Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=O)[CH3:8])=[CH:4][CH:3]=1.BrC1C=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CC(=O)Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Fc1ccc(Nc2ccc(F)cc2)cc1

Procedure:
A mixture of p-fluoroacetanilide (76.5 g, 0.5 mole), 4-bromofluorobenzene (262.5 g, 1.5 mole), K2CO3 (76 g, 0.55 mole), Cu2Br2 (157.8 g, 0.55 mole) and N-methylpyrrolidone (600 ml) were heated at 175°-180°. After allowing low boiling material to condense off, the mixture was heated at reflux for 7 days. The mixture was cooled to 60° and quenched into a mixture of 2 liters H2O, 600 ml ethylenediamine and 1.2 liters toluene, filtered and the toluene layer separated, back-washed 2×600 ml H2O, treated with activated carbon, dried over MgSO4 and concentrated to oil solids in vacuo. The latter were taken up in 1.5 liters 10% ethanolic KOH, refluxed 18 hours and concentrated in vacuo to an oil. The oil was partitioned between 750 ml H2O and 750 ml. ether. The water layer was washed 2× 200 ml ether. The organic layers were combined, back-washed 2×200 ml H2O, treated with activated carbon, dried over MgSO4, reconcentrated to an oil (60.3 g) and distilled to yield purified title product 41.6 g, b.p. 158°-160°/2 mm.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[S:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41]1>O1CCCC1.O>[F:3][C:4]1[C:9]([C:10]2[N:14]([S:45]([C:42]3[CH:43]=[CH:44][S:40][CH:41]=3)(=[O:47])=[O:46])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccsc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a suspension of sodium hydride (97.9 mg, 60% in oil) in tetrahydrofuran (10 mL) were added a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (311 mg) in tetrahydrofuran (3 mL), 15-crown-5 (449 mg), and thiophene-3-sulfonyl chloride (280 mg) under ice-cooling. The mixture was stirred at room temperature for 30 min, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 433 mg, 94%).
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:25]3[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][OH:19])[CH2:23][CH2:24]3)=[S:16])[C:11]([O:17][CH3:18])=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2nc(C(C)(C)C)sc2cc1N=C=S
Reactant: OCCN1CCNCC1
Solvent: CC(C)=O
Product: COc1cc2nc(C(C)(C)C)sc2cc1NC(=S)N1CCN(CCO)CC1
Reaction time: 2 h

