Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)#[N:2].[SH2:28]>N1C=CC=CC=1.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[O:12])=[CH:8][C:7]=2[CH:27]=1)(=[S:28])[NH2:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C#N)ccc3o2)cc1
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)COc1ccc(NC(=O)c2cc3cc(C(N)=S)ccc3o2)cc1
Reaction time: 16 h

Procedure:
Ethyl 4-[(5-cyano-2-benzofuranyl)carbonylamino]phenoxyacetate (1.49 g, 4.09 mmol) was dissolved in a mixed solvent of pyridine (50 ml) and triethylamine (5 ml). A hydrogen sulfide gas was blown in for 10 minutes at room temperature and the mixture was stirred for 16 hours. Low boiling matters were distilled away from the reaction mixture under reduced pressure to give ethyl 4-[(5-thiocarbamoyl-2-benzofuranyl)carbonylamino]phenoxyacetate as a yellow solid. Acetone (100 ml) and iodomethane (10 ml) were added to this solid, and the mixture was refluxed under heating for 2 hours. The reaction mixture was heated to room temperature. The resulting precipitate was collected by filtration to give ethyl 4-[[5-[(1-methylthio)iminomethyl]-2-benzofuranyl]carbonylamino]phenoxyacetate as a yellow solid. To this solid was added ethanol (50 ml) and benzylamine (0.5 ml, 4.6 mmol), and the mixture was refluxed under heating for 2 hours. The reaction mixture was concentrated to about 10 ml under reduced pressure, and diethyl ether (40 ml) was added. The resulting precipitate was collected by filtration to give 1.70 g of hydriodide of compound (1) as a yellow solid (69% in three steps).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[CH:15]=[CH:14]3)[C:8]([C:21]([O:23]C)=[O:22])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>>[C:1]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[CH:15]=[CH:14]3)[C:8]([C:21]([OH:23])=[O:22])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cnc(C(C)(C)C)nc1-c1ccc2c(ccn2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cn1ccc2cc(-c3nc(C(C)(C)C)ncc3C(=O)O)ccc21
Yield: 96.9 %

Procedure:
Using a procedure analogous to Example B32, methyl 2-tert-butyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylate (898 mg, 2.78 mmol) and lithium hydroxide hydrate (466 mg, 11.11 mmol) were combined to give 2-tert-butyl-4-(1-methyl-1 H-indol-5-yl)pyrimidine-5-carboxylic acid (833 mg, 97% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.39 (s, 9 H), 3.82 (s, 3H), 6.54 (s, 1 H), 7.40 (s, 1 H), 7.52 (m, 2 H), 7.94 (s, 1 H), 8.91 (s, 1 H), 12.70 (s, 1 H); MS (ESI) m/z: 310.0(M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]([NH2:16])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.CN([Si](C)(C)C)C(=O)C(F)(F)F.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[N:32]=[CH:31]1>ClCCl>[O:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH:8]([NH:16][S:35]([C:33]2[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=2)(=[O:37])=[O:36])[CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:15][CH2:14]1
Reactant: NC(CN1CCOCC1)CN1CCOCC1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: ClCCl
Product: Cn1cnc(S(=O)(=O)NC(CN2CCOCC2)CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4 g (17.5 mmol) of 1,3-dimorpholino-2-propylamine and 3.5 g (17.5 mmol) of MSTFA [N-methyl-N-(trimethylsilyl)trifluoroacetamide] are combined under argon and stirred at room temperature for 17 hours. The clear solution is then concentrated in vacuo at 40° C./0.1 torr. A solution of 3.16 g (17.5 mmol) of 1-methyl-4-imidazolesulfonyl chloride in 20 ml of absolute dichloromethane is added at 20° C. with stirring to the oil obtained. After further stirring for 6 hours at 20° C., the solvent is distilled off in vacuo at 20° C./18 torr. The oil remaining crystallizes from isopropanol. After decolorization with active carbon, recrystallization from methanol/isopropanol gives the title compound of melting point 191°-192° C.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:29][C:30]3[NH:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[C:34]([C:39]#[N:40])[CH:33]=4)[C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([CH2:29][C:30]3[NH:31][C:32]4[C:37]([CH:38]=3)=[CH:36][CH:35]=[C:34]([C:39]#[N:40])[CH:33]=4)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[CH2:13]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: COC(=O)C(Cc1cc2ccc(C#N)cc2[nH]1)c1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C(Cc3cc4ccc(C#N)cc4[nH]3)C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
An aqueous solution containing 3 g of sodium hydroxide dissolved in 10 ml of water was added to 100 ml of a methanol solution containing 22 g of methyl 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propionate, and the resulting mixture was stirred at room temperature for 24 hours. After distilling off the solvent, the remaining portion was adjusted to pH 4-5 with citric acid and then extracted with ethyl acetate. By drying the extract to distill off the solvent, 20 g of 2-[4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]phenyl]-3-(6-cyano-2-indolyl)propionic acid was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29][O:30][CH2:31]Cl>CN(C)C=O>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[CH:10]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:29][O:30][CH3:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(CCO)c1)Cc1ccccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccccc1CN(Cc1cccc(CCO)c1)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
A solution of (2-hydroxy-benzyl)-[3-(2-hydroxy-ethyl)-benzyl]-carbamic acid tert-butyl ester (250 mg) in anhydrous N,N-dimethylformamide (2 mL) was treated with sodium hydride (29 mg of 60% grade reagent) and the mixture stirred under nitrogen for 10 minutes. A solution of chloromethyl methyl ether (62 mg) in anhydrous N,N-dimethylformamide (0.5 mL) was added dropwise followed by stirring at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous brine, the organic layer was washed twice with aqueous brine, separated, dried and the solvent evaporated under reduced pressure. The residue was purified on silica eluting with 30% ethyl acetate in isohexane to yield the sub-titled compound (145 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]=1.[H][H]>[Ni].C(O)(C)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[NH:3]1
Reactant: [H][H]
Reactant: COc1ccc(C)c2ccc(C)nc12
Agent: [Ni]
Solvent: CC(C)O
Product: COc1ccc(C)c2c1NC(C)CC2

