Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([NH:18][C@@H:19]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20][C:21](=[O:24])[NH:22][CH3:23])=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>C(Cl)Cl>[CH3:23][NH:22][C:21](=[O:24])[CH2:20][C@H:19]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[NH2:18]
Reactant: CNC(=O)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CNC(=O)C[C@@H](N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 226.2 %

Procedure:
To tert-butyl N2-(((9H-fluoren-9-yl)methoxy)carbonyl)-N4-methyl-D-asparaginate (200 mg, 0.47 mmol) in DCM (0.93 mL) was added piperidine (233 μL, 2.35 mmol). The reaction mixture was stirred at room temperature for 1 h. All solvent was removed to give 215 mg of tert-butyl N4-methyl-D-asparaginate as a mixture with 1-((9H-fluoren-9-yl)methyl)piperidine. The mixture was used without purification in the next reaction. LCMS-ESI (m/z) calculated for C9H18N2O3: 202.1. found 203.1 [M+H]+, tR=0.534 min (Method 16).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[SH:10].[OH-].[Na+].Cl[CH:14]([F:16])[F:15].Cl>O1CCOCC1.O>[F:15][CH:14]([F:16])[S:10][C:2]1[S:1][C:9]2[C:4]([N:3]=1)=[N:5][CH:6]=[CH:7][CH:8]=2
Reactant: Sc1nc2ncccc2s1
Reactant: FC(F)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: FC(F)Sc1nc2ncccc2s1
Temperature: 70 °C
Yield: 33 %

Procedure:
A solution of thiazolo[4,5-b]pyridine-2-thiol (2.0 g, 12 mmol) in dioxane is treated with a solution of sodium hydroxide (4.8 g, 120 mmol) in water, heated to 70° C., treated with a steady stream of chlorodifluoromethane for 75 minutes, and poured onto ice. The resultant aqueous mixture is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic extract is dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and several ethyl acetate/hexanes solutions gives the title product as a light yellow solid (0.86 g, 33% yield, mp 41-43° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH:31]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38](B(O)O)[CH:39]=1)([CH3:33])[CH3:32]>COCCOC>[CH:31]([C:34]1[CH:35]=[CH:36][C:37]([O:43][CH3:44])=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:39]=1)([CH3:33])[CH3:32]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: COc1ccc(C(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(C(C)C)cc1-c1ccccc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 30.2 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 5-isopropyl-2-methoxy-phenylboronic acid (37 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a solid (18 mg, 31%). LC-MS m/e 459.35 (M+H+)
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:15][CH:14]2[NH:16][CH:10]1[CH2:11][C:12](=[CH:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:15][CH:14]2[N:16]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH:10]1[CH2:11][CH:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)C=C1CC2CC(O[Si](C)(C)C(C)(C)C)C(C1)N2
Solvent: ClCCl
Product: COC(=O)CC1CC2CC(O[Si](C)(C)C(C)(C)C)C(C1)N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of compound 109d (40 g, 0.13 mol, 1.0 eq) and TEA (40 g, 0.39 mol, 3.0 eq) in DCM (800 mL) was added a solution of CbzCl (45 g, 0.26 mol, 2.0 eq) in DCM (150 mL) slowly. The resulting mixture was stirred at room temperature for 16 h. The mixture was quenched with water, washed with 1N HCl (500 mL), the organic layer was dried over Na2SO4 and concentrated to give benzyl 6-[tert-butyl(dimethyl)silyl]oxy-3-(2-methoxy-2-oxo-ethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate 109e as a crude product.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]([NH:26][NH2:27])=[O:25].C(N(CC)CC)C>O1CCCC1>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[NH:21][C:22]1[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=1[C:24]1[O:25][C:1](=[O:2])[NH:27][N:26]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(Nc2ccccc2C(=O)NN)c1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(Nc2ccccc2-c2n[nH]c(=O)o2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
1,1'-Carbonyldiimidazole (912.3 mg, 5.63 mmoles) is added to a 0° C. solution of 2-[(2,3-dimethylphenyl)amino]benzoic acid hydrazide (1.041 g, 4.08 mmoles) and triethylamine (608 μl, 4.36 mmoles) in 20 ml of tetrahydrofuran. The reaction is stirred at room temperature for one hour. The volatiles are removed in vacuo, and the residue is dissolved in 1:1 ethyl acetate/ether. The organic solution is washed consecutively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated in vacuo. The resultant white solid is purified by flash chromatography with 1:1 hexane/ethyl acetate as eluant to give 968.8 mg (85%) of 5-[2-[(2,3-dimethylphenyl)amino]phenyl]-1,3,4-oxadiazol-2(3H)-one, mp 239°-241° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1.[CH:10](O)=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=[O:11])[CH:3]=1
Reactant: NCc1cc(Br)ccn1
Reactant: O=CO
Product: O=CNCc1cc(Br)ccn1
Temperature: 25 °C

