Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[N:11]1)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.Cl.[O:35]([NH2:37])[CH3:36].C([O-])(=O)C.[Na+]>CO>[CH3:36][O:35][N:37]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:1][N:10]1[C:15](=[O:16])[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:13]([C:24]2[CH:25]=[CH:26][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][CH:29]=2)[CH:12]=[N:11]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(=O)c3ccccc3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CON=C(Cn1ncc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)c1=O)c1ccccc1

Procedure:
A mixture of the product from Example 46, 2-phenacyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (220 mg, 0.476 mmol), methoxylamine hydrochloride (318 mg, 3.8 mmol), and sodium acetate (518 mg, 3.8 mmol) in methanol (100 mL) was stirred at reflux for 48 hours. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with brine then dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to provide a brown oil which was purified by column chromatography (silica gel, 70:30 hexanes/ethyl acetate). Fractions containing product were combined and concentrated in vacuo. The residue was crystallized from methanol/water to provide the title compound as a mixture of E and Z oximes (yield: 82 mg, 35%). mp 95-99° C. 1H NMR (300 MHz, CDCl3) δ 3.03 (s, 3H), 4.07 (s, 3H), 5.57 (s, 2H), 6.94 (t, J=9 Hz, 2H), 7.07 (dd, J=9 Hz, 3 Hz, 2H), 7.24 (d, J=9 Hz, 2H), 7.31-7.37 (m, 3H), 7.60-7.67 (m, 2H), 7.74 (s, 1H), 7.83 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 492 (M+H)+. Anal. calc. for C26H22FN3O4S: C, 63.53; H, 4.51; N, 8.54. Found: C, 63.40; H, 4.51; N, 8.31.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25](NC4C=C(S(N)(=O)=O)C=CC=4)[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1>>[CH:14]1([C:17]2[CH:21]=[C:20]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=4)[N:24]=3)[NH:19][N:18]=2)[CH2:16][CH2:15]1
Reactant: NS(=O)(=O)c1cccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)c1
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Product: CN(C)S(=O)(=O)c1ccc(Nc2nccc(Nc3cc(C4CC4)n[nH]3)n2)cc1
Yield: 9.8 %

Procedure:
Compound 103 (25.0 mg, 9.8%) was prepared from 4-amino-N,N-dimethylbenzenesulfonamide as described in Compound 82 and purified by prep HPLC. LC-MS (m/z): 400.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.69-0.73 (m, 2H), 0.91-0.96 (m, 2H), 1.86-1.90 (m, 1H), 2.58 (s, 6H), 6.28 (bs, 1H), 6.54 (bs, 1H), 7.60 (d, J=4.0 Hz, 2H), 8.04 (d, J=4.0 Hz, 3H), 9.66 (s, 2H), 12.08 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>CN(C)C=O>[C:24]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O
Reaction time: 8 h
Yield: 33.3 %

Procedure:
2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide prepared in Reference Example 2 was dissolved in 200 ml of N,N-dimethylformamide. 2.1 ml (15 mmol) of triethylamine and 1.06 ml (15 mmol) of acetyl chloride were added to the mixture while cooling with ice, followed by stirring overnight. The reaction product was concentrated under vacuum to obtain a crude product, which was recrystallized from hot methanol to obtain 0.86 g of 4-acetylamino-1-benzyl-5-imidazolecarboxamide (yield 33%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:25][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].[ClH:32]>CN(C=O)C.C(OCC)C>[ClH:25].[ClH:32].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2cnc(-c3ccc(O)cc3)cn2)CC1
Reactant: CN(C)C(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)N1CCN(c2cnc(-c3ccc(OCC(=O)N(C)C)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
4-(4-Isopropyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-yl)phenol (0.15 g, 0.404 mmol) was dissolved in DMF (4 mL) in a 5 mL microwave vial. NaH (0.039 g, 1.62 mmol) was added slowly and the mixture was stirred at rt for 30 min. Chloro-N,N-dimethylacetamide (0.147 g, 1.21 mmol) was added and the reaction mixture was heated for 2.5 h at 130° C. in a microwave oven. The reaction mixture was evaporated in vacuo and the residue was redissolved in a mixture of DCM and water. The phases were separated and the aqueous phase was extracted with DCM (2×25 mL). The combined organic extracts were evaporated, redissolved in MeOH and purified by preparative HPLC Method B. This afforded an oil which was treated with HCl in diethyl ether to give a solid material. Recrystallization from acetone and MeOH afforded 75 mg (41%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:19][NH2:20])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:11]3[C:16](=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[NH:20][N:19]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=NN)c2ccc(F)cc2F)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 120 °C