Procedure:
A mixture of the above 2,5-dimethyl-8-methoxyquinoline (260 g, 1.3 m), isopropanol (600 ml), and Raney nickel catalyst (25.0 g) was subjected to 1000 psi hydrogen for 3 hrs. in a stainless steel autoclave. The reaction mixture from the autoclave was filtered to remove the catalyst. Essentially a quantitative yield of product was obtained, after the removal of the isopropanol under vacuum, and the product was used without further purification.
Reaction SMILES: [CH2:1]([C@H:8]([C@@H:31]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[C@@H:32]([OH:34])[CH3:33])[CH2:9][O:10][CH2:11][C@@H:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[CH2:1]([C@H:8]([C@@H:31]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:45])[CH3:44])[CH:37]([CH3:38])[CH3:39])[C@@H:32]([OH:34])[CH3:33])[CH2:9][O:10][CH2:11][C@@H:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](O[C@H]([C@H](COC[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)Cc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[Si](O[C@H]([C@H](COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)Cc1ccccc1)[C@H](C)O)(C(C)C)C(C)C
Reaction time: 7 h
Yield: 99.8 %

Procedure:
To a solution of (R)-benzyl 3-((2S,3R,4S)-2-benzyl-4-hydroxy-3-(triisopropylsilyloxy)pentyloxy)-2-(tert-butoxycarbonylamino)propanoate (410 mg, 0.637 mmol, 1.00 equiv) in EtOAc (13.4 mL, 0.05 M) was added 5% Pd/C (71 mg, 0.033 mmol, 0.05 equiv). The vessel was capped with a septum and the atmosphere replaced with 1 atmosphere (atm) H2 via a needle-equipped balloon. This suspension was stirred for 7 h, filtered through a plug of Celite®, and the plug was washed with EtOAc. Solvent removal provided (R)-3-((2S,3R,4S)-2-benzyl-4-hydroxy-3-(triisopropylsilyloxy)pentyloxy)-2-(tert-butoxycarbonylamino)propanoic acid (352 mg, 100%) as a hard, white foam: IR (neat film) 2944, 2867, 1706, 1163, 1092, 1063, 907, 731 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.26 (s, 2H), 7.21-7.10 (m, 3H), 5.44 (d, J=7.7 Hz, 1H), 4.45 (s, 1H), 3.88 (t, J=6.2 Hz, 1H), 3.78 (dd, J=5.8, 2.5 Hz, 2H), 3.70-3.51 (m, 2H), 3.33 (dd, J=9.3, 5.7 Hz, 1H), 2.90 (dd, J=13.6, 5.2 Hz, 1H), 2.67 (dd, J=13.7, 10.5 Hz, 1H), 2.05 (s, 1H), 1.45 (s, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.04 (s, 21H); 13C NMR (101 MHz, CDCl3) δ 173.08, 155.56, 140.78, 129.08, 128.37, 125.96, 80.25, 71.20, 71.03, 69.08, 53.81, 46.81, 35.18, 28.30, 19.57, 18.20, 12.88; HRMS-ESI (m/z) [M+Na]+ calc'd for C29H51NO7SiNa, 576.3327. found, 576.3341.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([CH3:38])[C:29]1=[O:39]>C(Cl)(Cl)(Cl)Cl>[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([CH2:38][Br:1])[C:29]1=[O:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2ccccc2n(C)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(=O)c(CBr)nc2ccccc21

Procedure:
N-bromosuccinimide (3.36 g., 0.0189 mol.) and benzoyl peroxide (0.06 g.) were added to a solution of 1,3-dimethyl-2(1H)-quinoxalinone (3.0 g., 0.017 mol.) in carbon tetrachloride (250 ml.). The mixture was heated at reflux for four hours. Removal of the solvent left a tan solid. Chromatography on silica gel with methylenechloride as the eluent gave a tan solid. Recrystallization from methylene chloride gave light tan needles. (2.33 g., m.p. 192.5°-193.5°. 53%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:14]=[C:10]([C:11](O)=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1)=[O:5].S(Cl)([Cl:18])=O>>[CH3:1][O:2][CH2:3][C:4]([C:6]1[CH:14]=[C:10]([C:11]([Cl:18])=[O:12])[C:9]([OH:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: COCC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: O=S(Cl)Cl
Product: COCC(=O)c1ccc(O)c(C(=O)Cl)c1
Temperature: 25 °C
Yield: 101.5 %

Procedure:
The above prepared 5-methoxyacetylsalicylic acid (26.24 g, 0.1250 mol) was placed in a 500 ml round bottomed flask fitted with Argon purge and magnetic stir bar. Methylene chloride (125 ml) and several drops of dimethylformamide were then added. A 60 ml addition funnel was placed atop the flask and thionyl chloride (22.30 g, 0.1874 mol) was added dropwise over a period of 25 minutes. The addition funnel was replaced with a condenser and the reaction mixture was heated at reflux for a period of approximately 1 hour. Heating was stopped and the reaction mixture allowed to cool to room temperature. Excess thionyl chloride and methylene chloride were removed under-vacuum yielding 29.00 g of 5-methoxyacetylsalicyloyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C(CC(c2ccc(Br)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-methoxy-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.7:1) as a white foam, MS (ESI+): m/z=425.1 ([M+H]+, 1Br).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[NH4+:5].[C:6]([O:10][C:11]([CH2:13][CH:14]([O:16][N:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])[CH3:15])=[O:12])([CH3:9])([CH3:8])[CH3:7]>CO>[C:1]([O-:4])(=[O:3])[CH3:2].[C:6]([O:10][C:11]([CH2:13][CH:14]([O:16][N:17]=[C:18]([C:19]#[N:20])[C:21]([NH2:5])=[NH2+:22])[CH3:15])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(CC(=O)OC(C)(C)C)ON=C(C#N)C#N
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: CC(CC(=O)OC(C)(C)C)ON=C(C#N)C(N)=[NH2+]
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To ammonium acetate (18.5 g) dissolved in methanol (100 ml) was added 2-(tert-butoxycarbonylprop-2-oxyimino)malononitrile (19 g). After stirred for 2 hours, the mixture was standed overnight at room temperature. The reaction mixture was concentrated, and water (500 ml) was added therein. The obtained mixture was extracted with ethylacetate (500 ml). After the extract was dehydrated, filtered, and concentrated, ethylether was added therein, and stirred for 30 minutes. The precipitates were filtered to give the above-indicated compound (15 g) in pale yellow.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9](C(O)=O)[C:8]([Cl:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl

Procedure:
0.0008 moles of 2,5-dichloro-3-nitro-terephthalic acid were refluxed for 1 hour in 0.334 moles of dimethyl formamide (DMF), after which time the reaction mixture was flash evaporated to remove most of the DMF. To the residue was added 60 ml of water with agitation, and an orange precipitate formed which was filtered off and washed. The precipitate was dissolved in approximately 50 ml of saturated sodium bicarbonate solution, refiltered and then extracted with chloroform. The aqueous phase was acidified with 10% hydrochloric acid to complete precipitation, and the resulting precipitate was filtered, washed and dried to give an 85% crude yield of 2,5-dichloro-3-nitro-benzoic acid. Subsequent GLC analysis showed it to be 95.8% pure--thus, the yield of the process was 79.5% of theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[C:12]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:21][C:12]([CH3:14])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])=[O:7]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)NC(C)(C)c2ccccc2)c1
Yield: 98.2 %

Procedure:
In a similar manner to Step 1 of Example 16, 3-methoxybenzoylchloride (8.00 g, 46.9 mmol) was dissolved in dichloromethane (160 mL), and the solution was treated with cumylamine (7.40 mL, 51.6 mmol), triethylamine (9.80 mL, 70.4 mmol) and DMAP (573 mg, 4.69 mmol), followed by purification by slurry using diisopropylether to obtain 3-methoxy-N-(1-methyl-1-phenylethyl)benzamide (12.4 g, yield 98%).
Reaction SMILES: [NH:1]([C:19]([O:21]CC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([CH2:17][F:18])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Br>C(O)(=O)C>[NH:1]([C:19]([CH2:17][CH2:15][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:21])[C@H:2]([C:7]([NH:9][C@H:10]([C:15]([CH2:17][F:18])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)CF
Agent: Br
Solvent: CC(=O)O
Product: CCCCCCCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCC)C(=O)CF
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
The Z-Leu-Nle-CH2F (0.29 g) obtained in Example 1 was dissolved in acetic acid (4.5 ml) including 25% anhydrous hydrogen bromide and the mixture was agitated at room temperature for 3 hours. After the end of the reaction, the solvent was distilled off and the resultant residue was dissolved in anhydrous methylene chloride (5 ml). To this, under ice water cooling, were added triethylamine (0.20 g) and octanoylchloride (0.12 g) to dissolve it, then this was washed with a 10% aqueous citric acid solution, a 5% sodium hydrogencarbonate, then a saturated saline water in this order, then was dried on anhydrous sodium sulfate and the solvent distilled off under a reduced pressure. The residue was purified by silica gel medium pressure column chromatography to obtain the above-referenced compound Octanoyl-Leu-Nle-CH2F (120 mg, 0.31 mmole) at a yield of 42%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[C:3]=1[CH3:13].[Li]CCCC.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([CH3:29])[CH:22]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:25]([C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][C:23]=2[CH3:29])[OH:26])=[C:3]([CH3:13])[C:4]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(C=O)c(C)c1
Reactant: COc1ccc(Br)c(C)c1C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c(C(C)C)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
To a stirring solution of 1-bromo-3-iso-propyl-4-methoxy-2-methyl-benzene (compound 7-16, step c; 0.7 g, 2.88 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.6 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 hr and 4-methoxy-2-methyl-benzaldehyde (0.37 mL, 2.74 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (4′-methoxy-3′-iso-propyl-2′-methylphenyl)-(4-methoxy-2-methylphenyl)-methanol as a light yellow oil (1.0 g, 100%). This crude oil was dissolved into EtOAc (25 mL) and AcOH (5 mL) and Pd/C (0.1 g) was added. After stirring at rt for 6 hours, the reaction mixture was filtered through the Celite and concentrated under reduced pressure to afford crude 4-(4′-methoxy-2′-methyl-3′-iso-propylbenzyl)-3-methyl-anisole as a yellow oil (0.8 g, 93%): 1H NMR (300 MHz, DMSO-d6): δ 6.88-6.80 (m, 5 H), 3.77 (s, 2 H), 3.74 (s, 3 H), 3.71 (s, 3. H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.14 (s, 3 H), 1.28 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=8% ethyl acetate in hexanes; Rf=0.56.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](O)([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)[C:9]2=[O:29])=[CH:4][CH:3]=1.C1(C(C2C=CC=CC=2)N2C3C(=C(F)C=CC=3)C(O)(C3C(O)=CC4OCCOC=4C=3)C2=O)C=CC=CC=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[O:21][CH2:22][CH2:23][O:24][C:19]=4[CH:18]=3)[C:9]2=[O:29])=[CH:4][CH:3]=1
Reactant: O=C1N(c2ccc(F)cc2)c2ccccc2C1(O)c1cc2c(cc1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2ccccc2N1c1ccc(F)cc1

