Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)=[CH:11][C:10]([C:24]([O:26]CC)=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C(O)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)=[CH:11][C:10]([C:24]([OH:26])=[O:25])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Product: O=C(O)c1cc(-c2cc(F)cc(C(F)(F)F)c2)n(-c2cccc(Cl)c2)n1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 49A in analogy to the synthesis of the compound of Example 71A. 1.82 g (85% of theory) of the title compound are obtained.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH3:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][CH:20]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:27]1[CH2:28][CH2:29][N:24]([C:22]2[S:23][C:19]([CH3:18])=[CH:20][N:21]=2)[CH2:25][CH2:26]1)=[O:9])([CH3:2])[CH3:3]
Reactant: Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: Cc1cnc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C)CC2)s1
Yield: 75 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-methyl-thiazol-2-yl)-piperazine. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as an off-white foam (yield 75%). MS (m/e): 424.3 (M+H+, 100%).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[C:8]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:10][CH:11]=2)[C:6](=[O:17])[N:5]1[CH:18]([CH3:22])[C:19](O)=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.O>CN(C=O)C.C(OCC)(=O)C>[ClH:1].[CH3:19][C@H:18]1[N:5]2[C:6](=[O:17])[C:7]3[C:12]([C@@H:4]2[CH2:3][NH:2][CH2:22]1)=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:16])([F:15])[F:14]
Reactant: CC(C(=O)O)N1C(=O)c2c(cccc2C(F)(F)F)C1CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1CNC[C@H]2c3cccc(C(F)(F)F)c3C(=O)N12
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A stirring solution of 2-(1-aminomethyl-3-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid hydrochloride (185 mg, 0.55 mmol) and triethylamine (268 mg, 2.65 mmol) in dry DMF (10 mL) was added benzotriazol-1-yloxy-tris(pyrrolidinyl)-phosphonium hexafluorophosphate (354 mg, 0.68 mmol). The reaction was stirred for 4 h and then conc. in vacuo to a yellow oil. The oil was partioned between water and ethyl acetate. The organic layer was separated, dried over Na2SO4, and conc. in vacuo to a yellow solid. The solid was purified by radial chromatography (silica gel, EtOAc) to give 84 mg of the desired product as a white solid. MS (ESI) 285 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:41])=[O:40])[N:33](C(OC(C)(C)C)=O)[CH2:32]1)=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(Cl)Cl.[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]>>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][NH:38][S:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)(=[O:40])=[O:41])[NH:33][CH2:32]1)=[O:21])[CH:7]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[C:58]([OH:64])([C:60]([F:63])([F:62])[F:61])=[O:59]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](CNS(=O)(=O)c2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2R,5R)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]-5-{[(phenylsulfonyl)amino]methyl}morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1>N.[Ni]>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCc1cccc(C(F)(F)F)c1
Agent: [Ni]
Agent: N
Product: NCCc1cccc(C(F)(F)F)c1
Yield: 97.8 %

Procedure:
Using analogous reaction conditions as described in Example 16, step 1, (3-trifluoromethyl-phenyl)-acetonitrile (2 g, 10.81 mmol) in methanolic ammonia (50 mL) was reacted with to Raney nickel (400 mg) to afford 2 g of the product (97.89% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH2:21][O:22][S:31]([CH3:30])(=[O:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1CO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(OCc2ccccc2)CC1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The 4-benzyloxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid t-butyl ester (219.09 mg, 0.71 mmol) was taken up in anhydrous DCM and triethylamine (215.53 mg, 2.13 mmol, 0.30 mL) was added under argon. The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (89.81 mg, 0.78 mmol, 0.06 mL) was added via syringe. The reaction was stirred at 0° C. for 30 min and then allowed to warm to room temp and stir for 12 h. The reaction was slowly poured into a 1N HCl solution and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (3:1 hexane-ethyl acetate) Yield 234.14 mg. 1H NMR (CDCl3, 300 MHz): δ 1.47 (bs, 9H), 2.05-2.32 (m, 2H), 2.98 (s, 3H), 3.31-3.63 (m, 2H), 4.04-4.78 (m, 6H), 7.27-7.40 (m, 5H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].Br[CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:15]([CH3:17])[CH3:16])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Methyl 3-cyano-4-hydroxybenzoate 3 (18 g, 0.1 mol) was dissolved in 100 mL of DMF and treated with 14.2 mL (0.15 mol) of 2-bromopropane and 41.9 g (0.3 mol) of anhydrous potassium carbonate. The system was flushed with nitrogen, and the mixture was heated to 90° C. and stirred overnight. After cooling to room temperature, the mixture was diluted with 200 mL of water and extracted with CH2Cl2 (2×200 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated to dryness to give 20.5 g (99% yield) of 4 as an oil that was characterized by LCMS and HNMR.
Reaction SMILES: Br.[C:2]1([C:12]2[N:13]=[C:14]([NH2:17])[S:15][CH:16]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl>N1C=CC=CC=1>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:17][C:14]2[S:15][CH:16]=[C:12]([C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[CH:4][CH:3]=3)[N:13]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cccc3ccccc23)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cccc4ccccc34)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
A mixture of 0.5 g of 4-(1-naphthyl)-thiazol-2-ylamine hydrobromide with 0.34 g of p-toluenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and extracted twice with 40 ml of ethyl acetate each time. The organic extracts were combined, dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.4 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 60 ml of 50% ethanol yielded 0.46 g of 4-methyl-N-(4-naphthalen-1-yl-thiazol-2-yl)-benzenesulfonamide as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]=[CH2:26]>CN(C=O)C.C(OCC)(=O)C.CO.[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[C:12]2[C:7](=[C:8]([CH2:24][CH2:25][CH3:26])[C:9]([OH:13])=[CH:10][CH:11]=2)[O:6][C:5](=[O:14])[CH:4]=1
Reactant: O=c1cc(C(F)(F)F)c2ccc(O)cc2o1
Reactant: C=CCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2c(C(F)(F)F)cc(=O)oc12
Reaction time: 18 h

