Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@@H:7]([C@@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11]([CH3:17])([CH3:16])[O:10]2)[OH:8])[CH2:4][O:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]([O:8][S:20]([CH3:19])(=[O:22])=[O:21])[C@@H:9]2[C@H:13]([CH2:14][O:15][S:20]([CH3:19])(=[O:22])=[O:21])[O:12][C:11]([CH3:17])([CH3:16])[O:10]2)[CH2:4][O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@H]([C@@H](O)[C@H]2COC(C)(C)O2)[C@H](CO)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)O[C@H]([C@@H](OS(C)(=O)=O)[C@H]2COC(C)(C)O2)[C@H](COS(C)(=O)=O)O1
Temperature: 0 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
4.1 g (0.016 mol) of {(4R)-(2,2-dimethyl[1,3]dioxolan-4-yl)}-{(4R,5S)-(5-hydroxymethyl-2,2-dimethyl[1,3]dioxolan-4-yl)}-(S)-methanol from the aforementioned Experimental Example 2 were dissolved in a mixed solvent of 1.0 L dichloromethane and 25 mL pyridine. After cooling the mixture to 0° C., 18 mL (0.236 mol) of methanesulfonyl chloride were added and the resulting solution was stirred for 5 h at 0° C. Saturated sodium bicarbonate solution was added and the compound was extracted with chloroform. The extract was dried, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography using the eluant hexane:ethyl acetate=2:1 to obtain 6.4 g (yield: 98%) of methanesulfonic acid {(4R)-(2,2-dimethyl[1,3]dioxolan-4-yl)}-{(4S,5S)-(5-methanesulfonyloxymethyl-2,2-dimethyl[1,3]dioxolan-4-yl)}-(S)methyl ester as an oil.
Reaction SMILES: I(Cl)(=O)=O.I(Cl)(=O)=O.I(Cl)(=O)=O.I([Cl:16])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH3:28][O:29][C:30]([C:32]1[C:37]([Cl:38])=[C:36]([Cl:39])[C:35]([Cl:40])=[C:34]([C:41]2[O:42][CH:43]=[CH:44][CH:45]=2)[N:33]=1)=[O:31]>C(O)(=O)C.C(OCC)C>[Cl:38][C:37]1[C:32]([C:30]([O:29][CH3:28])=[O:31])=[N:33][C:34]([C:41]2[O:42][C:43]([Cl:16])=[CH:44][CH:45]=2)=[C:35]([Cl:40])[C:36]=1[Cl:39]
Reactant: COC(=O)c1nc(-c2ccco2)c(Cl)c(Cl)c1Cl
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1nc(-c2ccc(Cl)o2)c(Cl)c(Cl)c1Cl
Reaction time: 1 h
Yield: 51.5 %

Procedure:
Benyltrimethylammonium tetrachloroiodate (292 mg, 0.70 mmol) was added to a solution of methyl-3,4,5-trichloro-6-(2-furyl)pyridine-2-carboxylate (101 mg, 0.33 mmol) in acetic acid (5 mL). After one hour, the suspension was diluted with diethyl ether and the organic mixture was washed with 0.1 N sodium thiosulphate, 0.1 N sodium bicarbonate and dried (MgSO4). The residue was purified by column chromatography (diethyl ether:hexane, 5:95) to give methyl 3,4,5-trichloro-6-(5-chloro-2-furyl)pyridine-2-carboxylate (58 mg, 0.17 mmol): 1H NMR (CDCl3): δ 7.41 (d, J=3.6 Hz, 1H), 6.40 (d, J=3.6 Hz, 1H), 4.05 (s, 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].[H-].[Na+].[Na+].[I-].Cl[CH2:26][C:27]1[S:31][C:30]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[N:29][C:28]=1[CH3:42]>CN(C=O)C>[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])[CH2:26][C:27]2[S:31][C:30]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[N:29][C:28]=2[CH3:42])=[CH:9][C:8]=1[CH2:15][CH2:16][CH2:17][O:18][CH3:19])[CH3:2]
Reactant: CCOC(=O)COc1ccc(NC)cc1CCCOC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(N(C)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1CCCOC
Reaction time: 0.5 h

