Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@@H:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>C(Cl)Cl>[F:33][C:32]([F:35])([F:34])[C:30]([OH:36])=[O:31].[Si:1]([O:8][CH:9]1[CH2:13][NH:12][C@@H:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1[C@H]1CC(O[Si](C)(C)C(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.8 %

Procedure:
To a solution of (R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine-1-carboxylate (2.648 g, 6.222 mmol) in CH2Cl2 (26 mL) at 0° C. was added TFA (9.3 mL). The resulting mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude material that was azeotroped with toluene-CH2Cl2 (2×) and dried under reduced pressure to provide (R)-4-(tert-butyldimethylsilyloxy)-2-(5-fluoro-2-methoxyphenyl)pyrrolidine 2,2,2-trifluoroacetate (assumed to be a mixture of cis and trans isomers; 2.92 g, 106.8% yield), which was used directly without further purification. LC/MS (ES+APCI) m/z=326.3 (M+H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][N:25]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]1[S:15][CH:16]([CH2:19][C:20]([OH:22])=O)[CH2:17][N:18]=1)=[CH:10]2)[CH3:3].Cl.[CH2:35]([N:37]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.CN>O.CN(C)C=O.C(N(CC)CC)C>[CH3:35][NH:37][C:20](=[O:22])[CH2:19][CH:16]1[S:15][C:14]([C:11]2[NH:12][C:13]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][N:25]=2)=[CH:6][C:5]=3[O:4][CH:2]([CH3:3])[CH3:1])=[N:18][CH2:17]1
Reactant: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(C)C)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.4 %

Procedure:
A mixture of {2-[7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (200 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (120 mg), 1-hydroxybenzotriazole (80 mg), methylamine hydrochloride (60 mg), triethylamine (70 mg) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 15 h. Water was added to the mixture and the resultant was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:methanol=100:0 to 95:5, volume ratio) to give colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (120 mg, 57%) as colorless prisms. MS 503 (MH+). mp 190-192° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]3[CH2:21][CH2:20][N:19]3C(OC(C)(C)C)=O)[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[ClH:15].[ClH:15].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:10]=[C:11]([O:16][CH2:17][C@@H:18]3[CH2:21][CH2:20][NH:19]3)[CH:12]=[N:13][C:14]=2[Cl:15])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(C=Cc2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1ncc(OC[C@@H]2CCN2)cc1C=Cc1ccncc1
Yield: 186.5 %