Procedure:
A mixture of 12.1 g of 1-acetyl-4-(2,4-difluorobenzoyl)-piperidine hydrazone, 11.8 g of potassium carbonate and 120 ml of dimethylformamide was stirred and heated at 120° C. for 16 hrs. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and the solvent concentrated to give a solid. Recrystallization of the solid from ethyl acetate (twice) yielded 4.1 g (42% with concentration of mother liquor) of product, mp 162°-164° C.
Reaction SMILES: [C@H:1]12[CH2:7][CH:4](CC1)[CH2:3][C:2]2=[O:8].[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].OO>C(O)(=O)C>[OH:8][C:2]1([CH2:10][C:9]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:7][CH2:1]1
Reactant: O=C1CC2CC[C@@H]1C2
Reactant: CC(=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CC1(O)CCCC1
Yield: 66.7 %

Procedure:
This product is oxidized by the Baeyer-Villiger procedure. (1R)-Norbornanone (81, 18 mmol) is stirred with sodium acetate (9 g, water-free), hydrogen peroxide (27 ml, 30%), and acetic acid (9 ml) at 5° C. in the dark for 40 hours. The reaction is quenched by the addition of sodium sulfite (50 ml of a 10% aqueous solution) at 0° C. The product is extracted twice with EtOAc (600 ml). The extract is washed with the sodium sulfite solution, then with sodium bicarbonate solution (50 ml, saturated), then with sodium chloride solution (saturated), dried and evaporated. The product is chromatographed on silica (380 g, ether) to yield the lacton of 3 hydroxycyclopentane-1-acetic acid (82, 12 mmol, 67%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][NH:7][N:6]=1)=[O:4].N#N.[H][H]>[Pd].C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][NH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: COC(=O)c1n[nH]cc1N
Temperature: 29 °C
Yield: 98.9 %

Procedure:
A 20 L reaction vessel equipped with a digital thermometer and stirrer was charged with palladium on carbon (10% wet paste, 0.170 Kg, 0.14 wt) under nitrogen. In a separate vessel a slurry of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.210 Kg, 7.07 mol, 1 wt) in ethanol (12.10 L, 10 vol) was warmed to 30 to 35° C. to effect dissolution and the solution added to the catalyst under nitrogen. Following a nitrogen-hydrogen purge sequence an atmosphere of hydrogen was introduced and the reaction mixture maintained at 28 to 30° C. until reaction completion (5 to 10 hours) was noted by 1H NMR analysis (d6-DMSO). Following a purge cycle, the reaction mixture under nitrogen was filtered and the liquors concentrated under reduced pressure to give 4-amino-1H-pyrazole-3-carboxylic acid methyl ester (0.987 Kg, 98.9%).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[O:11])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:33][C:7]([NH:9][C:10]([C:12]1[CH:20]=[CH:19][C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=1)=[O:11])([CH3:8])[C:6]([OH:34])=[O:5]
Reactant: CC(C)(C)OC(=O)C(C)(C)NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc2sccc2c1OCc1ccc(C(F)(F)F)cc1)C(=O)O
Yield: 64.9 %

Procedure:
113 mg of 2-Methyl-2-{[4-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid tert-butyl ester were dissolved in 2 ml dichloromethane and treated with 2 ml trifluoroacetic acid. After 30 min at 60° C. the volatiles were evaporated. The residue was treated with ethanol and 2 M HCl and evaporated three times. The resulting residue was crystallized from diethylether/heptane to afford 65 mg of 2-Methyl-2-{[4-(4-trifluoromethyl-benzyloxy)-benzo[b]thiophene-5-carbonyl]-amino}-propionic acid.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:11][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Oc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To THF was added 3-methoxy-5-(trifluoromethyl)aniline (1.10 g, 5.7 mmol), potassium carbonate (2 equivalents), phenyl chloroformate (3 equivalents) and 4-dimethylaminopyridine (0.1 equivalent) and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc, filtered, concentrated in vacuo, and purified by silica gel column chromatography (5-15% EtOAc/hexanes) to give phenyl 3-methoxy-5-(trifluoromethyl)phenylcarbamate (1.02 g, 3.28 mmol, 57%). 1H NMR (300 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.50-7.35 (m, 4H), 7.31-7.22 (m, 3H), 6.94 (s, 1H), 3.81 (s, 3H); LC-MS (ESI) m/z 312 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C)nc(Oc2ccc(I)cc2)n1
Yield: 68.4 %

Procedure:
Under an argon atmosphere, phosphorus oxychloride (2 ml) was added to 4,6-dimethyl-2-hydroxypyrimidine (400 mg), and the resulting mixture was stirred for 1 hour while heating the mixture to reflux. The reaction solution was cooled to room temperature, and the cooled solution was added in small portions to water. After adding sodium hydrogen carbonate in small portions to the resulting mixture to neutralize it, the mixture was extracted with ethyl acetate. Organic layer was washed twice with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to obtain 2-chloro-4,6-dimethylpyrimidine (350 mg). (2) In the same manner as in Reference Example 8, 4-iodophenol (223 mg) and 2-chloro-4,6-dimethylpyrimidine (157 mg) were reacted by using sodium hydride to obtain 2-(4-iodophenoxy)-4,6-dimethylpyrimidine (226 mg).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5].[OH-].[K+].Cl[CH:27]([F:29])[F:28]>CC(O)C>[F:28][CH:27]([F:29])[O:1][C:2]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]1)=[O:5]
Reactant: FC(F)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(I)ccc2O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(I)ccc2OC(F)F)CC1
Temperature: 80 °C