Procedure:
20.00 g of C-(4-bromopyridin-2-yl)methylamine are taken up in 60 ml of formic acid and the solution is heated to reflux over 3 hours. The reaction solution is cooled to room temperature and concentrated by evaporation, and the residue is taken up in saturated aqueous sodium hydrogencarbonate solution (300 ml) and the aqueous solution is extracted with dichloromethane (3×300 ml). The combined organic phases are washed with water (300 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:22][C:23](=O)[CH:24]([CH:29]=O)[CH2:25][CH2:26][O:27][CH3:28]>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][CH:13]3[O:17][C:16]4=[N:18][C:23](=[O:22])[C:24]([CH2:25][CH2:26][O:27][CH3:28])=[CH:29][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCC(C=O)C(=O)OC
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: ClC(Cl)Cl
Product: COCCc1cn2c(nc1=O)OC(COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (S) -5-(4-cyclohexyl-phenoxy methyl)-4,5-dihydro-oxazol-2-ylamine and 2-formyl-4-methoxy-butyric acid methyl ester employing the procedure described in Step2 of Example 87. [α]D25 −19.00 (c 0.5, CHCl3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]1.O>CS(C)=O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: OC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(N2CCC(O)CC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and K2CO3 (6.92 g, 50 mmol) in dimethyl sulfoxide (20 mL) was added piperidin-4-ol (2.22 g, 22 mmol) and the reaction was heated to 100° C. for 4 hours. This solution was poured into 200 ml of water and extracted with ethyl acetate (30 mL×3). The organic phase was combined and washed with saturated brine and dried over anhydrous sodium sulfate. The solid was filtered and the filtrate, 10% Pd/C (100 mg) was added and the mixture was stirred under hydrogen atmosphere at ambient temperature overnight. The catalyst was filtered, and the filtrate was concentrated to afford tan solid 3.7 g. MS (m/z): 193 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH3:14])[O:12]C(=O)N2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C[C:25]([OH:27])=[O:26])C=CC=1F.[Li+].CC([N-]C(C)C)C.C(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]([CH3:14])[OH:12])[C:25]([OH:27])=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: C[C@@H]1OC(=O)N[C@H]1c1ccc(F)c(F)c1
Agent: CC(C)[N-]C(C)C
Agent: CC=O
Agent: [Li+]
Product: CC(O)C(C(=O)O)c1ccc(F)c(F)c1

Procedure:
4(S)-(3,4-difluorophenyl)-5(S)-methyloxazolidin-2-one precursor to Compound A can be prepared by treating 3,4-difluorophenylacetic acid with LDA, followed by reaction with acetaldehyde to form 2-(3,4-difluorophenyl)-3-methyl-3-hydroxypropionic acid, and then cyclizing the hydroxypropionic acid with diphenyldiphosphorylazide to form the oxazolidinone. The oxazolidinone can then be activated by treatment with p-nitrophenylchloroformate. The oxazolidinones can be resolved into their optical isomers via chromatography prior to activation, or the unresolved material can be activated directly. The activated oxazolidinone is then acylated to give Compound A by treatment with 3-[4-(4-fluorophenyl)piperidin-1-yl]propylamine.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>C1COCC1.O>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cc(-c2ccccc2)n[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2ccccc2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of methyl 3-phenyl-1H-pyrazole-5-carboxylate (6.02 g, 29.8 mmol) in THF and H2O (3:1, 140 mL) was added LiOH (3.42 g, 142.8 mmol) and the mixture was stirred overnight at room temperature. It was poured into 2N HCl solution (150 mL) and extracted with ethyl acetate. After extration, the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated at reduced pressure to afford product (3.2 g, 57.1%): MS (EI) for C10H8N2O2: 189.26 (MH+).
Reaction SMILES: [CH3:1][CH:2]1[CH:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17](Cl)=[O:18].[OH-].[NH4+:21]>O1CCCC1.O>[CH3:1][C@H:2]1[C@@H:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:4][N:3]1[C:17]([NH2:21])=[O:18]
Reactant: [NH4+]
Reactant: CC1C(Oc2cccc(C(F)(F)F)c2)CN1C(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](Oc2cccc(C(F)(F)F)c2)CN1C(N)=O
Reaction time: 6 h
Yield: 87 %

