Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>CCOCC>[CH2:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ccccc1
Reactant: BrCCCCCOCc1ccccc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: c1ccc(CCCCCOCc2ccccc2)cc1
Temperature: -5 °C
Reaction time: 2.5 h

Procedure:
Into a flask containing magnesium turnings (about 750 mg, about 31 mmol), ether (about 10 ml) was added, and then a small amount of iodine (about 1 mg˜about 5 mg) was added, and the resulting mixture was stirred for several min until it was colorless. Bromobenzene (about 100 ml, about 0.9 mmol) was added to the mixture and then heated to thus initiate the reaction. While the mixture was weakly refluxed, a mixture solution of bromobenzene (about 3.2 ml, about 30 mmol) and ether (about 50 ml) was added in droplets thereto for about 2.5 hours. The deeply browned mixture was stirred at ambient temperature for about 3 hours in a nitrogen atmosphere and then cooled in an ice-salt bath at about −5° C. To the mixture, a mixture solution of 5-benzyloxy-1-bromopentane (about 1.54 g, about 6 mmol) and ether (about 10 ml) was added in droplets. The resulting mixture was stirred for about 2 hours, cooled, heated to reflux for about 3 hours, and then cooled at ambient temperature. The above solution was poured onto ice water while being stirred, and hydrochloric acid (about 1 N) was added in droplets thereto. The pH thereof was maintained at about 4. The film was separated, after which the water-soluble film was extracted three times with methylene chloride. The organic layer was dried using MgSO4, filtered and concentrated to thus obtain brown oil, which was then subjected to column chromatography, yielding 5-phenylpentyl benzyl ether. A mixture of 5-phenylpentyl benzyl ether and methanol (about 50 ml) was blended with about 10% Pd/C catalyst, stirred for about 3 hours in a hydrogen atmosphere, and then filtered through a Celite pad. The filtrate was concentrated, thus obtaining 5-phenylpentylalcohol. Using 5-phenylpentylalcohol as a starting material, the same procedure as in Example 1 was performed, thereby obtaining the precursor compound 2 of the above formula.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl>[Si:13]([O:1][C@@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1OCC[C@H]1O
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@@H]1CCOC1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
To a stirred solution of (R)-3-hydroxydihydrofuran-2(3H)-one (41.0 g, 401 mmol), imidazole (61.4 g, 920 mmol), and CH2Cl2 (175 mL) at 0° C., under N2, was added t-butyldiphenylsilyl chloride (129 mL, 138 g, 497 mmol) dropwise over 30 minutes. The mixture was stirred at room temperature for 19 hours. The mixture was partitioned between CH2Cl2 (700 mL) and H2O (100 mL). The organic portion was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc in hexane) to afford (R)-3-(tert-butyldiphenylsilyloxy)dihydrofuran-2(3H)-one (127 g, 373 mmol, 93% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.84-7.82 (m, 2H), 7.73-7.71 (m, 2H), 7.50-7.40 (m, 6H), 4.41-4.31 (m, 2H), 4.06-4.00 (m, 1H), 2.29-2.19 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][N:22]=[C:23]=[S:24]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[S:24])[N:8]=1
Reactant: NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Reactant: CN=C=S
Solvent: CC#N
Product: CNC(=S)NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine in warm acetonitrile (15 ml.) was allowed to cool to room temperature. A solution of methylisothiocyanate (0.15 g.) in acetonitrile (1 ml.) was added and the mixture stirred overnight. Evaporation to dryness gave a yellow solid which was recrystallised from a small volume of ethyl acetate to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[3-(3-methylthioureido)-propylthio]pyrazine (0.32 g.), m.p. 165°-167°.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([O:23]C(C)(C)C)=[O:22])[CH2:19][CH2:18][NH:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:1]1([CH2:7][O:8][C:9](=[O:28])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH:20]([C:21]([OH:23])=[O:22])[CH2:19][CH2:18][N:17]2[C:44]([O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C1CCNC1CCCCCCC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCC1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of Example 17 (0.1 mol.) is added to a mixture of dichloromethane (200 ml.), triethylamine (0.11 mol.) and benzyloxycarbonyl chloride. The mixture is stirred for 2 hours at room temperature, washed with 5% potassium bisulfate, water, dried, and concentrated to dryness. The residue, 3-(t-butoxycarbonyl)-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester is dissolved in trifluoroacetic acid and the solution stored at room temperature for 1 hour. The solution is concentrated to dryness in vacuo yielding 3-carboxy-1-[(phenylmethyloxy)carbonyl]-2-pyrrolidineheptanoic acid phenylmethyl ester.
