Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[H-].[Na+].[CH3:11]Br>O1CCCC1>[CH3:11][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(O)cc1

Procedure:
Hydroquinone can be added to a solution of sodium hydride (NaH) dissolved in tetrahydrofuran (THF) and combined with methyl bromide yielding para-methoxyphenol. The para-methoxyphenol can be extracted and added to a solution of tosyl chloride (TsCl) dissolved in pyridine and tetrahydrofuran (THF) at room temperature, yielding para-methoxytosyloxybenzene. The para-methoxytosyloxybenzene can be extracted and added to a solution of diatomic iodine (I2) and potassium iodide trioxide (KIO3) dissolved in sulfuric acid (H2SO4) and acetic acid (CH3COOH) yielding 4-methoxy-3-iodo-1-tosyloxybenzene. The 4-methoxy-3-iodo-1-tosyloxybenzene can be extracted and added to a solution of aqueous sodium hydroxide (NaOH) and tert-butanol, removing the tosylate protecting group and yielding 4-methoxy-3-iodophenol. The 4-methoxy-3-iodophenol can be extracted and exposed to resin-bound triphenyphosphine (PPh3) in a solution of azopyridine and ethanol (CH3CH2OH) in a salt bath at 0° C., yielding 4-ethoxy-2-iodomethoxybenzene. The 4-ethoxy-2-iodomethoxybenzene can be extracted and added to a solution of titanium tetrachloride (TiCl4) and 1,1-dichlorodimethylether (CHCl2OCH3) dissolved in dichloromethane (CH2Cl2) in a salt bath at −10° C., yielding 2-ethoxy-4-iodo-5-methoxybenzaldehyde. The 2-ethoxy-4-iodo-5-methoxybenzaldehyde can be added to lithium aluminum hydride (LiAlH4) and methanesulfonyl chloride (CH3SO2Cl) dissolved in pyridine, and then sodium iodide (NaI) and triethyl phosphite (P(OCH2CH3)3) can be added to the reaction mixture, yielding diethyl 2-ethoxy-4-iodo-5-methoxybenzylphosphonate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14].C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1)=[O:14]
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccn1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
2-Amino-4-chloropyridine (90 mg, 0.70 mmol, 1.1 eq), 3-chlorobenzoic acid (0.1 mg, 0.6 mmol, 1 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (135 mg, 0.704 mmol, 1.10 eq) and 4-dimethylaminopyridine (7.8 mg, 0.064 mmol, 0.10 eq) were dissolved in CH2Cl2 (5 ml) and stirred at rt overnight. Water was added and the layers separated. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 160 mg (94%) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s, 1H), 8.39 (d, J=5.4 Hz, 1H), 8.27 (d, J=1.6 Hz, 1H), 8.06 (t, J=1.8 Hz, 1H), 7.96 (dt, J=7.6, 1.2 Hz, 1H), 7.67 (ddd, J=8.0, 2.1, 1.0 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.32 (dd, J=5.4, 2.0 Hz, 1H); ES-MS [M+1]+: 267.1.
Reaction SMILES: [OH-].[K+].[CH2:3](Br)[CH:4]=[CH2:5].C1OCCOCCOCCOCCOCCOC1.[OH:25][CH:26]1[CH2:43][CH2:42][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:3]([O:25][CH:26]1[CH2:27][CH2:28][C:29]2([CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:31][CH2:30]2)[CH2:42][CH2:43]1)[CH:4]=[CH2:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Reactant: C=CCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=CCOC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Yield: 92 %