Procedure:
A solution of 4.02 g (0.01 mole) of crude (73%) 2-methyl-3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride cis isomer in 20 ml of tetrahydrofuran was treated while stirring with 2 ml (0.02 mole) of 57% aqueous ammonium hydroxide. After stirring for 6 hr, the reaction mixture was diluted with 100 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give 4.2 g. A sample of the oil crystallized at -78° C. and was used to seed the bulk of the material. The resulting solid was recrystallized from benzene/isooctane to yield 2.35 g (87%) of white crystalline product, m.p. 107°-108° C.
Reaction SMILES: I[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9].C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C(O)C.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>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CCCC1CCC(c2ccc(B(O)O)cc2)CC1
Reactant: Ic1ccc[se]1
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: CCO
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(-c3ccc[se]3)cc2)CC1

Procedure:
A mixture 0111.0 g (41.1 mmol) of 2-iodoselenophene, 7.98 g (32.4 mmol) of 4-(4-propylcyclohexyl)phenylboronic acid, 3.70 g (3.20 mmol) of tetrakis(triphenylphosphine)palladium(0) and 60 ml of 2 N sodium carbonate soln. in 160 ml of toluene/ethanol (1:1) is heated under reflux for 22 h. After cooling, water is added, and the batch is extracted a number of times with MTBE. The combined organic phases are washed with water, sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1). The further purification is carried out by recrystallisation from n-heptane; 2-[4-(4-propylcyclohexyl)phenyl]selenophene is obtained as a colourless solid.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.CC(=O)OCC>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:21][CH2:20]1
Reactant: ClCc1nc2cccnc2s1
Reactant: Fc1ccccc1N1CCNCC1
Solvent: CCOC(C)=O
Product: Fc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-fluorophenyl)piperazine (215 mg, 1.2 mmol), and D1 EA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.77 (m, 4H) 3.10 (m, 4H) 4.06 (s, 2H) 7.08 (m, 4H) 7.56 (dd, J=8.14, 4.75 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H) 8.59 (dd, J=4.58, 1.53 Hz, 1H); (ESI) m/z 329 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.[C:14]([NH:22][C:23]1[CH:32]=[C:31](Br)[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C.C(N(CC)CC)C>[C:14]([NH:22][C:23]1[CH:32]=[C:31]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1NC(=O)c1ccccc1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
2.7 mL of (trimethylsilyl)acetylene was added to 30 mL of toluene suspension containing 3.2 g of methyl 2-(benzamido)-4-bromobenzoate, 92 mg of copper (I) iodide, 0.34 g of bis(triphenylphosphine)palladium (II) chloride and 2.7 mL of triethylamine at room temperature and stirred under nitrogen atmosphere at 70 to 80° C. for 2 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 1.0 mol/L hydrochloric acid were added and insoluble were removed by filtration. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated, under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 3.5 g of methyl 2-(benzamido)-4-(2-(trimethylsilyl)ethynyl)benzoate as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[Cl:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([Cl:17])[N:11]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([N:3]2[C:2]([CH3:8])([CH3:1])[CH2:6][O:5][C:4]2=[O:7])[CH:13]=[C:12]([Cl:17])[N:11]=1
Reactant: CC1(C)COC(=O)N1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 4,4-dimethyloxazolidin-2-one (0.103 g, 0.895 mmol) and 2,4,6-trichloropyrimidine (0.181 g, 0.984 mmol, 1.10 equiv) in DMF (3 mL) was treated with NaH (60%, 0.0429 g, 1.07 mmol, 1.2 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 mL), washed with saturated aqueous NaCl (2×20 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided 3-(2,6-dichloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (0.146 g, white solid) in 62.3% yield. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 4.16 (s, 2H), 1.74 (s, 9H); LCMS m/z 261.9 (M+H)+, Rt 0.91 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:10][C:9]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[S:13][CH2:14][C:8]=2[C:7](=[O:19])[C:6]=1[CH3:20])=[O:4].[OH-].[Na+]>CO>[CH3:20][C:6]1[C:7](=[O:19])[C:8]2[CH2:14][S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:9]=2[O:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1oc2c(c(=O)c1C)CSc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C(=O)O)oc2c(c1=O)CSc1ccccc1-2