Procedure:
21 g (0.076 mole) of 2-tert.-butyl-6-isothiocyano-5-methoxy-benzthiazole are dissolved in 400 ml of acetone and a solution of 12 g (0.092 mole) of N-(2-hydroxyethyl)-piperazine in 40 ml of acetone is added dropwise. The mixture is stirred for 2 hours, cooled to 0° , filtered and washed with acetone, then with ether and finally with petroleum ether. 2-tert.-butyl-5-methoxy-6-{[4-(2-hydroxyethyl)-piperazin-1-yl]-thiocarbonylamino}-benzthiazole having a melting point of 161-162° is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1)[NH2:5].O=[C:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH:26]2[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:22])[CH3:23])=[C:16]([Cl:24])[CH:15]=2)[N:10]=1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(N)cc3Cl)n2)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(NC4CC(C(=O)O)C4)cc3Cl)n2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)aniline (200 mg, 0.549 mmol) and 3-oxocyclobutanecarboxylic acid (62.7 mg, 0.549 mmol) in methanol (1280 μl) at room temperature was added acetic acid (842 μl, 14.72 mmol). The reaction mixture was stirred at room temperature for 10 minutes before addition of sodium cyanoborohydride (17.25 mg, 0.275 mmol) as a single portion. The reaction mixture was stirred at room temperature overnight. LCMS (2007—9476) indicated a 43% by ELSD (2.90 min)s conversion to (M+H) 462.16. The solvent was removed and the crude material purified by FCC (50% EA/Hept) to afford 3-(3-chloro-4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenylamino)cyclobutanecarboxylic acid (135 mg, 0.292 mmol, 53.2% yield) as a white solid. LCMS (Table A, Method b) indicated 100% by UV (3.06 mins) to (M+H)+ 364.12.
Reaction SMILES: Cl.N[C@@H](C)[C@@H:4](C1C=CC(OC)=CC=1)[OH:5].[O:15]=[C:16]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:17]([NH:20]C(=O)OC(C)(C)C)[CH2:18][CH3:19]>>[NH2:20][C@@H:17]([CH2:18][CH3:19])[C@@H:16]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([O:5][CH3:4])[CH:33]=1)[OH:15]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Reactant: COc1ccc([C@@H](O)[C@H](C)N)cc1
Agent: Cl
Product: CC[C@H](N)[C@H](O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as 90b from (S)-tert-butyl 1-oxo-1-phenylbutan-2-ylcarbamate (97c, 225 mg, 0.768 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[CH2:24]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-amino-phenylacetic acid benzyl ester p-toluene sulphonic acid was prepared by adding 3-aminophenylacetic acid (10 g) and p-toluene sulphonic acid monohydrate (13.2 g) to benzyl alcohol (27.2 ml) in toluene (30 ml). The mixture was heated under reflux and the water formed collected in a Dean-Stark receiver. When all the water had been distilled off the mixture was allowed to cool to 25° C. before diluting with diethyl ether and placing in an ice-bath for 1 hr. The crystalline p-toluene sulphonate was filtered off and dried in a dissicator (23.5 g) NMR δ2.31(s)3H, 3.82(s)2H, 5.11(s)2H, 7.11(d)2H, 7.25-7.45(m)8H, 7.52(d)2H.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:42])=[C:13]([N:15]2[C:22](=[O:23])[C:21]3[CH:20]=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[N:18]([CH:32]([CH3:34])[CH3:33])[C:17]=3[CH:16]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:14]=1.CN(C=O)C>CC#N>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:42])=[C:13]([N:15]2[C:22](=[O:23])[C:21]3[C:20]([C:6]#[N:5])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])[N:18]([CH:32]([CH3:34])[CH3:33])[C:17]=3[CH:16]2[C:35]2[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=2)[CH:14]=1
Reactant: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1ccccc1-c1c(C#N)c2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Chlorosulfonyl isocyanate [1189-71-5] (0.453 mmol) was added to a mixture of 5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-2-(2-methoxy-phenyl)-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Example 9) (0.302 mmol) in CH3CN (2 mL) at 0° C. After stirring at rt for 2.5 h, additional chlorosulfonyl isocyanate (0.226 mmol) was added. After another 4 h, the reaction mixture was cooled to 0° C., treated with DMF (0.4 mL), stirred for 15 min and then warmed to 50° C. After 30 min, the reaction mixture was cooled to rt, poured onto ice-H2O and extracted with EtOAc. The organic layer was successively washed with a 1N aqueous solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography to afford the title compound as an off-white solid. tR: 5.59 min (HPLC 1); ESI-MS: tR=1.39 min, [M+H]+ 530/532/534 (LC-MS 1); TLC: Rf=0.12 (1:3 EtOAc/heptanes); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 7.79/7.83 (s, 1H), 7.58 (m, 1H), 7.35-7.46 (m, 3H), 7.31 (m, 2H), 7.25 (m, 1H), 7.21 (m, 1H), 7.09-7.17 (m, 2H), 6.61 (s, 1H), 3.97/4.01 (m, 1H), 3.77/3.83 (s, 3H), 1.93 (s, 3H), 1.26/1.35 (m, 3H), 0.42/0.58 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].[SH:23][CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Cl:21][C:19]1[CH:20]=[C:2]([S:23][CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]2)[C:3]([CH3:22])=[C:4]([CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6]
Reactant: O=C1CCC(S)CC1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(Br)c2C)c(=O)[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(=O)CC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 126.9 %

Procedure:
A solution of 3-bromo-5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)-methyl)-2-methylbenzamide (0.35 g, 0.91 mmol.), 4-mercaptocyclohexanone (0.142 g, 1.09 mmol) and DIPEA (0.235 g, 1.82 mmol) in dioxane was purged with argon for 10 min. Then, Pd(OAc)2 (0.01 g, 0.044 mmol) and Xantphos (0.052 g, 0.089 mmol) were added and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. overnight. After completion of the reaction, water was added and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to afford the title compound (0.50 g, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]2[C:12](=[O:13])[N:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:52]([O:59][NH2:60])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>CN(C=O)C>[CH2:52]([O:59][NH:60][C:15](=[O:17])[CH:14]([N:11]1[C:12](=[O:13])[CH:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=2)[NH:9][C:10]1=[O:21])[CH:18]([CH3:20])[CH3:19])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of the compound obtained in step h above (22h) (300 mg, 0.782 mmol), NMM (0.19 mL, 1.72 mmol) and HOBt (179 mg, 1.329 mmol) in DMF (11 mL) were stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCI (165 mg, 0.860 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, BnONH2HCl (137 mg, 0.860 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography which gave the title compound as colorless oil (426 mg, 83% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH3:2].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([O:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C)cc1OCCCOC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1ccc(CBr)cc1OCCCOC
Reaction time: 1 h