Procedure:
KOH (257.46 mmol, 21.0 eq.), allyl bromide (36.8 mmol, 3.0 eq.) and 18-crown-6 (4.9 mmol, 0.4 eq.) were added to a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (12.26 mmol, 1.0 eq.) in toluene (65 ml) at 0° C. and then reaction mixture was heated at reflux for 1 h. Then the reaction mixture was diluted with ethyl acetate (150 ml) and washed with water (150 ml) and brine (150 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to yield the crude product which was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as a yellow oil. Yield: 92%
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([N:16](C(C)C)[CH2:17]C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl.O>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:13])=[O:5]
Reactant: O=C(O)c1cc(I)cc(F)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)cc(F)c1F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
2,3 Difluoro-5-iodobenzoic acid (10.8 g, 38 mmol) was suspended in 80 mL of dry dichloromethane under nitrogen. Di-iso-propylethylamine (6.6 mL, 38 mmol) was added and the mixture was cooled to 0° C. Pivaloyl chloride (4.7 mL, 38 mmol) was added and the solution was stirred at 0° C. for 1.5 hrs. Dimethylamine was added (40% wt solution in water, 10.6 mL, 83 mmol) and the reaction mixture was stirred for 5 hrs. The reaction was quenched with sodium bicarbonate and diluted with dichloromethane (50 mL). The layers were separated, the organic phase was washed with 1 N hydrochloric acid and brine. The organic phase was dried over magnesium sulfate and concentrated to give 10.3 g (33 mmol, 87%) of 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide as a colorless solid. 1H NMR (500 MHz, DMSO-d6) δ 7.95 (ddd, J1=10 Hz, J2=7.5 Hz, J3=2 Hz, 1H), 7.57 (dt, J1=10 Hz, J2=2 Hz, 1H), 2.98 (s, 3H), 2.84 (s, 3H); MS: m/z 312 [MH+]
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:23][CH3:24])=[C:13]([C:15]2[CH:20]=[C:19]([NH2:21])[N:18]=[C:17]([NH2:22])[CH:16]=2)[CH:14]=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26]>>[NH2:22][C:17]1[N:18]=[C:19]([NH:21][C:30]2[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=2)[CH:20]=[C:15]([C:13]2[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=2[O:23][CH3:24])[CH:16]=1
Reactant: COc1ccc(Cl)cc1-c1cc(N)nc(N)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cl)cc1-c1cc(N)nc(Nc2ccc(C=O)cc2)c1
Yield: 22 %

Procedure:
Following the method described in Example 8, 4-(5-chloro-2-methoxy-phenyl)-pyridine-2,6-diamine trifluoroacetic acid salt and 4-formyl-phenylboronic acid provided the title compound (22% yield). 1H NMR (acetone-d6) δ3.85 (s, CH3), 5.51 (bs, 2H, NH2), 6.27 (d, 1H, J=1.1 Hz, Ar), 6.38 (d, 1H, J=1.1 Hz, Ar), 7.14 (d, 1H, J=8.8 Hz, Ar), 7.32 (d, 1H, J=2.7 Hz, Ar), 7.38 (dd, 1H, J=8.8 Hz, J=2.7 Hz, Ar), 7.78 (d, 2H, J=8.7 Hz, Ar), 7.96 (d, 2H, J=8.7 Hz, Ar), 8.59 (s, 1H, NH), 9.84 (s, 1H, CH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](OC)=[O:15])([O-])=O>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:10][C:8]1[CH:9]=[C:4]2[C:5]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14](=[O:15])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)NC(=O)C2(O)C(F)(F)F
Reaction time: 8 h
Yield: 6.2 %

Procedure:
To a solution of methyl 2-(2,4-dinitrophenyl)-3,3,3-trifluoro-2-hydroxypropanoate (1.3 g, 4.01 mmol) in ethyl acetate (18 mL) was added pH3HCl (5.2 mL) followed by 10% Pd/C (350 mg) in ethyl acetate (3 mL). The mixture was stirred overnight under an atmosphere of H2. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The crude residue obtained was partitioned between, dichloromethane (25 mL) and aqueous saturated NaHCO3 (15 mL). The organic phase was separated and the aqueous phase was extracted dichloromethane (2×25 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated. Purification by silica gel chromatography (50-100% ethyl acetate/hexanes) provided 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (921 mg, 99%) To a solution of 6-amino-3-hydroxy-3-(trifluoromethyl)indolin-2-one (58 mg, 0.25 mmol) in THF (0.5 mL) at 0° C. was added BH3 THF complex (1M in THF, 1 mL, 0.95 mmol) dropwise. The mixture was stirred for 5 min at 0° C. then for 3 h at room temperature. The reaction was quenched by adding very carefully 6M HCl (3.5 mL) until no more gas release was observed. The mixture was then stirred at 80° C. for 2 h. The solvent was removed under reduce pressure and the solid residue obtained was dissolved in DMF (3 mL), filtered and purified by reverse phase HPLC (10-99% CH3CN/H2O) to provide 3-(trifluoromethyl)-1H-indol-6-amine (30 mg, 54%, TFA salt).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:21][C@@H:22]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CNC(=O)[C@@H](NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (2S)-2-amino-N,3,3-trimethyl-butanamide (CAN 89226-12-0) as starting materials, MS (D): m/e=411.4 [M+H]+.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:46])[NH:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:46])[NH:29][CH2:30][CH2:31][NH:32][C:33]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([N+:43]([O-:45])=[O:44])=[CH:39][CH:38]=3)=[O:34])[N:27]=2)[CH2:20]1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(C(=O)NCCNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NCCNC(=O)c1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (1.21 g, 1.84 mmol) (obtained as described in Reference Example 56(4)) in anhydrous tetrahydrofuran (60.6 ml) were added successively acetic acid (0.13 ml, 2.27 mmol) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (2.2 ml, 2.2 mmol) in an ice bath. The mixture was stirred for 2.5 hours under the same conditions. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. To the residue was added isopropyl ether, and the mixture was stirred, washed and filtered off to give 3-hydroxy-1-{4-[2-(p-nitrobenzyloxycarbonylamino)-ethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (667 mg, yield 86%) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[C:21]1([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH:30]([C:34]([NH2:36])=[O:35])[CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:29][CH:30]2[C:34]([NH2:36])=[O:35])=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 61.9 %