Procedure:
To a solution of 5-(2-(4-Pyridinyl)ethenyl)-6-chloro-3-(1-BOC-2-(S)-azetidinylmethoxy)pyridine from step 89a (176 mg) in CH2Cl2 (3 mL) and TFA (1.5 mL) was stirred at room temperature for 3 hours. The solvent was removed, and the residue was chromatographed on a silica gel column, eluting with CHCl3 :MeOH:NH4OH 10:1:0.1 to afford the free base of the title compound (102 mg, 79% yield). MS (CI/NH3) m/z 302 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ2.24-2.48 (m, 2H), 3.42-2.54 (m, 1H), 3.76 (q, J=7.5 Hz, 1H), 4.02-4.17 (m, 2H), 4.26-4.39 (m, 1H), 7.0 (d, J1=1.0 Hz, 1H), 7.36-7.44 (m, 2H), 7.52-7.62 (m, 2H), 8.05 (d, J=3.0 Hz, 1H), 8.58-8.73 (m, 2H). The base was treated with HCl in EtOH to afford the hydrochloride salt. mp 195-197° C. MS (CI/NH3) m/z 302 (M+H)+. 1H NMR (D2O, 300 MHz) δ1.17 (d, J=6, 1H), 2.52-2.66 (m, 2H), 2.68-2.89 (m, 4H), 4.96-5.25 (m, SH), 6.97-7.12 (m, 1H), 7.33 (d, J=3, 1H), 7.48-7.54 (m, 1H), 7.86-7.95 (m, 1H), 8.04-8.22 (m, 2H), 8.44-8.53 (m, 1H), 8.63-8.71 (m, 1H). Anal. Calcd for C16H16N3OCl·1.5 C6H8O7 ·0.5 H2O: C, 50.13; H, 4.88; N, 7.01. Found: C, 49.95; H, 4.80; N, 7.31. [α]25D=-1.14° (c 0.18, MeOH).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[F:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:21])[NH:16]2>ClCCCl>[Br:5][CH2:6][C:7]([C:20]1[C:11]([F:10])=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:21])[CH2:14][CH2:13]2)=[O:8]
Reactant: O=C1CCc2c(F)cccc2N1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C1CCc2c(ccc(C(=O)CBr)c2F)N1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
To a stirring suspension of aluminum chloride (8.0 g, 60 mmol) in 1,2-dichloroethane (16 ml) was added bromoacetyl bromide (4.2 ml, 48 mmol) at 0° C. After 30 min, to a suspension was added 5-Fluoro-3,4-dihydroquinolin-2(1H)-one (4.0 g, 24 mmol) portionwise, then the mixture was allowed to warm to 50° C. and stirred for 4 h. After cooling, the solvent was evaporated in vacuo and the residue was quenched with ice-water and extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1/1) to afford 6-(Bromoacetyl)-5-fluoro-3,4-dihydroquinolin-2(1H)-one (2.0 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Br:26][C:27]1[CH:28]=[C:29]2[C:35]([CH:36]=O)=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1>CO.N1CCCCC1>[Br:26][C:27]1[CH:28]=[C:29]2[C:35](/[CH:36]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ncc(Br)cc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.020 g, 0.058 mmol) obtained in Example A16, Step 1 in methanol (1.0 mL) was added with 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.010 g, 0.044 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was suspended in methylene chloride and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.018 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:17]([Cl:18])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:19].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CS(C)=O>[Cl:18][C:17]1[C:9]([C:5]2[CH:4]=[C:3]([O:19][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:2]([Cl:1])=[CH:7][C:6]=2[F:8])=[N:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=12
Reactant: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of 2-chloro-5-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-fluorophenol (0.5 g) and 2-chloropyrimidine (0.25 g),in a mixed solvent of 2-butanone:dimethylsulfoxide (1:4) (50 ml) was added potassium carbonate (0.35 g) at room temperature. After addition, the mixture was heated at reflux for 12 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:1) to give the desired compound (0.47 g).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Cc2c(Cl)ccc(C(=O)O)c2O1
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2c(Cl)c([N+](=O)[O-])cc(C(=O)O)c2O1
Temperature: 5 °C

Procedure:
To a mixture of 40 ml of nitric acid and 40 ml of sulfuric acid cooled to 5° C. by means of an external ice bath were added 10 g of 4-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid over a period of 28 minutes. After stirring at 5° C. for minutes, the mixture was added to ice with stirring. The resulting solid was collected by filtration and washed with water. After air drying, the residue was crystallized twice from ethyl acetate/hexane to provide 3.5 g of the desired subtitle intermediate, m.p. 260°-262° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[O:23][CH:22]=[CH:21][C:4]=2[C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]2[O:23][CH:22]=[CH:21][C:4]=2[C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccoc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(N2CCNCC2)c2ccoc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A stirred solution of tert-butyl 4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazine-1-carboxylate (step A) (2.34 g, 7.37 mmol) in dichloromethane (4.1 ml) was cooled to 0° C., trifluoroacetic acid (8.41 g, 5.68 ml, 73.7 mmol) was added drop wise and the reaction mixture was allowed to stir for 10 min at 0° C. and for 30 min at room temperature. The solution was poured onto ice and 2N sodium carbonate solution (50 ml) and extracted with dichloromethane (2×25 ml). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product (1.59 g) was further purified by flash chromatography on silica gel (100% dichloromethane/MeOH/NH4OH 80:10:1) to yield 7-methyl-4-(piperazin-1-yl)-furo[3,2-c]pyridine as a yellow solid (1.27 g, 79%), MS (ISP) m/z=218.4 [(M+H)+], mp 111.5° C.
Reaction SMILES: [S:1]([N:11]=[C:12]1[NH:16][CH2:15][CH2:14][NH:13]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:17](Cl)([Cl:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[Cl:19][C:17]([N:16]1[CH2:15][CH2:14][N:13]=[C:12]1[NH:11][S:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3])=[O:18]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N=C2NCCN2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2=NCCN2C(=O)Cl)cc1
Temperature: 0 °C