Procedure:
To a solution of 4-trifluoromethyl-7-hydroxycoumarin (5.0 grams, 22.0 mmol) and potassium carbonate(3.6 grams, 26.0 mmol) in DMF (20.0 mL) at 40° C., was added 3-bromoprop-1-ene (2.0 mL, 23.0 mmol). This mixture was stirred 18 hours and then diluted with ethyl acetate. The organic phase was washed with 1M hydrochloric acid solution and brine. The organic was then dried over sodium sulfate and the solvent removed to give a tan solid. This was filtered through a pad of silica gel using 20% ethylacetate in hexane. This material was then dissolved in 1,2-dichlorobenzene (150 mL) and refluxed for 18 hours. The solvent was removed in vacuo to give a tan solid. This material was dissolved in methanol (150 mL) with 10% palladium on carbon (300.0 mg) under a hydrogen atmosphere (1 Atm) for 2 hours. The mixture was then filtered through a celite pad and the solvent removed in vacuo to give tan solid. This was chromatographed on silica gel using 20% ethyl acetate in hexane to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](#[N:17])[CH2:15]C>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:14]([CH3:15])=[N:17][N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=1)=[O:13]
Reactant: COC(=O)C=CNc1ccccc1
Reactant: CCC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: COC(=O)c1cn(-c2ccccc2)nc1C
Yield: 16 %

Procedure:
According to AVV A, 3-phenylamino acrylic acid methylester (177.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into propionitrile (3.0 ml, 41.9 mmol, 41.9 equiv.) for 19 hours at 120° C. The orange-brown oily raw product (191.2 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 98:2→0:100), whereby the pure product was obtained in the form of a white solid (37.2 mg, 0.16 mmol, 16%).
Reaction SMILES: Br.Br.C([O:5][C:6]([C@@H:8]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[S:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:7])C.C(O)(=O)C>[Na]>[C:6]([C@@H:8]([NH:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][C:29]([OH:31])=[O:30])[C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[S:22][CH2:21]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Br
Agent: [Na]
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)CSc2ccccc21
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
In 10 ml of 1N aqueous sodium hdyroxide solution is dissolved 0.45 g of 3(R)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5acetic acid.dihydrobromide, and the solution is allowed to stand at room temperature for 30 minutes. The reaction solution is neutralized with 2 ml of acetic acid and purified by MCI gel column chromatography (water:methanol=2:1). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.3 g of 3(R)-[1(S)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=C(C=CC=2)C(NC)=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:25])[NH:23][CH3:24])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(C(=O)NC)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CNC(=O)c1cccc(NCC2CCCC2)c1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CNC(=O)c1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-methylcarbamoyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3-(cyclopentylmethyl-amino)-N-methyl-benzamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12].C(O[SiH:16]([O:20][CH2:21][CH3:22])OCC)C>O1CCCC1>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH:22]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[O:11][CH3:12])[CH2:21][O:20][SiH3:16]
Reactant: CCO[SiH](OCC)OCC
Reactant: COc1ccc(Br)c(OC)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(CO[SiH3])c2ccc(OC)cc2OC)c(OC)c1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Into a four-necked flask (vi) was charged 3.1 g of magnesium and 20 ml of tetrahydrofuran under nitrogen flow. Into the mixture was dropped mixed liquid of 25 g of 1-bromo-2,4-dimethoxybenzene and 80 ml of tetrahydrofuran while stirring. After completion of dropping, the mixture was thermally insulated for 2 hours under reflux. Into a four-necked flask (vii) was charged 9.5 g of triethoxysilane and 40 ml of tetrahydrofuran. Into this mixture was dropped under ice cooling the above-mentioned reaction solution thermally insulated for 2 hours under reflux, and after completion of dropping, the mixture was stirred for 2 hours at 80° C. The resultant reaction mixture was washed with 100 ml of ammonium chloride water and saturated saline sequentially. The organic phase after washing was dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtrated off, then, to the resultant organic phase was added silica gel for decoloration. The organic phase after decoloration was concentrated, to obtain 16.7 g of bis(2,4-dimethoxyphenyl)ethoxysilane. To the above-mentioned bis(2,4-dimethoxyphenyl)ethoxysilane was added at 0° C. 50 ml tetrahydrofuran and 50 ml of 1N-hydrochloric acid. Then, 100 g of toluene was added and extraction was performed. The organic phase was washed with saturated saline twice. To the organic phase after washing was anhydrous magnesium sulfate and dried. Anhydrous magnesium sulfate was filtrated, then, the filtrate was concentrated and a solvent was distilled off. The residue after solvent distillation was thermally insulated at 155° C. for 2 hours, then, further thermally insulated at 160° C. for 5 hours. Thereafter, a component of low boiling point was distilled off at 230° C. To the reaction mixture after distilling off a component of low boiling point was added a mixed solution of 2-propanol/toluene to cause deposition of a crystal, obtaining 5.3 g of compound 4.
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:23][C:24]2[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=2)(=O)=O)C=CC=CC=1.[OH-].[K+].Cl>C(O)C>[CH2:32]([O:31][C:29]([C:27]1[O:28][C:24]([CH2:23][C:11]2[NH:10][C:18]3[C:13]([CH:12]=2)=[CH:14][C:15]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:16][CH:17]=3)=[CH:25][CH:26]=1)=[O:30])[CH3:33]
Reactant: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3n2S(=O)(=O)c2ccccc2)o1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1ccc(Cc2cc3cc(S(C)(=O)=O)ccc3[nH]2)o1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of the compound obtained in Example 30 (4) (0.1722 g) in ethanol (14 ml), potassium hydroxide (0.047 g) was added and the mixture was stirred at 15 to 30° C. for 30 minutes. To the mixture was added 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate 1:1) to obtain 0.0748 g of the desired product.
Reaction SMILES: C([O:8][C:9](=[O:24])[CH2:10][C@@H:11]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:12][C:13]([NH2:15])=[O:14])C1C=CC=CC=1>C(OCC)(=O)C.[Pd].ClCCl.CCCCCCC>[Si:17]([O:16][C@H:11]([CH2:10][C:9]([OH:24])=[O:8])[CH2:12][C:13]([NH2:15])=[O:14])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H](CC(N)=O)CC(=O)O
Temperature: 5 °C