Procedure:
Following the procedure as described in PREPARATION 82C and making non-critical variations using 1-(4-fluorophenyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one, 1-(4-fluorophenyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (59%) as a colourless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 1H), 7.51-7.39 (m, 4H), 7.17 (dd, J=7.6 Hz, 7.6 Hz, 1H), 7.05-6.96 (m, 2H), 6.67 (s, 1H), 6.68 (d, J=7.8 Hz, 1H), 6.27 (s, 1H), 4.84 (s, 1H), 4.19-4.12 (m, 4H): MS (ES+) m/z 378.2 (M+1).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S([N:22]=[N+:23]=[N-])(=O)=O)=CC=1.N12CCCN=C1CCCCC2>C(#N)C>[CH2:11]([O:10][C:8](=[O:9])[C:7](=[N+:22]=[N-:23])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCOC(=O)Cc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(=[N+]=[N-])c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl phenylacetate (3.28 g) in acetonitrile (60 mL) is added para-toluenesulfonylazide (4.53 g). The reaction mixture is cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 mL) is added dropwise. The reaction mixture is kept at 5° C. overnight. Solvent is removed to dryness and the residue is purified by chromatography (gradient petroleum ether/dichloromethane from 90/10 to 80/20) to give diazophenylacetic acid ethyl ester;
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:10]=1[NH2:18])([CH3:3])[CH3:2].N[C:21]1C([N+]([O-])=O)=CC=C[C:22]=1OCC1OC1.C(N)(C)C.C(N)(C)(C)C>>[CH3:21][C:22]1[NH:18][C:10]2[C:9]([O:8][CH2:7][CH:6]([OH:19])[CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])=[CH:14][CH:13]=[CH:12][C:11]=2[N:15]=1
Reactant: CC(C)NCC(O)COc1cccc([N+](=O)[O-])c1N
Reactant: Nc1c(OCC2CO2)cccc1[N+](=O)[O-]
Solvent: CC(C)N
Solvent: CC(C)(C)N
Product: Cc1nc2cccc(OCC(O)CNC(C)C)c2[nH]1

Procedure:
The 1-isopropylamino-2-hydroxy-3-(2-amino-3-nitrophenoxy)-propane (m.p. 108° - 110°C.) used as starting material can be obtained, in the manner described in Example 1, from 1-(2-amino-3-nitrophenoxy)-2,3-epoxy-propane, using 35 g. isopropylamine instead of 35 g. tert.-butylamine.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12](=[N:17][C:18]#[N:19])OCCC)[CH:9]=[N:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>CO>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12](=[N:29][CH2:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])[NH:17][C:18]#[N:19])[CH:9]=[N:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cncc(C(=NC#N)OCCC)c1
Reactant: NCCc1ccccc1Cl
Solvent: CO
Product: CCCCNc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
To a solution of propyl 5-n-butylamino-N-cyano-3-pyridinecarboximidate (99 mg, 0.38 mmol) in methanol (2 ml) was added 2-(2-chlorophenyl)ethylamine (71 mg, 0.46 mmol), and the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue obtained was purified by silica gel column chromatography (Wako Gel C-200, 30 g; eluted with chloroform:methanol=200:1) and further crystallized from diethyl ether to give the title compound (90 mg, 0.25 mmol) as colorless crystals in the yield of 67%.