Procedure:
A mixture of 74.2 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 43.8 parts of 4-(phenylmethyl)-2-piperazinecarboxamide, 38.9 parts of N,N-diethylethanamine and 1350 parts of N,N-dimethylformamide was stirred for 20 hours at 70° C. The reaction mixture was evaporated in vacuo and the residue was stirred in dichloromethane. The precipitate was filtered off. The filtrate was washed three times with 200 parts of water and once with 200 parts of a diluted ammonium hydroxide solution, dried, filtered and evaporated. The residue was purified by column chromatography over silical gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 58.9 parts (61.9%) of 1-[5,5-bis(4-fluorophenyl)-4-pentenyl]-4-(phenylmethyl)-2-piperazinecarboxamide as a residue (int. 33).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH:6]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])[CH2:7][C:8](O)=[O:9].Cl>C(O)C>[CH2:1]([O:3][C:8](=[O:9])[CH2:7][CH:6]([NH2:5])[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC(CC(=O)O)c1cc(F)ccc1F
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(N)c1cc(F)ccc1F
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (4 ml) was added dropwise at room temperature to a round-bottom flask containing ethanol (50 ml). 3-Amino-3-(2,5-difluorophenyl)propionic acid (2.94 g) was added to the ethanolic hydrochloric acid solution thus prepared, and the mixture was stirred at 50° C. for three hours. Subsequently, the mixture was concentrated under reduced pressure, and the residue was admixed with 1N sodium hydroxide solution (100 ml) and extracted immediately with dichloromethane (3×50 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated. The product (3.2 g) was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([C:10]#N)=[CH:8][N:7]=[CH:6][CH:5]=1.CO.C([O-])(O)=[O:15].[Na+]>Cl.C(Cl)(Cl)Cl>[C:10]1(=[O:15])[C:9]2=[CH:8][N:7]=[CH:6][CH:5]=[C:4]2[CH2:3][CH2:2][O:1]1
Reactant: N#Cc1cnccc1CCO
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C1OCCc2ccncc21
Yield: 67.75 %

Procedure:
4-(2-Hydroxyethyl)nicotinonitrile (I-65b: 1.1 g) in concentrated HCl (30 mL) was refluxed overnight. The reaction was monitored by TLC (10% methanol in CHCl3). The reaction mass was concentrated under reduced pressure and the crude residue was dissolved in water. The resulting reaction mass was basified with saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 750 mg of the product (67.75% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C(O)(=O)C.[Br:17]Br>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[S:11][CH3:12])=[O:10]
Reactant: CSc1ccc(F)cc1C(C)=O
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(F)cc1C(=O)CBr
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a stirring solution of 20c (2.07 g, 11.34 mmol), carbon tetrachloride (62 ml) and glacial acetic acid (2.07 ml) was added at room temperature a solution of bromine (μL 546.6, 10.66 mmol) in carbon tetrachloride (34 ml). The first drop was added and after 20 minutes the solution was added dropwise in 4 hours. After stirring for 16 hours the solvent was distilled and to the residue was added water and solid sodium bicarbonate (to pH 7), the organic phase was separated and water extracted with dichloromethane (3×30 ml), the organic layers were dried and evaporated. The crude product was chromatographed (70% petroleum ether 40-60° in dichloromethane) to give 1.90 g of 21c as a yellowish solid (64% yield). 1H NMR (CDCl3) δ7.47-7.42 (dd, 1H, J=8.85, 2.84 Hz); 7.38-7.18(m, 2H); 4.42 (s, 2H); 2.43 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH2:18][CH2:19][CH2:20][C:21]3[S:25][C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[N:23][C:22]=3[CH3:36])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+]>>[CH3:36][C:22]1[N:23]=[C:24]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=2)[S:25][C:21]=1[CH2:20][CH2:19][CH2:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:37])=[O:5]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1cccc2c1ccn2CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1cccc2c1ccn2CC(=O)O