Reaction SMILES: [CH2:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=O)[O:7][N:6]=1)[CH:2]([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:37][C@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[C:58]([Cl:60])[CH:57]=[CH:56][C:55]=2[F:61])=[CH:50][CH:49]=1)[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:60][C:58]1[CH:57]=[CH:56][C:55]([F:61])=[C:54]([C:51]2[CH:50]=[CH:49][C:48]([CH2:47][C@@H:38]([NH:37][C:10]([C:8]3[O:7][N:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH:9]=3)=[O:12])[CH2:39][C@:40]([CH2:45][OH:46])([CH3:44])[C:41]([OH:43])=[O:42])=[CH:53][CH:52]=2)[CH:59]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: CC(C)Cc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Cc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.1 %

Procedure:
3-Isobutylisoxazole-5-carboxylic acid (9 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (0.3 mg). MS m/z [M+H]+ calc'd for C27H30ClFN2O5, 517.18. found 517.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:11])[C:8]([OH:10])=O)[CH:6]=1.[NH2:12][C:13]1[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[O:34])[CH2:28]2)[N:14]=1.N1C=CC=CC=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:11])[C:8]([NH:12][C:13]2[C:18]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([C:33]([N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)=[O:34])[CH2:28]3)[N:14]=2)=[O:10])[CH:6]=1
Reactant: C[C@H](C(=O)O)n1cc(Cl)cn1
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@H](C(=O)Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)OC(C)(C)C)n1cc(Cl)cn1
Temperature: 0 °C
Yield: 98.2 %

Procedure:
(R)-2-(4-Chloro-1H-pyrazol-1-yl)propanoic acid (105 mg, 0.60 mmol) and (R)-tert-butyl 2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamate (195 mg, 0.50 mmol) were dissolved in ethyl acetate (0.5 mL) with pyridine (0.20 mL, 2.5 mmol) at room temperature. The mixture was cooled to 0° C. 1-Propanephosphonic acid cyclic anhydride (0.375 mL, 50% solution in ethyl acetate, 1.25 mmol) was added while stirring at 0° C. The resulting mixture was stirred for 15 min, and then warmed to room temperature. After stirring for 1.5 h at room temperature, the mixture was quenched with an aqueous solution of hydrochloric acid (0.5 M, 1 mL). The mixture was partitioned between ethyl acetate (10 mL) and water (5 mL). The organic layer was washed sequentially with water (5 mL), a saturated aqueous solution of sodium bicarbonate (5 mL), and brine (5 mL). The organics were dried over magnesium sulfate, filtered, and concentrated. The residue was dried under reduced pressure to afford tert-butyl 2-((R)-2-(4-chloro-1H-pyrazol-1-yl)propanamido)-6-((R)-3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamate (268 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 1.48-1.55 (m, 1H), 1.73-1.76 (m, 1H), 1.80-2.05 (m, 6H), 1.86 (d, 3H), 2.53-2.59 (m, 1H), 2.84-2.90 (m, 1H), 2.96-3.01 (m, 1H), 3.43-3.51 (m, 3H), 3.55-3.60 (m, 1H), 4.12 (br d, 1H), 4.33 (br d, 1H), 5.10 (br s, 1H), 6.56 (d, 1H), 7.30 (br s, 1H), 7.57 (s, 1H), 7.61 (s, 1H), 7.76 (br s, 1H), 8.58 (br s, 1H); MS (ES+) (M+H) 546.3; Chiral HPLC retention time 4.61 min (Method: Chiralpak AS-H 0.46×25 cm; Mobile Phase: CO2/methanol; Flow: 2.5 mL/min); 97.1% de.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([C:25]([S:28]([CH3:31])(=[O:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:10]=2)=[CH:5][CH:4]=1.[CH3:32][S:33]([O-:35])=[O:34].[Na+]>CN(C=O)C.O>[CH3:32][S:33]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[C:17]([C:25]([S:28]([CH3:31])(=[O:30])=[O:29])([CH3:27])[CH3:26])[CH:18]=[C:19]4[C:24]=3[N:23]=[CH:22][CH:21]=[CH:20]4)[CH:10]=2)=[CH:5][CH:4]=1)(=[O:35])=[O:34]
Reactant: CS(=O)[O-]
Reactant: CC(C)(c1cc(-c2cccc(-c3ccc(CBr)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(c1cc(-c2cccc(-c3ccc(CS(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 8-(4′-Bromomethyl-biphenyl-3-yl)-6-(1-methanesulfonyl-1-methyl-ethyl)-quinoline (1.0 eq.) in DMF (0.1M) was added sodium methanesulfinate (1.3 eq.). The mixture was stirred at rt for 2 h, poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EA; 1:4) and stirring in EtOAc:Hex:Et2O (1:7:2) afforded the title compound as a white solid after filtration. 1H NMR (400 MHz, acetone-d6): δ 8.96 (dd, 1H), 8.49 (dd, 1H), 8.32 (d, 1H), 8.25 (d, 1H), 8.08 (t, 1H), 7.81–7.75 (m, 4H), 7.63–7.59 (m, 4H), 4.48 (s, 2H), 2.90 (s, 3H), 2.75 (s, 3H), 2.03 (s, 6H).