Procedure:
12 parts by weight of 2-tosylimino-imidazolidine (produced as described by Gompper and Hagele, Ber. 99, 2892 [1966]) were partly dissolved by 10 minutes' boiling in 150 parts by volume of absolute tetrahydrofurane, and thereafter rapidly cooled to 0°C by swirling in an ice bath. 6 parts by weight of phosgene were added to the suspension while stirring, the mixture was stirred for 30 minutes at 0°C, 5 parts by weight of triethylamine were then added dropwise and the whole was then stirred for a further 3 hours at room temperature. The excess phosgene was blown out by means of a stream of dry air and the precipitated triethylamine hydrochloride was removed from the tetrahydrofurane solution by filtration and was thoroughly eluted with absolute tetrahydrofurane. The combined solutions were evaporated to dryness in vacuo and the residual oil was caused to crystallize by trituration with methylene chloride and ether, filtered off and dried in vacuo.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([C:35]([CH3:40])([CH3:39])[CH:36]([CH3:38])[CH3:37])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][OH:30])[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[CH3:41][Si:2]([CH3:1])([C:35]([CH3:39])([CH3:40])[CH:36]([CH3:37])[CH3:38])[O:3][C:4]1[C:21]2[CH2:20][S:19][CH2:18][C@@H:17]([C:22]3[O:26][N:25]=[C:24]([CH3:27])[N:23]=3)[NH:16][C:15](=[S:28])[CH2:14][CH2:13][C@@H:12]([CH2:29][O:30][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:11][O:10][C:9](=[O:31])[C:8]=2[C:7]([CH3:32])=[C:6]([O:33][CH3:34])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](CO)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Solvent: c1ccncc1
Product: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OC[C@H](COS(C)(=O)=O)CCC(=S)N[C@H](c1nc(C)no1)CSC2
Yield: 131.9 %

Procedure:
A solution of 31 mg of (4R,9S)-16-[dimethyl-(1,1,2-trimethylpropyl)-silanyloxy]-9-hydroxymethyl-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one and 11.5 mg of methanesulfonyl chloride in 0.2 ml of pyridine was stirred at 20° C. for 3 h. The solution was partitioned between dichloromethane and 1M aqueous oxalic acid. The organic layer was washed with brine, dried over sodium sulfate and evaporated in vacuo to yield 46 mg of (4R,9R)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-9-(methylsulfonyloxymethyl)-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one as an amorphous solid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:27])[S:10][C@@H:9]2[C@H:11]([NH:14]C(C[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=O)[C:12](=[O:13])[N:8]2[C@H:7]1[C:24]([OH:26])=[O:25]>>[CH3:5][C:6]1([CH3:27])[S:10][C@@H:9]2[C@H:11]([NH2:14])[C:12](=[O:13])[N:8]2[C@H:7]1[C:24]([OH:26])=[O:25].[C:18]1([CH2:2][C:1]([OH:4])=[O:3])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CC(=O)[O-]
Product: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Product: O=C(O)Cc1ccccc1

Procedure:
To 400 ml of a sterile 1.1% chisosan acetate solution (chitosan-hv) were added 100 ml of an E. coli cell suspension having a wet biomass proportion of 50 g and well suspended. This suspension was thereafter transferred into the immobilization apparatus having been described. By applying pressure (1.3 bars) by means of sterile air, the suspension was added dropwise through the steel tubes into the 2% Na tripolyphosphate cross-linking agent solution (pH 8). The sterile air stream used to blow off the beads was selected such that beads having a final diameter of 0.6 mm were obtained. After the complete cross-linking throughout, curing and shrinkage of the chitosan biocatalyst beads, they could be used directly for the cleavage of Penicillin G to form 6-aminopenicillanic acid and phenylacetic acid. The resultant biocatalyst beads had an activity of 60 U/g KFM with a residual activity of 63%.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[C:22]([Cl:23])=[C:21]([Cl:24])[C:20]([Cl:25])=[C:19]([Cl:26])[C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]([CH2:42][CH3:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH3:29]>C(OC(=O)C)(=O)C>[CH2:38]([N:37]([CH2:40][CH3:41])[C:33]1[CH:32]=[C:31]([N:30]([CH2:28][CH3:29])[CH2:42][CH3:43])[CH:36]=[CH:35][C:34]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:17]1)[CH3:39].[CH3:42][N:30]([CH3:28])[C:31]1[CH:32]=[C:33]([N:37]([CH3:38])[CH3:40])[CH:34]=[CH:35][C:36]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH3:1])[C:4]=2[CH3:27])[C:14]2[C:15](=[C:19]([Cl:26])[C:20]([Cl:25])=[C:21]([Cl:24])[C:22]=2[Cl:23])[C:16](=[O:18])[O:13]1
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c(N(CC)CC)c1
Product: Cc1c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc2n1C