Procedure:
In analogy to the procedure described in example 2 c], (4-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester was treated with NaOH to obtain (4-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid as white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH2:23]([C:25]([OH:30])([CH2:28][CH3:29])[C:26]#[CH:27])[CH3:24].C1COCC1>C(OCC)(=O)C.[Cu](I)I>[CH2:26]([C:25]([C:23]1[N:3]=[N:2][N:1]([CH2:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:10][C:11](=[O:15])[O:12]3)=[CH:7][CH:6]=2)[CH:24]=1)([OH:30])[CH2:28][CH3:29])[CH3:27]
Reactant: C#CC(O)(CC)CC
Reactant: Cc1cccc(-c2cc(=O)oc3cc(CN=[N+]=[N-])ccc23)c1
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)(CC)c1cn(Cc2ccc3c(-c4cccc(C)c4)cc(=O)oc3c2)nn1
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-(3-methylphenyl)-2H-chromen-2-one (100 mg, 0.34 mmol) and 3-ethyl-1-pentyn-3-ol (46 mg, 0.41 mmol) in THF (4 mL) N,N-diisopropylethylamine (296 uL, 1.7 mmol) and copper iodide (97 mg, 0.51 mmol) were added. After overnight stirring, the reaction was diluted with ethyl acetate, filtered and washed with water and brine. The organic layer was then dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2 20:80) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 7.90 (s, 1H), 7.54 (d, 1H), 7.47 (t, 1H), 7.43-7.33 (m, 4H), 7.25 (d, 1H), 6.33 (s, 1H), 5.78 (s, 2H), 3.70 (s, 1H), 2.45 (s, 3H), 1.95-1.75 (m, 4H), 0.79 (t, 6H).
Reaction SMILES: I[Si](C)(C)C.C(OC([N:13]1[C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][S:15][CH:14]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.O>C(Cl)(Cl)Cl>[CH2:25]([CH:14]1[NH:13][C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][S:15]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1
Reaction time: 1 h
Yield: 111.3 %

Procedure:
C tert-Butyl (2RS,4R)-2-benzyl-4-thiazolidinecarboxalate may be prepared in the following 11.8 cm3 of iodotrimethyl-silane are introduced slowly at a temperature in the region of 25° C. into a solution of 30.5 g of tert-butyl (4R)-3-tert-butoxycarbonyl-2-benzyl-4-thiazolidine-carboxylate (isomer A) in 250 cm3 of chloroform. The reaction mixture is stirred for 1 hour, and 10 cm3 of water are then added. The organic phase is separated and the aqueous phase is extracted with twice 20 cm3 of methylene chloride. The combined organic phases are washed with 100 cm3 of water and with 100 cm3 of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. 25.0 g of tert-butyl (2RS,4R)-2-benzyl-4-thiazolidinecarboxylate are thereby obtained in the form of a yellow oil, which is used in the subsequent syntheses without further treatment.
Reaction SMILES: [NH:1]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@@H:2]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:29])[NH2:28])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.Cl.Cl.CC(O)=O>CO>[NH:1]([C:33]([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34])[C@@H:2]([C:15]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[NH:28])[NH2:29])=[O:20])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)O
Yield: 74.6 %

Procedure:
2.7 Grams (3.5 mM) of Z-D-Lys(BOC)-Gly-Arg-CHA.HCl was dissolved in a small amount of MeOH, followed by addition of 7 ml of 2N-HCl/AcOH and the mixture was reacted at room temperature for 1 hour. The reaction mixture was reprecipitated from dry diethyl ether and the crystals precipitated were collected by filtration and dried to obtain crude Z-D-Lys-Gly-Arg-CHA.2HCl. This crude product was purified by means of a column chromatography by using "TOYOPEARL HW 40F" column using MeOH as a developing solvent to obtain 1.8 g (74.6%) of Z-D-Lys-Gly-Arg-CHA.2HCl. Rf2 =0.31. Melting point: 220.0° C. (decomposed). [α]D20 -16.0 (C=1, 50% AcOH).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>O1CCCC1>[C:33]([N:15]1[CH2:16][CH2:17][CH:12]([C:6]2([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:13][CH2:14]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-4-yl-1,3-dihydro-indol-2-one (35 mg, 0.09 mmol) (from Example 15a supra) in tetrahydrofuran (3 mL) was added triethylamine (14.1 mg, 0.139 mmol), followed by the addition of acetyl chloride (8.7 mg, 0.11 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with another two portions of ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give rac-3-(1-acetyl-piperidin-4-yl)-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one as a white solid. (Yield 25 mg, 65%). Further purification by precipitation in a cosolvent of dichloromethane and hexanes gave the product as a white solid. (18 mg).