tide compound was prepared from 5-acetyl-2-amino-4-methylthiazole and 4-(3-chloro-2-cyanophenoxy)benzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (9.9 mg) with purity >90%. LCMS (pos) m/z 448.0; LCMS (neg) m/z 446.0.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:23])[C:12]3[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=3)[S:8][C:7]=2[CH:32]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:23])[C:12]3[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:16][CH:17]=3)=[C:9]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[S:8][C:7]=2[CH:32]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(C=CC(=O)O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a −5° C. solution of 6-methoxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-methoxyphenyl)benzo[b]thiophene (900 mg, 2.0 mmol) in 40 mL of anhydrous CH2Cl2 under N2 was added BBr3 (0.76 mL, 8.0 mmol) slowly via syringe. After warming to 5° C., the mixture was stirred for 1 h at 5° C., then quenched by pouring into ice water (100 mL). The mixture was extracted with EtOAc (3×100 mL). The organic was then dried (Na2SO4) and concentrated in vacuo to a solid residue that was chromatographed (SiO2, 1% MeOH/CHCl3) to provide 730 mg (86%) of (E)-6-hydroxy-3-[4-(2-carboxyvinyl)benzoyl]-2-(4-hydroxyphenyl)benzo[b]thiophene as a yellow solid. mp 155-160° C. 1H NMR (DMSO-d6) δ12.55 (bs, 1H), 9.81 (s, 1H), 9.73 (s, 1H), 7.67 (s, 4H), 7.54 (d, J=16.0 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H), 6.89 (dd, J=9.0, 2.5 Hz, 1H), 6.65 (d, J=9.0 Hz, 2H), 6.58 (d, J=16.0 Hz, 1H). FD mass spec: 416. Anal. Calcd. for C24H16O5S: C, 69.22; H, 3.87. Found: C, 68.95; H, 3.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N+:10]#[C-:11])[S:13]([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: COCCOC
Product: [C-]#[N+]C(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: -5 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a solution of N-((2,4-difluorophenyl)(tosyl)methyl)formamide (7.31 g, 22.5 mmol) in DME (100 mL) at about −10° C. was added phosphorus oxychloride (Fluka, 6.28 mL, 67.4 mmol) followed by dropwise addition of TEA (15.7 mL, 112 mmol) in DME (10 mL). The reaction mixture was stirred at about −5° C. for about 3 h. The reaction mixture was poured into ice-cold water (250 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography using heptane/EtOAc (gradient; 1:0 to 1:1) to give the title compound (1.38 g, 20.0%), as a yellow solid. LC/MS (Table 1, Method a) Rt=2.96 min; MS m/z: 306.1 (M−H)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>>[C:2]1([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: Ic1ccccc1
Solvent: CCN(CC)CC
Product: C(=Cc1ccccc1)c1ccccc1
Yield: 100 %

Procedure:
A solution of iodobenzene (1 mmol), of styrene (1.5 mmol), of PdBr2 or PdSO4 (10 mol %) and of triethylamine (2 mmol) in N,N′-butylmethylimidazolium methyl H-phosphonate (2 g) is brought to 110° C. for 5 hrs. The formed trans-stilbene is extracted with ether (3×10 mL), the structure of which is confirmed by 1H NMR. (yield=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:13]=2[C:14]([Cl:26])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)O)cc1OC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c(C(=O)Cl)cc1OC
Temperature: 42.5 °C
Reaction time: 2.5 h
Yield: 92.6 %

Procedure:
25.90 g (0.07 mol) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoic acid were mixed with 75 ml of toluene, 17.30 g (0.08 mol) of phosphorus pentachloride were added and the mixture was stirred at 40-45° C. for 2.5 h. Then the mixture was concentrated in vacuo to half of its volume and the product that precipitated was filtered off with suction and washed with a small amount of toluene. 25.30 g (93%) of 2-(4-chloro-phenylsulfonylamino)-4,5-dimethoxy-benzoyl chloride having a melting point of 175-177° C. were obtained.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:9][S:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])(=[O:12])=[O:11])=[O:8])=[CH:3][CH:2]=1.[NH2:26][OH:27].Cl>C(N(CC)CC)C>[OH:27][NH:26][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][S:10]([CH2:9][C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:2][CH:3]=1)=[O:8])(=[O:12])=[O:11]
Reactant: NO
Reactant: O=C(O)CCCCS(=O)(=O)CC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(CCCCS(=O)(=O)CC(=O)c1ccc(-c2ccccc2)cc1)NO
Yield: 52 %

Procedure:
Following the procedure described in Example 14, step 3, but substituting carboxylic acid 228b for 37, and using 1.1 equivalent of NH2OH.HCl and triethylamine each, the title compound 228b was obtained in 52% yield. 1H NMR: (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.70 (s, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.77 (dd, J=1.4 Hz, J=8.5 Hz, 2H), 7.53-7.43 (m, 3H), 5.08 (s, 2H), 3.38-3.25 (t, 2H), 1.99 (t, J=6.6 Hz, 2H), 1.72-1.61 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH3:16]C1C=CC=C(C)C=1O>>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccccc1OCCCCC(=O)O
Reactant: Cc1cccc(C)c1O
Product: Cc1cccc(C)c1OCCCCC(=O)O

Procedure:
5-(2,6-Dimethylphenoxy)pentanoic acid 26c was prepared in the same manner as 26b, except that 2,6-dimethylphenol was used as the starting material. 1H NMR: (400 MHz, CDCl3): 7.0-7.1 (m, 3H), 3.83 (t, 2H, J=6 Hz), 2.37 (t, 2H, J=6 Hz), 2.73 (s. 6H), 1.92 (m, 4H). MS (ESI): 223 [M+H]+; 245 [M+Na]+.