Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH:5]=[C:6]1[CH:12]2[CH:9]([C:10](Cl)(Cl)[C:11]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2].C(O)(=O)C>C(Cl)Cl.[Zn]>[C:1]([O:4][CH:5]=[C:6]1[CH:12]2[CH:9]([CH2:10][C:11]2=[O:13])[CH:8]=[CH:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=C1C=CC2C1C(=O)C2(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC=C1C=CC2CC(=O)C12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.2 %

Procedure:
A mixture of 540 mg of 4-(acetoxymethylene)-7,7-dichloro-6-oxobicyclo[3.2.0]hept-2-ene, 600 mg of zinc dust and 10 mL of acetic acid was stirred at room temperature for 15 min under argon. An additional 500 mg of zinc was then added; the mixture was stirred between 75° and 80° for 1 hr. The temperature was raised to between 85° and 90° and after addition of 1 g of zinc dust the mixture was stirred for 1 hr. The cooled reaction mixture was diluted with methylene chloride, filtered and evaporated to dryness on a rotary evaporator. The product was purified by preparative thin layer chromatography on three 20×20×0.2 cm silica gel plates, eluting with methylene chloride-hexane (2:1), to afford 246 mg (63.0%) of 4-(acetoxymethylene)-6-oxobicyclo[3.2.0]hept-2-ene (cis, trans mixture) as an oil. NMR (220 MHz; CDCl3): δ2.02 (3 H, s), 2.05 (3H, s), 2.59 (1H, t, J=3.3), 2.68 (1H, t, J=3.3), 3.25 (2H, m), 3.50 (2H, m), 4.25 (1H, m), 4.55 (1H, m), 6.11 (3H, m), 6.43 (1H, d, J=5.5), 7.0 (1H, broad s), and 7.25 (1H broad s). A small amount of this mixture was successfully separated by preparative thin layer chromatography on a 0.25 mm silica gel plate. The mass spectra of the two components were identical. HRMS: Calcd for C10H10O3, 178.0630; found, 178.0617.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([N:9]1[C:17]3[C:12](=[CH:13][C:14]([NH2:18])=[CH:15][CH:16]=3)[CH:11]=[CH:10]1)[CH2:2]2.I.CS[C:22]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)=[NH:23]>C(O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([N:9]1[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:22]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[NH:23])=[CH:15][CH:16]=3)[CH:11]=[CH:10]1)[CH2:2]2
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2c(ccn2C2CN3CCC2CC3)c1
Agent: I
Solvent: CCO
Product: N=C(Nc1ccc2c(ccn2C2CN3CCC2CC3)c1)c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
Compound 70 (60 mg, 0.249 mmol) is charged to a small, argon purged flask fitted with a magnetic stir bar. Anhydrous ethanol (5 mL) and thiophene-2-carboximidothioic acid methyl ester hydroiodide (124 mg, 0.435 mmol) are added to the flask and the reaction was stirred under argon at ambient temperature for 18 hours, at which time the solvent was evaporated and the residue was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered, concentrated and the residue purified via chromatography on silica gel (2M NH3 in methanol:CH2Cl2, 5:95 to 7.5:92.5) then a second time on silica gel (methanol:CH2Cl2, 1:9 to 2 M NH3 in methanol:CH2Cl2, 1:9) to yield a yellow solid, 71 (30 mg, 34.4%). 1H NMR (DMSO-d6) δ 1.27-1.53 (2×m, 2H), 1.60-1.69 (m, 1H), 1.79-1.96 (2×m, 2H), 2.69-2.87 (m, 3H), 3.03-3.13 (m, 1H), 3.19-3.30 (m, 1H), 3.34-3.44 (m, 1H), 4.57-4.68 (m, 1H), 6.28 (brs, 2H), 6.39 (d, 1H, J=3.1 Hz), 6.70 (dd, 1H, J=8.4, 1.6 Hz), 7.00 (d, 1H, J=1.2 Hz), 7.09 (dd, 1H, J=4.9, 3.9 Hz), 7.39 (d, 1H, J=8.6 Hz), 7.59 (d, 1H, J=5.1 Hz), 7.67 (d, 1H, J=3.2 Hz), 7.71 (d, 1H, J=3.5 Hz); ESI-MS (m/z, %): 351 (M+1, 60%), 176 (M++doubly charged, 100%); ESI-HRMS calculated for C20H23N4S (MH+): 351.1637, observed: 351.1639.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].N1C=CC=CC=1>>[C:34]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][S:22][C:21]([CH3:26])([CH3:25])[C@@H:20]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#CCCCCO)cc2)CCSC1(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.1 %

Procedure:
A mixture of 0.452 g (0.908 mmol) of tert-butyl (3S)-4-({4-[(7-hydroxy-2-heptynyl)oxy]phenyl}sulfonyl)-2,2-dimethyl-3-thiomorpholinecarboxylate, 2.6 mL (27 mmol) of acetic anhydride and 0.22 mL (2.7 mmol) of pyridine was stirred at room temperature for 6 h and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:5) to provide 0.476 g (97%) of tert-butyl (3S)-4-[(4-{[7-(acetyloxy)-2-heptynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholinecarboxylate as a colorless oil. Electrospray Mass Spec: 540.0 (M+H)+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[OH:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[I-].[Na+].[OH2:29]>CN(C)C=O.O1CCCC1>[CH2:3]([O:15][C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[C:21]2[O:26][CH2:17][CH:16]([OH:15])[CH2:25][OH:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O
Reactant: CCCCCCCCCCCCOc1cccc2c(O)cccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1cccc2c(OCC(O)CO)cccc12
Reaction time: 8 h

Procedure:
To a suspension of 2.19 g of 50% sodium hydride in 80 ml of dimethylformamide, under argon, was added with stirring a solution of 12 g of 5-(dodecyloxy)-1-naphthalenol in 60 ml of tetrahydrofuran over 1/2 hour. A 2 g portion of sodium iodide and 9.77 g of solketal mesylate were added and the mixture was stirred overnight. The mixture was diluted with water and extracted with ether. The ether extract was washed with dilute sodium hydroxide, then brine, dried, filtered through silica gel and the solvent removed. The residue was refluxed in a mixture of 100 ml of methanol, 16 ml of water and 1 ml of concentrated sulfuric acid for one hour, then cooled and the solid collected. This solid was dissolved in boiling chloroform containing magnesium sulfate and activated carbon and filtered through diatomaceous earth. The filtrate was evaporated and the residue recyrstallized from carbon tetrachloride, giving 8 g of the desired compound as an off-white solid, mp 143°-144° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH2:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[N:35]=[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[O:49][CH3:50])[N:33]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[CH:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][C:36]2[N:35]=[C:34]([NH:39][C@@H:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH3:50])[N:33]=[C:32]([Cl:31])[N:37]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1COCc1ccccc1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(N[C@H]2CC(O[Si](C)(C)C(C)(C)C)[C@H](COCc3ccccc3)C2)n1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of (1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanamine (486.5 mg, 0.001450 mol) and triethylamine (0.55 mL, 0.0040 mol) in THF (2.1 mL) was added 4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (410 mg, 0.0013 mol) and the mixture was stirred for 2 hours. The reaction was concentrated and the residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to obtain 250 mg (31%) of the title compound. LC/MS: Rt=2.96 min, ES+ 610 (FA standard).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[N:8]=[C:9]([S:12][CH2:13][C:14]([NH:16][CH2:17][C@H:18]2[O:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:15])[S:10][CH:11]=1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:20]2[CH2:21][CH2:22][O:23][C@@H:18]([CH2:17][NH:16][C:14](=[O:15])[CH2:13][S:12][C:9]3[S:10][CH:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]=3)[CH2:19]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1csc(SCC(=O)NC[C@@H]2CNCCO2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)cc3)CCO2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The resultant product (899 mg) of (75-3) was dissolved in methylene chloride (12.5 mL), 4-chlorobenzaldehyde (387 mg) and acetic acid (143 μL) were added and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (1.06 g) was added to the reaction mixture and the mixture was further stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and acetone as an eluent. The solvent was evaporated from the eluent to give the title compound (1.16 g) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][C:39](O)=[O:40]>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[CH2:38][C:39]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:40]