Procedure:
The mixture of 2.01 g of 1-ethoxy-2-(3-methoxypropoxy)-4-methylbenzene, 1.76 g of N-bromosuccinimide and 0.150 g of 2,2′-azobis(2-methylpropionitrile) in 90 ml of carbon tetrachloride is kept at reflux with stirring over 1 hour. The reaction mixture is cooled and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a beige solid from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:21]=[CH:20][C:19]2[S:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[C:22]3[O:23][C:24]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:25][C:26](=[O:28])[CH:27]=3)[CH2:11][C:10]=2[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:9]=[C:10]2[C:19]([S:18][C:17]3[C:16]([C:22]4[O:23][C:24]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)=[CH:25][C:26](=[O:28])[CH:27]=4)=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(c1)Cc1cccc(-c3cc(=O)cc(N4CCOCC4)o3)c1S2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [5-(6-Morpholin-4-yl-4-oxo-4H-pyran-2-yl)-9H-thioxanthen-2-yl]-carbamic acid tert-butyl ester (19) (1.08 g, 2.19 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (2 ml) and left under stirring at room temperature overnight. The solvent was dried in vacuo revealing a viscous dark brown liquid. Saturated sodium bicarbonate solution (20 ml) was added to the residue, which was left to stir for 20 mins. The brown precipitate was filtered, washing with water and left to dry in the vacuum oven overnight (0.77 g, 90%). 1HNMR (300 MHz, DMSO-d6): δH=3.40 (4H, t), 3.70 (4H, t), 3.77 (2H, s), 5.23 (2H, bs), 5.50 (1H, d), 6.17 (1H, d), 6.44 (1H, dd), 6.65 (1H, d), 7.09 (1H, d), 7.35 (1H, t), 7.47-7.59 (2H, m); m/z (LC-MS, ESP), RT=3.51 minutes, (M++1)=392.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19]C)=[O:18])=[O:14])[N:3]=1.N[C@H](C(N)=O)CC(C)C>>[NH2:19][C:17](=[O:18])[C@@H:16]([NH:15][C:13]([C:4]1[N:3]=[C:2]([Br:1])[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]=12)=[O:14])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C)CCC2
Agent: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1nc(Br)n2c1CN(C)CCC2)C(N)=O

Procedure:
This intermediate was prepared following the synthesis of (S)-3-bromo-8-methyl-N-(4-methyl-1-(methylamino)-1-oxopentan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxamide (intermediate 55B) by replacing H-Leu-NHMe with Leucine amide 59A(Chem-Impex). LCMS (+ESI) m/z 386.1 [M+H]+.
Reaction SMILES: [Cl:1]C1C2C(=CC=C(C(Cl)=O)C=2)C(Cl)=CN=1.ClN1C(=O)CCC1=O.[Br:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][NH:31][C:32]2=[O:35])=[CH:27][CH:26]=1>CC#N>[Br:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([Cl:1])=[CH:30][NH:31][C:32]2=[O:35])=[CH:27][CH:26]=1
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Reactant: O=C(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccc(Br)cc12
Temperature: 25 °C

Procedure:
1,4-Dichloro-7-isoquinolinecarbonyl chloride ##STR166## A solution of N-chlorosuccinimide (4.13 g, 31 mmol) in MeCN (50 mL) was added dropwise to a stirred solution of 7-bromo-1-(2H)-isoquinolone (6.6 g, 29.5 mmol) in MeCN (150 mL) which was heating under reflux. The mixture was heated under reflux for an additional 3 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 7-bromo-4-chloro-1(2h)-isoquinolone (6.72 g, 26.0 mmol) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]([NH2:28])=[N:26][OH:27])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:42](=O)[C:43]([O:45][CH2:46][CH3:47])=[O:44]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[N:28]=[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[O:27][N:26]=1)=[CH:14][CH:13]=2)=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C(N)=NO)ccc2c1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)no1
Temperature: 80 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
To a mixture of tert-butyl{6-[amino(hydroxyimino)methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.23 g, 0.50 mmol) and pyridine (0.043 mL, 0.53 mmol) in toluene (20 mL), was added ethyl chlorooxoacetate (0.059 mL, 0.53 mmol), and the mixture was stirred at room temperature for 1 h and at 80° C. for 1 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1–1:3 (v/v)) and recrystallized from diisopropyl ether-ethyl acetate (20:1, v/v, 5 mL) to give ethyl 3-(3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)-1,2,4-oxadiazole-5-carboxylate (0.13 g, 48%) as colorless crystals.
Reaction SMILES: I[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:4][C:3]=1[O:19][CH3:20].C([Li])CCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:20][O:19][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:6]=[C:7]([CH3:8])[C:2]=1[C:26]([OH:28])=[O:27]
Reactant: O=C=O
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)O
Temperature: 0 °C
Yield: 48 %