Procedure:
Following a procedure similar to that described in part B of Example 2 above, 4.45 g (0.01 mole) of 2-(1-ethyl-2-methyl-3-indolyl)carbonyl-3,4,5,6-tetrachlorobenzoic acid and 2.20 g (0.01 mole) of N,N,N',N'-tetraethyl-m-phenylenediamine were interacted in the presence of ten ml of acetic anhydride to obtain 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)-4,5,6,7-tetrachlorophthalide (Formula III: R°=R1 =R2 =R3 =Cl; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3 ; Y1 =H) melting at 100°-103° C. and showing a significant infrared absorption maxima at 1770 cm-1 (C=O; s). A toluene solution of this compound developed an intense blue color when spotted on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][C:31]1([CH3:38])[O:35][CH:34]([CH2:36]O)[CH2:33][O:32]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:36][CH:34]5[CH2:33][O:32][C:31]([CH3:38])([CH3:30])[O:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC1(C)OCC(CO)O1
Product: CC1(C)OCC(CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)O1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (2,2-dimethyl-[1,3]dioxolan-4-yl)methanol following General Procedure J.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=O)[CH2:24][C:25](=O)[CH3:26])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1.[CH2:51]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([NH:67][NH2:68])[CH2:63][CH2:62]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[CH2:51]([O:58][C:59]([N:61]1[CH2:62][CH2:63][CH:64]([N:67]2[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[CH:24][C:25]([CH3:26])=[N:68]2)[CH2:65][CH2:66]1)=[O:60])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(C)=O
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1C1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 308d, (2S,4R)-1-(3-oxo-butyryl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192f) was reacted with Lawesson's reagent (CAS Reg. No. 19172-47-5) and 4-hydrazino-piperidine-1-carboxylic acid benzyl ester (CAS Reg. No. 280111-51-5) to give the title compound as yellow oil.
Reaction SMILES: [CH3:1][Mg]Br.[O:4]1[CH2:13][C@H:5]1[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.[Cu]I>[OH:4][C@@H:5]([CH2:13][CH3:1])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: C[Mg]Br
Reactant: CCCCOC(=O)[C@@H]1CO1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@@H](O)CC
Yield: 99 %

Procedure:
Under argon, copper(I) iodide (594 mg) was suspended in anhydrous diethyl ether (20.0 mL). A solution of methylmagnesium bromide in anhydrous tetrahydrofuran (60.2 mL, M) was added dropwise to the suspension at −15° C. or lower, and the mixture was allowed to react at the same temperature for 20 minutes. After completion of reaction, a solution (8.0 mL) of n-butyl(S)-(−)-2,3-epoxypropionate (3.0 g, 97.3% ee) (product of Osaka Organic Chemical Industry Co., Ltd.) in anhydrous diethyl ether was added dropwise to the reaction mixture at −78° C., and the resultant mixture was allowed to react for 15 minutes at the same temperature. After completion of reaction, an aqueous saturated ammonium chloride solution (50.0 mL) was added to the reaction mixture, followed by filtration by means of a Celite. The filtrate was extracted twice with diethyl ether (50 mL×2), and the organic layer was washed with saturated brine (40 mL). The washed organic layer was dried over sodium sulfate anhydrate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography including elution with methylene chloride/diethyl ether=5/1, to thereby yield 3.37 g of colorless oil (yield 99.0%). Since the compound was also able to be purified through distillation under reduced pressure, another aliquot of the residue obtained through the same procedure was distillated under reduced pressure, to thereby yield 2.73 g of colorless oil (yield 81.8%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][C:15]([CH3:17])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl.C1COCC1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(N2CCNCC2)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)N1CCN(c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a mixture of 1-(4-iodophenyl)piperazine (1.44 g, 5 mmol) and acetone (1.47 mL, 20 mmol) in DCE/THF (45 mL/15 mL) was added NaBH(OAc)3 (1.38 g, 6.5 mmol), followed by AcOH (0.5 mL). After addition, the resulting mixture was stirred O/N at rt. The reaction as quenched with sat. NaHCO3 (10 mL) and H2O (20 mL), and was then extracted with EtOAc (2×60 mL), dried over MgSO4 and concentrated to give the crude title compound as a light yellow solid (1.396 g, 85%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 3.12-3.07 (m, 4H), 2.65 (p, J=6.5 Hz, 1H), 2.56-2.52 (m, 4H), 0.98 (d, J=6.4 Hz, 6H); MS ESI 330.9 [M+H]+, calcd. for [C13H19IN2+H]+ 331.1.