Reactant: O=C(O)Cc1cc(F)ccc1F
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Product: O=C(Cc1cc(F)ccc1F)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidine (see Example 3, Step H) and (2,5-difluorophenyl)acetic acid using the coupling conditions described in Example 5. 1H NMR (400 MHz, DMSO-d6): δ 3.76 (s, 2H), 6.53 (d, 1H, J=5.3 Hz), 6.94 (m, 1H), 7.10-7.27 (m, 7H), 7.41-7.48 (m, 2H), 7.69-7.76 (m, 3H), 7.89 (m, 1H), 8.27 (d, 1H, J=5.3 Hz), 8.48 (m, 1H), 8.83 (m, 1H), 9.56 (s, 1H), 10.39 (s, 1H). ES-LC/MS m/z=533 [M+H]+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH3:33])=[C:25]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([CH:53]([OH:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35]>CS(C)=O>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH3:33])=[C:25]1[C:34]([NH:36][C@H:37]([C:41]([NH:43][CH:44]([C:53](=[O:65])[CH2:54][O:55][CH2:56][C:57]1[C:62]([Cl:63])=[CH:61][CH:60]=[CH:59][C:58]=1[Cl:64])[CH2:45][C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])=[O:42])[CH:38]([CH3:40])[CH3:39])=[O:35]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CS(C)=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Dess-Martin periodinane (195 mg) was added as a solid to a solution of N-[(1,3-dimethylindole-2-carbonyl)valinyl]-3-amino-4-hydroxy-5-(2',6'-dichorobenzyloxy)pentanoic acid, t-butyl ester (96 mg) in DMSO (1.5 ml). The resulting solution was stirred under a nitrogen atmosphere at room temperature for thirty minutes, then partitioned between EtOAc and water. The organic phase was washed with water (2×) and brine, dried (Na2SO4), and concentrated to give a white solid (83 mg). Flash chromotographic purification with EtOAc/hexanes (1:1) afforded the title product as a white solid (54 mg). TLC(EtOAc/hexanes; 1:1, silica gel): Rf =0.52.
Reaction SMILES: C1CO[CH:20]2[CH:3]([CH2:4][C:5]34O[C@H:6]3[C:7](=[CH2:30])[C@@H:8]3[C@@H:17]([C@@:18]4([CH3:24])[C@@H:19]2[CH3:23])[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@:11]3([F:29])OCC[O:25][CH:12]32)[O:2]1.[Mg].[CH3:33]I>C1C=CC=CC=1.C(OCC)C>[F:29][C@@H:11]1[CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]2([CH3:14])[C:12]1=[O:25])[C@:18]1([CH3:24])[C:5](=[CH:4][C:3](=[O:2])[CH2:20][C@H:19]1[CH3:23])[C@H:6]([CH3:33])[C:7]3=[CH2:30]
Reactant: CI
Reactant: C=C1[C@@H]2[C@H](CC[C@]3(C)C4OCCO[C@@]4(F)C[C@@H]23)[C@@]2(C)[C@H](C)C3OCCOC3CC23O[C@@H]13
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: C=C1[C@@H](C)C2=CC(=O)C[C@@H](C)[C@]2(C)[C@H]2CC[C@]3(C)C(=O)[C@H](F)C[C@H]3[C@H]12
Reaction time: 3 h
Yield: 80.5 %

Procedure:
3,17-bis(ethylenedioxy)-5,6α-epoxy-16α-fluoro-1β-methyl-7-methylenandrostane (431 mg) in benzene solution (40 ml), is added to a Grignard mixture prepared from magnesium (122 mg) and methyl iodide (710 mg) in diethylether (10 ml). Solvent is removed until the boiling point reaches ~78° C. Heating is then continued for a further 3 hrs. Ice and saturated ammonium chloride solution are added, the product extracted with ethyl acetate and the organic layer is evaporated in vacuo after having washed and dried it. The residue is dissolved in a 2:1 mixture of acetic acid and water (10 ml) and the solution heated for about 6 hrs at 40°-50° C. Then water is added and the product extracted with ethyl acetate. The organic layer is washed with sodium bicarbonate solution, dried and evaporated in vacuo. The residue is submitted to column chromatography thus giving pure 16α-fluoro-1β,6β-dimethyl-7-methylenandrost-4-ene-3,17-dione (275 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1.Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4cccc(F)c4)c3F)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 130 mg, 0.436 mmol) in 3.5 mL of tetrahydrofuran, 0.31 mL of pyridine was added. 3-Fluoro-benzenesulfonyl chloride (30, 127 mg, 0.654 mmol) was added and the solution was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0005, 167 mg). MS(ESI)[M+H+]+=457.6.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]=[O:13].O>O1CCCC1>[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: COc1ccc(F)c(C=O)c1