Procedure:
To 0.216 g (0.77 mmol) of the above prepared [2-(3-methoxy-propyl)-4-methylamino-phenoxy]-acetic acid ethyl ester, dissolved in 2.4 ml of abs. DMF, were added successively at 0° C. 0.037 g of NaH (60% in mineral oil, 1.2 eq.), 0.115 g (1 eq.) of NaI and 0.215 g (0.96 eq.) of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (WO02/28433). The reaction was allowed to proceed for 5 min at 0° C. and for 0.5 h at ambient temperature. Pouring onto crashed ice/aqueous 10% KHSO4, twofold extraction with EtOAc, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/EtOAc=78/22), yielded 0.284 g of the title compound as light yellow oil, MS: 537.5 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=2[C:19]([OH:21])=O)C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O-:25])(=O)[CH3:23].[Na+].[C:27](OC(=O)C)(=[O:29])[CH3:28]>>[C:27]([O:21][C:19]1[C:13]2[C:14]([O:18][C:22](=[O:25])[CH3:23])=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: O=C(O)c1c(O)cccc1SC(C(=O)O)c1ccccc1
Agent: [Na+]
Product: CC(=O)Oc1cccc2sc(-c3ccccc3)c(OC(C)=O)c12
Temperature: 60 °C

Procedure:
A mixture of 2-phenyl-2-(2'-carboxy-3'-hydroxyphenylthio)-acetic acid (0.19 g, 0.62 mmol), sodium acetate (0.38 g) and acetic anhydride (2 ml) was heated at 60° C. for 10 minutes, with vigorous gas evolution taking place. The mixture was poured into ice-water and extracted with diethyl ether. The combined organic extracts were washed with 1% aqueous sodium hydroxide, water, dried (sodium sulfate), and evaporated. The residue was subjected to chromatography and evaporated. The residue was subjected to chromatography on a column of silica gel (Merck No. 7734), eluting with 1:1 hexane-ether to afford 3,4-diacetoxy-2-phenylbenzo[b]thiophene as a white solid; yield 29 mg (14%); m/z 326 (M+.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:18])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[C:8]([NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:7]=[CH:6][C:5]=1[O:18][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 5-1 (5 g, 19.7 mmol) in DMF (125 mL) was treated with cesium carbonate (3.17 g, 9.73 mmol), stirred for 10 minutes and treated with ethyl bromoacetate (2.2 mL, 19.8 mmol) at room temperature. After 1.5 hours the solution was concentrated under high vacuum and the residue was absorbed to silica gel and chromatographed in a gradient of 20 to 30% EtOAc/hexanes to give 5-2 as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:34])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[C:22]([O:31][CH2:32][CH3:33])=[CH:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=3)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:42](Cl)([Cl:44])=[O:43]>C(Cl)Cl.C1(C)C=CC=CC=1>[C:27]([C:24]1[N:25]=[CH:26][C:21]([C:10]2[N:11]([C:42]([Cl:44])=[O:43])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([CH3:34])[N:9]=2)=[C:22]([O:31][CH2:32][CH3:33])[CH:23]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reaction time: 0.5 h