Procedure:
(S)-Benzyl-3-(tert-butyl dimethylsilyloxy)glutaramate (100 g) was dissolved in ethyl acetate and placed in pressure flask. To this Palladium on charcoal (5%, 1 g) was added and stirred under hydrogen atmosphere (˜2.8 Kg). Palladium was removed by filtration. The filtrate was mixed with water and adjusted pH to ˜9.0 by using Aq ammonia solution. The reaction mass was stirred and layers were separated. The aqueous phase was washed with dichloromethane and dichloromethane was added to aqueous phase. The reaction mass was cooled to 5° C. and pH was adjusted to 4.0 with Aq phosphoric acid. The reaction mass was stirred and layers were separated. The organic phase was washed with water and dried over sodium sulphate. The organic layer was evaporated under vacuum to yield residue. Residue was dissolved in dichloromethane and to this solution heptane was added, stirred, filtered and dried to yield (S)-3-(tert-butyl dimethylsilyloxy)glutaric acid monoamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:31])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][CH2:25][N:26]([CH3:31])[C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)N(C)CCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C=CC(=O)N(C)CCOc1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.2 %

Procedure:
A mixture of 113a (80 mg, 0.115 mmol) and LiOH.H2O (24 mg, 0.573 mmol) in THF/i-PrOH/water (3.0 mL/1.0 mL/1.0 mL) was stirred at rt for 6 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (EA/MeOH=25/1) to give 113 (50 mg, 67%) as white solid. 1H NMR (300 MHz, DMSO-d6, 80° C.): δ 8.42 (s, 2H), 8.35 (s, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 7.33-7.30 (m, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.68-6.59 (m, 1H), 6.19 (d, J=8.1 Hz, 1H), 6.05-5.99 (m, 1H), 5.56 (m, 1H), 4.37-4.32 (m, 2H), 3.68 (t, J=5.4 Hz, 2H), 3.62 (s, 3H), 3.07 (s, 3H), 2.95-2.86 (m, 6H), 1.91-1.89 (m, 4H). ESI-LCMS: m/z=657.3 [C34H33FN6O5S+H]+
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.O1CCOCC1.[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>O>[C:17]1([N:23]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: NNc1ccccc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O
Product: NN(C(=O)c1ccc(I)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 70.9 %

Procedure:
A solution of 44.7 g. (0.168 mole) of p-iodobenzoyl chloride in 100 ml. of dioxane was added to 18.2 g. (0.168 mole) of phenylhydrazine dissolved in 250 ml. of pyridine at 5° to 15° C,. The resulting suspension was stirred at about 25° C. for 3 days, poured into 2 liters of water, the solids were filtered and washed with water, dilute aqueous hydrochloric acid and then again with water. The product thus obtained was crystallized from ethanol to give 40.0 g. (70.9% yield) of p-iodobenzoic acid phenylhydrazide having a melting point of 210° to 211° C.