Procedure:
A solution of 7.70 g (19.6 mmol) of 4-iodo-3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl in 190 ml of THF was cooled down to −75° C.; then, 13.5 ml (21.6 mmol) of an n-butyl lithium solution (1.6 molar in n-hexane) was added slowly below −70° C. One hour later, the dark-brown reaction mixture was treated with an excess of carbon dioxide gas (dried by bubbling through H2SO4 conc. in a gas washing device) during 2 hours and then warmed up to 0° C. It was subsequently poured into crashed ice, the pH was then adjusted to 3-4 with HCl/H2O (1N) and the mixture was extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by re-crystallization from EtOAc/heptane to give 2.90 g (48%) of the title compound as colorless solid. MS: 309.3 (M−H−).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[O:6])[CH:2]=[CH2:3].Cl[CH:9]([C:15]([C:17]([F:20])([F:19])[F:18])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>>[CH2:1]([NH:4][C:5]1[O:6][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([C:17]([F:18])([F:20])[F:19])[N:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCNC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: C=CCNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Yield: 36.1 %

Procedure:
By the procedure of Example 4, 6 g (60 mmol) of allyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from methylcyclohexane to yield 4.77 g of a yellow solid product (m.p.=48°-49° C.) identified in Table I.
Reaction SMILES: [Li]CCCC.C([Mg]Cl)CCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[N:14]=1.CN([CH:23]=[O:24])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.O>[Br:19][C:15]1[N:14]=[C:13]([CH:23]=[O:24])[CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: CCCC[Mg]Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Br)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a −10° C. solution of n-BuLi (2.5 M in hexane, 5.6 mL, 14 mmol) in anhydrous toluene (20 mL) was added a solution of n-BuMgCl (2 M in THF, 3.5 mL) over 20 min, maintaining the temperature between −10° C. and 0° C. The mixture was stirred at −10° C. for 30 min. A solution of 2,6-dibromo-pyridine (4.74 g, 20 mmol) in toluene (20 mL) was added drop-wise over a period of 30 min while keeping the temperature below −5° C. The resulting suspension was stirred at −10° C. for 2.5 h. The mixture was transferred via cannula to a −10° C. solution of DMF (1.9 g, 26 mmol) in toluene (10 mL). The solution was allowed to stand between −5° C. and −10° C. for 30 min and then was transferred into a solution of citric acid (8.00 g) in H2O (15 mL), maintaining the temperature below 20° C. The resulting solution was stirred for 10 min and the layers were separated. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified (SiO2: 10% ethyl acetate/hexanes) to afford the title compound (1.94 g, 52%).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:9][S:10][CH3:11])[NH:5][C:6](=[O:8])[CH3:7].O.[NH2:14][NH2:15]>C(O)C>[CH3:11][S:10][CH2:9][C@@H:4]([C:3]([NH:14][NH2:15])=[O:2])[NH:5][C:6](=[O:8])[CH3:7]
Reactant: NN
Reactant: COC(=O)[C@H](CSC)NC(C)=O
Solvent: O
Solvent: CCO
Product: CSC[C@H](NC(C)=O)C(=O)NN
Yield: 58 %

Procedure:
In 20 ml of ethanol were dissolved 1.70 g (8.9 mmole) of S-methyl-N-acetyl-L-cysteine methylester and 6 ml of aqueous 80% hydrazine hydrate solution and the solution was heated at reflux for 2 hours. After the reaction solution was concentrated in vacuo, a small amount of water was added to the residue and then distilled off in vacuo and this procedure was repeated three times to give white crystals. The crystals were washed with small amount of ethanol and dried to give 0.99 g (58% yield) of S-methyl-N-acetyl-cysteinylhydrazine.