Procedure:
To a solution of rac-5-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-2-tert-butyl-4-ethoxy-pyridine (20 mg) and triethylamine (200 uL, 1.43 mmol) in 5 mL of methylene chloride at 0° C. was added 0.3 mL of 1.9 M phosgene in toluene solution (Fluka). After stirring for 30 min the mixture was taken up in methylene chloride and washed with water, dried over anhydrous sodium sulfate, filtered and concentrated to give rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride as a white solid (22 mg). It was used in the next reaction without purification
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16](B1OC(C)(C)C(C)(C)O1)[NH:17]2>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:11][C:4]1[N:3]=[C:2]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[C:13]([F:12])[CH:21]=[CH:20][CH:19]=3)[C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(Cl)nc1Cl
Reactant: CC1(C)OB(c2cc3c(F)cccc3[nH]2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: OCCc1ccc(Cl)nc1-c1cc2c(F)cccc2[nH]1
Temperature: 90 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
To a degassed solution of 2-(2,6-dichloropyridin-3-yl)ethanol (200 mg, 1.04 mmol) and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (272 mg, 1.04 mmol) in 1,4-dioxane (8 mL) and water (200 μl) was added CS2CO3 (679 mg, 2.08 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium chloride (68 mg, 0.10 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature overnight. The reaction was cooled, filtered through a pad of the celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. Preparative TLC (eluted with 20% EtOAc/DCM) to provide 2-(6-chloro-2-(4-fluoro-1H-indol-2-yl)pyridin-3-yl)ethanol (60 mg, yield: 19%) MS (M+H)+: 291.
Reaction SMILES: [Cl-:1].[NH4+:2].C([Al](CC)CC)C.[CH2:10]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[CH2:11][CH3:12]>C1(C)C=CC=CC=1.CCCCCC>[ClH:1].[CH2:10]([O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]([NH2:2])=[NH:17])[CH2:11][CH3:12]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCCOc1ccccc1C#N
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCOc1ccccc1C(=N)N
Product: Cl
Temperature: 2.5 °C

Procedure:
21.41 g (400 ml) of ammonium chloride are suspended in 400 ml of toluene and cooled to from 0 to 5° C. 200 ml of a 2M solution of triethylaluminium in hexane are added dropwise, and the mixture is stirred at room temperature until evolution of gas has ceased, 32.2 g (200 mmol) of 2-propoxybenzonitrile are added, and the reaction mixture is then stirred at 80° C. (bath) overnight. The cooled reaction mixture is, with ice-cooling, added to a suspension of 300 g of silica gel and 2.85 ml of ice-cold chloroform and stirred for 30 minutes. The mixture is filtered off with suction and the filter residue is washed with the same amount of methanol. The solvent is distilled off under reduced pressure, the residue is stirred with 500 ml of a mixture of dichloromethane and methanol (9:1), the solid is filtered off and the mother liquor is evaporated. The residue is stirred with petroleum ether and filtered off with suction. This gives 22.3 g (52%) of product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:11]=1[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=NN=N1.[CH2:24]([O:27][P:28]([O:36][CH2:37][CH:38]=[CH2:39])N(C(C)C)C(C)C)[CH:25]=[CH2:26].C([O:44]O)(C)(C)C>>[P:28]([O:13][CH2:12][C:11]1[C:14]([CH3:18])=[CH:15][CH:16]=[CH:17][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])([O:27][CH2:24][CH:25]=[CH2:26])([O:36][CH2:37][CH:38]=[CH2:39])=[O:44]
Reactant: CC(C)(C)OO
Reactant: Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Agent: c1nnn[nH]1
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1CO[Si](C)(C)C(C)(C)C
Yield: 88.4 %

Procedure:
According to a similar procedure to that described in Example 1-(10), 2-[(tert-butyldimethylsilyl)oxymethyl]-6-methylbenzylalcohol (4.92 g, 18.5 mmol) obtained from Example 22-(2), tetrazole (3.23 g, 46.2 mmol), bis(allyloxy)(diisopropylamino)phosphine (described in Tetrahedron Lett., 30, 4219 (1989); 5.43 g, 22.2 mmol), and tert-butyl hydroperoxide (80% di-tert-butyl peroxide solution; Merck; 1.8 g, 16 mmol) were reacted, and the reaction mixture was worked up to afford, after extraction, an oily residue. The residue was subjected to chromatography on a silica gel (200 g) column (eluent; ethyl acetate:hexane=1:4˜2:3) to afford the title compound (6.03 g, 74% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)Cl
Reactant: O=[N+]([O-])c1ccccc1NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)N(Cc1ccccc1)c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of N-benzyl-2-nitroaniline (1.62 g, 7.1 mmol) and methyl 3-chloro-3-oxopropanoate (1.17 mg, 8.5 mmol), Et3N (1.8 g, 17.8 mmol) in 50 mL of CH2Cl2 was stirred at 80° C. for 2 days. The solvent was evaporated, and the residue was purified by combi-flash to give methyl 3-(benzyl(2-nitrophenyl)amino)-3-oxopropanoate as a yellow solid. LRMS (M+H)+: 328 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([CH2:10]C=O)=N)[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]([NH2:16])=[O:15].[CH3:17]O>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:10]=[N:13][C:14]([OH:15])=[N:16][CH:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: N=C(CC=O)c1cccc(F)c1
Reactant: CO
Product: Oc1ncc(-c2cccc(F)c2)cn1