Procedure:
A mixture of 3-methyl-4-oxo-4H,5H-[1]benzothiopyrano[4,3-b]pyran-2-carboxylic acid methyl ester (1.60 g, 5.56 mmoles, described in Example 7) in a solution of sodium hydroxide (0.5 g) in methanol (50 ml) is refluxed for 2 hr and evaporated. The residue is dissolved in water, and the solution is washed with diethyl ether and added with stirring to 3 N hydrochloric acid (25 ml). The fine precipitate is collected, washed with very dilute hydrochloric acid, small amount of water and then dried (1.506 g), mp 299°-301° C. The precipitate is crystallized from dimethyl sulfoxide-water to obtain crystals of the title compound, mp 302°-303° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:39]=[CH:38][C:31]([O:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:30][CH:29]=3)[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:41]=[CH:40][C:16]([CH2:17][N:18]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:38][CH:39]=3)[S:19]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:21])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)OC)cc3)S(=O)(=O)c3cccs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(OCC(=O)O)cc3)S(=O)(=O)c3cccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a solution of methyl (4-{[{4-[(4-butylphenyl)ethynyl]benzyl}(2-thienylsulfonyl)amino]-methyl}phenoxy)acetate (30 mg, 0.051 mmol) in MeOH/THF (4 ml, (1/1)) was added an aqueous solution of NaOH (2 mL, 1N). The reaction mixture was stirred at rt for 2 hrs. Then an aqueous solution of HCl (9 mL, 1N) was added and extracted with Et2O (2×10 mL). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure to give 30 mg (97%) of the title compound as a green oil. HPLC, Rt: 5.3 min (purity: 95.3%). LC/MS, M+(ESI): 574.2, M−(ESI): 572.3. 1H NMR (CDCl3) δ: 7.60 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.38 (d, J=7.9 Hz, 2H), 7.17 (d, J=7.9 Hz, 2H), 7.12 (m, 1H), 7.05 (m, 4H), 6.80 (d, J=8.7 Hz, 2H), 4.66 (s, 2H), 4.33 (s, 2H), 4.31 (s, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.61 (m, 2H), 1.37 (m, 2E), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2].Cl[CH:22]([C:26]1[C:27]([CH3:42])=[N:28][C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)=[CH:30][CH:31]=1)[CH2:23][CH2:24][CH3:25].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:14])[CH:22]([C:26]2[C:27]([CH3:42])=[N:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24][CH3:25])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2]
Reactant: CCCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Reactant: CCOC(=O)COc1ccc(NC)cc1CCCOC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(c1ccc(-c2cccc(C(F)(F)F)c2)nc1C)N(C)c1ccc(OCC(=O)OCC)c(CCCOC)c1
Reaction time: 5 h

Procedure:
To 0.0944 g (0.336 mmol) of the above prepared (example 1H]) [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester and 0.100 g (0.305 mmol) of the above prepared [rac]-3-(1-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine, dissolved in 1.9 ml of abs. DMSO, were added successively 0.0505 g of K2CO3 (0.366 mmol) and 0.0503 g (0.336 mmol) of NaI. The reaction was allowed to proceed for 5 h at 50° C. Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=8/2), afforded 0.082 g of the title compound as light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].Cl[C:14](=O)[CH2:15][C:16]([O:18]CC)=[O:17]>CN(C)C(=O)C.C(OCC)C.O>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14]([CH2:15][C:16]([OH:18])=[O:17])=[N:12][S:9](=[O:11])(=[O:10])[C:3]=2[CH:4]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
2-Amino-5-iodo-benzenesulfonamide (Example 4a, 2.0 g, 6.71 mmol) was dissolved in N,N-dimethylacetamide (5 mL) and diethyl ether (7 mL). Ethyl 3-chloro-3-oxo-propionate (0.916 g, 6.71 mmol) was added and the reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with diethyl ether (10 mL) and water (20 mL). Upon mixing vigorously, a precipitate formed. The solid was collected by vacuum filtration, rinsed with 1.0 M aqueous hydrochloric acid solution (2×10 mL) and dried in vacuo for 2 h. The solid was dissolved in 8% aqueous sodium hydroxide solution (50 mL) and stirred at 100° C. for 15 min. Upon cooling to 25° C., the solution was neutralized with 6.0 M aqueous hydrochloric acid solution. Additional 1.0 M aqueous hydrochloric acid solution (20 mL) was added and the desired product precipitated. The solid was collected by vacuum filtration, rinsed with 1.0 M aqueous hydrochloric acid solution (2×10 mL) and dried in vacuo for 16 h to afford the desired product, (7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (2.0 g, 5.46 mmol, 81% yield) as a pale pink powder. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (3H, s), 7.13 (1H, d, J=8.5 Hz), 7.98 (1H, dd, J1=8.6 Hz, J2=1.7 Hz), 8.03 (1H, d, J=2.5 Hz), 12.33 (1H, bs), 13.05 (1H, bs). LC-MS (ESI) calcd for C9H7IN2O4S 365.92, found 366.95 [M+H+].