Procedure:
A stirred slurry of tert-butyl 4-(2-hydroxy-5-iodobenzoyl)piperazine-1-carboxylate (7.06 g, 16.33 mmol) and potassium hydroxide (30% aqueous, 120 mL) in 2-propanol (200 mL) at 50° C. was treated with chlorodifluoromethane by bubbling a stream of the gaseous reagent through the stirring reaction mixture for 6 min. The reaction mixture was placed in a Parr high pressure reaction vessel, heated at 80° C. for 16 h and then cooled to ambient temperature. The resulting solution was concentrated to remove 2-propanol and the aqueous portion was extracted with ethyl acetate (3×200 mL). The organic portions were dried (Na2SO4) and concentrated. The residue was purified by reverse phase HPLC to give 5.55 g of tert-butyl 4-(2-(difluoromethoxy)-5-iodobenzoyl)piperazine-1-carboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9]COC)[CH:6]=[CH:5][C:4]=1[C:13]1[C:14]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]2[CH3:25].Cl.O1CCOCC1>O1CCOCC1.C(OCC)(=O)C>[OH:9][C:7]1[CH:6]=[CH:5][C:4]([C:13]2[C:14]([CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18]([CH3:24])([CH3:23])[CH:17]=[C:16]3[CH3:25])=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COCOc1ccc(-c2ccc3c(c2CNc2ccccc2OC)C(C)=CC(C)(C)N3)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccccc1NCc1c(-c2ccc(O)cc2OC)ccc2c1C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 61.6 %

Procedure:
6-(2-Methoxy-4-methoxymethoxyphenyl)-5-(2-methoxyphenylaminomethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 181 mg, 0.381 mmol) was dissolved in 1,4-dioxane (3 mL), 4N HCl/1,4-dioxane solution (1 mL) was added thereto, and then the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate (30 mL), washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (101 mg) as a pale orange solid. (Yield 62%)
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][C@@H:12]1[N:17]([C:18]([O:20][CH2:21][CH:22]=[CH2:23])=[O:19])[CH2:16][CH2:15][C:14]([C:24]2[N:25]=[C:26]([SH:29])[S:27][CH:28]=2)=[CH:13]1.O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:21]([O:20][C:18]([N:17]1[C@@H:12]([CH3:11])[CH:13]=[C:14]([C:24]2[N:25]=[C:26]([S:29][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:27][CH:28]=2)[CH2:15][CH2:16]1)=[O:19])[CH:22]=[CH2:23]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CCC(c2csc(S)n2)=C[C@@H]1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of lithium hexamethyldisilazide in THE (1M, 1.26 ml, 1.26 mmol) was added at 0° C. to a solution of allyl (6S)-6-methyl-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2H)-pyridine carboxylate (373 mg, 1.26 mmol) in THF (15 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.80 g, 2.52 mmol) and the solution was allowed to stand in a refrigerator for 60 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-methyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (590 mg, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:7]C(=O)OC(C)(C)C)[S:5][CH:6]=1.[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16]
Reactant: Cc1csc(NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1csc(N)c1

Procedure:
A solution of tert-butyl 4-methylthiophen-2-ylcarbamate (0.880 g, 4.13 mmol) in CH2Cl2 (8 mL) and TFA (6 mL) wad stirred at room temperature for 3 h. Solvents was removed in vacuo to give 4-methylthiophen-2-amine as trifluoroacetic acid salt (0.920 g).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH2:41])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([NH:41][S:47]([CH3:46])(=[O:49])=[O:48])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(N)c4)oc3C)c(OC)c2)cs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(NS(C)(=O)=O)c4)oc3C)c(OC)c2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}amine (100 mg), methanesulfonyl chloride (0.013 mL), triethylamine (0.024 mL) and tetrahydrofuran (1 mL) was stirred at room temperature for 1 hr. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The eluate was subjected to reversed phase HPLC and eluted with acetonitrile-water (10:90-100:0, v/v). The obtained fraction was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give N-{3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}methanesulfonamide (37 mg, yield 33%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 113-115° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:9]=1[S:21][CH3:22].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CC(C)=O>[CH3:22][S:21][C:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][C:8]=1[O:7][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CSc1c(O)ccc2c1[nH]c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CSc1c(OCC(=O)OC(C)(C)C)ccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.5 %

Procedure:
135 mg of powdered potassium carbonate was added to a solution of 112 mg of 2-hydroxy-1-methylthiocarbazole, as obtained in Example 2, in 4 ml of acetone. 956 mg of tert-butyl bromoacetate was added to the reaction mixture which was then stirred for 2 hours at room temperature. After this time, the reaction mixture was poured into ice water, and concentrated by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 3 g of silica gel with a 9:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 140 mg of the title compound as an oil.