Procedure:
By the procedure described in Example 4, (m-fluorophenyl)formimidoylacetaldehyde is reacted with urea to give the product of the Example (recrystallized from methanol), m.p. 259°-261° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][C:44]([OH:46])=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:48][NH:49][O:50][CH3:51]>>[CH3:51][O:50][N:49]([CH3:48])[C:44](=[O:46])[CH2:43][CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: CNOC
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 1.65 g of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propionic acid are reacted with N,O-dimethylhydroxylamine hydrochloride to afford the title compound as a grey oil. Rf=0.18 (EtOAc-heptane 5:1); Rt=5.09.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH:4]=[CH:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11].CO>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH3:1][CH:2]([CH3:13])[C:3](=[O:12])[CH2:4][CH2:5][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH3:11]
Reactant: Cc1ncsc1C=CC(=O)C(C)C
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ncsc1CCC(=O)C(C)C

Procedure:
The title compound was prepared as described in General Method 3 using 1.73 g (8.86 mmol) of 4-methyl-1-(4-methyl-thiazol-5-yl)-pent-1-en-3-one (prepared in Example B-1) and 0.4 g of 5% Pd/BaSO4 in THF:MeOH (25 mL:25 mL). The crude product was chromatographed on silica gel, eluting with 2:1 hexane:EtOAc, to give the title compound. 1H NMR (CDCl3): δ 1.03 (d, 6H), 2.35 (s, 3H), 2.49-2.56 (m, 1H), 2.72 (t, 2H), 2.98 (t, 2H), 8.49 (s, 1H).
Reaction SMILES: [CH2:1]1COCC1.[O:6]=[C:7]1[C@@H:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][CH2:11][C:10]2[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=2[NH:8]1.CI>[H-].[Na+].CCOC(C)=O.CCCCCCC.CCOC(C)=O>[CH3:1][N:8]1[C:9]2[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=2[CH2:11][CH2:12][C@H:13]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:7]1=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc2NC1=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CCc2ccccc21

Procedure:
0.898 mg of sodium hydride in suspension at 60% in oil (22.44 mmol) is introduced, at AT, into a 500 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 260 ml of THF and 6.2 g of 2a (22.44 mmol). The medium is stirred for 1 h and then 3.823 g (26.94 mmol) of methyl iodide are added. The medium is left stirring overnight, 500 ml of EtOAc are added and the organic phase is washed twice with 500 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 6.85 g of crude product are obtained. After chromatography on a silica cartridge (250 g, eluent heptane/EtOAc—as an EtOAc gradient: 10 to 50%). 4.47 g of product 7a (white solid) are obtained.
Reaction SMILES: P(OCC)(OCC)([S-])=[S:2].[CH3:10][O:11][C:12]([C:14]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:20]#[N:21])[CH:19]=1)=[O:13]>C1COCC1.O>[CH3:10][O:11][C:12]([C:14]1[C:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:16][CH:17]=[C:18]([C:20](=[S:2])[NH2:21])[CH:19]=1)=[O:13]
Reactant: COC(=O)c1cc(C#N)ccc1-c1ccccc1[N+](=O)[O-]
Reactant: CCOP(=S)([S-])OCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 45 h
Yield: 51.8 %