Reactant: Br[Mg]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylmagnesium bromide (1.6 mL, 1.0 M tetrahydrofuran solution, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 2-Fluoro-5-methoxybenzaldehyde (500 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) in tetrahydrofuran (16 mL, manufactured by Wako Pure Chemical Industries, Ltd.) at 0° C., and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×20 mL), washed with brine (20 mL) and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 480 mg of the title compound. LC-MS: HPLC retention time 3.90 minutes, m/z 233 (M+H), condition B-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:58])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([O:42]CC3C=CC=CC=3)=[O:41])=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[C:52]([F:57])[CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:58])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([N:35]3[CH2:39][CH2:38][CH2:37][C@H:36]3[C:40]([OH:42])=[O:41])=[O:34])[N:28]([C:50]3[CH:55]=[CH:54][C:53]([F:56])=[C:52]([F:57])[CH:51]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)OCc3ccccc3)n(-c3ccc(F)c(F)c3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)O)n(-c3ccc(F)c(F)c3)n2)CC1
Reaction time: 24 h

Procedure:
To a solution of 3.5 g 4-((S)-2-{[5-[2-((S)-2-Benzyloxycarbonyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-(3,4-difluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 80 ml ethyl acetate were added under argon 1.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 24 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was used in the subsequent reaction. Yield: 2.5 g colorless foam.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1.O>O1CCCC1>[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)c2c1CCCC2
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
Tert-butyl amine [8.5 g, 12.32 ml, 116.0 mmol) was added dropwise to a stirred suspension of 4-bromo-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride (59a, 12.0 g, 38.8 mmol) in 150 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at a temperature of about 25° C. for 2 hours. The progress of the reaction was monitored by TLC. Water (100 ml) was added to the reaction mixture, and the mixture so obtained was extracted with ethyl acetate (2×150 ml). The combined organic layer was then dried over sodium sulphate, and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (2.34 g, 17.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=1[CH3:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)c(C)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c(C)c1

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo, this yielded 250.2 mg (71.7%) of the product as a off red solid, m.p.>131° C(dec.), mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:59][C:60]1[N:61]([C:70]2[C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[C:73]([CH:80]3[CH2:82][CH2:81]3)=[CH:72][CH:71]=2)[C:62]([S:65][CH2:66][C:67](O)=[O:68])=[N:63][N:64]=1>ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:67](=[O:68])[CH2:66][S:65][C:62]3[N:61]([C:70]4[C:79]5[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=5)[C:73]([CH:80]5[CH2:82][CH2:81]5)=[CH:72][CH:71]=4)[C:60]([Br:59])=[N:64][N:63]=3)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(CCCCN)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(CCCCNC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-6-aminohexanoate (N-α-Fmoc-Lysine (NH2)—OMe, 1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then is purified by SGC (0-100% EtOAc/Hexanes).