Procedure:
O,O′-Diethyl dithiophosphate (available from Aldrich Chemical Company, Inc.; 6.85 g, 36.8 mmol) was added to a solution of compound 4-cyano-2′-nitro-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 3; 8.62 g, 30.5 mmol) in a mixture of THF (96 mL) and water (24 mL). The resulting mixture was stirred at 80° C. for 45 h and then evaporated to a small volume. Ethyl acetate (500 mL) was added and the mixture was washed with water (250 mL) and sat. NaHCO3 (250 mL), dried over anhydrous sodium sulfate, filtered, evaporated, and purified by silica gel chromatography, using 17-50% ethyl acetate/petroleum ether as eluent, to give 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (5.0 g, 52%). 1H NMR (300 MHz, CDCl3) δ 8.50 (d, J=2.1 Hz, 1H), 8.18-8.15 (m, 2H), 7.70-7.54 (m, 3H), 7.32 (s, 1H), 7.30 (s, 1H), 7.24 (d, J=1.2 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][CH2:18][C:19]3[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:21](=[O:37])[C:22]4[C:27]([C:28]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:26][C:25]([C:34]([NH2:36])=[S:35])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46].O.[CH2:51](O)[CH3:52]>>[CH2:30]([O:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:34]3[S:35][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:51]([CH3:52])[N:36]=3)[CH:26]=2)[C:21](=[O:37])[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:19]=1[CH2:18][NH:17][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:42])[CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)CCl
Reactant: CCO
Reactant: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Solvent: O
Product: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(-c3nc(C)c(C(=O)OCC)s3)cc12
Yield: 65.3 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (2.33 g, 4 mmol) and ethyl 2-chloroacetate (1.32 g, 8 mmol) in ethanol (20 ml) was refluxed under heating for 10 h. The resulting reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-[4-butoxy-3-({[(9H-fluoren-9-ylmethoxy)carbonyl]amino}methyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-4methyl-1,3-thiazole-5-carboxylate (1.81 g, 65.3%) as crystals.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:19]=1)[CH2:15][OH:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([O:20][C:21]([F:22])([F:23])[F:24])[CH:19]=1)[CH:15]=[O:16]
Reactant: OCc1cc(Cl)cc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1cc(Cl)cc(OC(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of DMSO (16.1 g, 205.9 mmol) in anhydrous CH2Cl2 (300 mL) was cooled to −78° C. Oxalyl chloride (13.1 g, 103.0 mmol) was added slowly via a syringe (gas evolution was observed). The resulting solution was stirred at −78° C. for 15 minutes. A solution of 3-chloro-5-trifluoromethoxybenzyl alcohol (21.2 g, 93.6 mmol; see step (v) above) in CH2Cl2 (200 mL) was added via an addition funnel over a period of 15 minutes. The cloudy solution was stirred at −78° C. for 40 minutes and DIPEA (60.5 g, 468.0 mmol) was added via an addition funnel over 10 minutes. The resulting homogeneous solution was stirred at −78° C. for 1.5 hours, then warmed to room temperature and stirred 18 hours. The crude solution was concentrated in vacuo, the residue diluted with EtOAc and washed with H2O (1×), 2N HCl (1×), brine (1×), aqueous NaHCO3 (1×) and brine (1×). The organics were dried (Na2SO4), filtered and concentrated in vacuo to give the crude sub-title compound (19.9 g, 95%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16](O)=[O:17])[CH:14]=2)[C:9](=[O:19])[N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:7]=1[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:2][CH2:3][CH3:4].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.O>[C:29]([O:28][C:26](=[O:27])[NH:25][CH2:24][C:7]1[N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:9](=[O:19])[C:10]2[C:15]([C:6]=1[O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)([CH3:32])([CH3:30])[CH3:31]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(=O)O)cc12
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(CO)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 4-butoxy-3-{{(tert-butoxycarbonyl)-amino}methyl}-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinecarboxylic acid (synthesized according to the method similar to that in Example 76 (1)) (0.45 g, 3.5 mmol) and N-methylmorpholine (0.13 ml, 1.2 mmol) in tetrahydrofuran (10 ml) was added ethyl chloroformate (0.12 ml, 1.2 mmol) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the obtained mixture was added sodium tetrahydroborate (0.11 g, 3 mmol) and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give tert-butyl(4-butoxy-6-hydroxymethyl-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.33 g, 76.7%) as crystals.