Reaction SMILES: C(O[C:4]1[CH2:5][C@@H:6]([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)[CH2:7][C:8](=[O:10])[CH:9]=1)C.[CH3:25]COCC.C[Li]>O1CCCC1>[CH3:25][C:4]1[CH2:5][C@H:6]([CH2:11][C@H:12]2[N:16]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15](=[O:24])[CH2:14][CH2:13]2)[CH2:7][C:8](=[O:10])[CH:9]=1
Reactant: CCOCC
Reactant: CCOC1=CC(=O)C[C@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1=CC(=O)C[C@@H](C[C@@H]2CCC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of (5S,1R)-5-[(3-ethoxy-5-oxo-3-cyclohexen-1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone (3.94 g, 12.0 mmol) in 150 ml of 1:1 tetrahydrofuran:ether was added a solution of methyllithium (41 mL, 1.4M in ether, 57.4 mmol) at -78° C. over 10 min. The mixture was stirred for 30 min at -78° C. and quenched by the addition of 50 mL of 50% aqueous acetic acid. The mixture was allowed to warm to room temperature and was extracted with methylene chloride. The combined extracts were washed with saturated sodium bicarbonate, dried over Na2SO4 and concentrated on a rotary evaporator to give 4.05 g of a crude oil. Chromatography of the crude product on silica gel (100 g) eluting with 1% methanol in ethyl acetate afforded 1.85 g (52% yield) of (5S,1R)-5-[(3-methyl-5-oxo-3-cyclohexen- 1-yl)methyl]-1-(phenylmethyl)-2-pyrrolidinone as an oil. A sample was evaporatively distilled at 200°-210° C./0.05 torr for analysis. 1H NMR (CDCl3) δ 1.94 (s, 3 H, CH3), 1.35-2.55 (m, 11 H, CH2 and CH), 3.45 (m, 1 H, NCH), 3.95 and 4.98 (AB,Jgem =15 Hz, 2 H, CH2Ph), 3.87 (s, 1 H, vinyl H), 7.50 (m, 5 H, phenyl). MS (EI) m/e 297 (M+). [α]25D =+59.86°(c 0.2155 in methanol). CD (ethanol) 326 ([ϑ]=-1425, max), 283 ([ϑ]=-42, min), 238 ([ϑ]=+13,620, infl), 218 ([ϑ]=+50,100, max), 212 nm ([ϑ]=+39,820°, min). Anal. Calcd for C19H23NO2 : C, 76.74; H, 7.80; N, 4.71. Found: C, 74.55; H, 7.53, N, 7.41.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]O)=[CH:23][CH:22]=1>>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][O:16][C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=2)=[CH:25][CH:26]=1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc(C(F)(F)F)cc2)cc1
Yield: 75.7 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol) prepared in Example 1 (1a) and 2-[4-(trifluoromethyl)phenyl]ethanol (209 mg, 1.10 mmol) prepared according to the method disclosed in the document (J. Med. Chem., (2002), 45, 4321-4335) to give 278 mg of the title compound (white powder, yield: quantitative).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of 2-ethyl-5-nitroaniline (200 mg, 1.20 mmol) in DCM (5 mL) was added pyridine (0.195 mL, 2.41 mmol) and methanesulfonyl chloride (0.11 mL, 1.44 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine and dried to give Intermediate 78A (290 mg, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (1H, d, J=2.26 Hz), 8.04 (1H, dd, J=8.53, 2.26 Hz), 7.44 (1H, d, J=8.53 Hz), 6.59 (1H, br. s.), 3.15 (3H, s), 2.76 (2H, q, J=7.53 Hz), 1.32 (3H, t, J=7.53 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])[C:18]([Cl:33])=[CH:17][N:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>C(Cl)Cl>[Cl:33][C:18]1[C:19]([NH:21][C:22]2[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([NH:26][CH3:27])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)NC(=O)CCO2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCO3)ncc1Cl

Procedure:
Into an 8 ml sealed tube was placed 2-Amino-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one (0.080 g, 0.45 mmol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (0.16 g, 0.49 mmol), and 10-Camphorsulfonic acid (0.11 g, 0.49 mmol). Isopropyl alcohol (2 mL, 0.03 mol) was added. The reaction was microwaved at 120° C. for 40 minutes, diluted with CH2Cl2, washed with aqueous sat'd NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. The reaction mixture was purified by silica gel chromatography (ISCO amine column 0-100% EtOAc in hexanes) to afford title compound as a yellow solid. LCMS: 457.17 (M+H), HPLC: 95% purity, 1H-NMR (CDCl3, 400 MHz) δ 8.78 (s, 1H), 8.05 (d, J=1.8 Hz, 1H), 7.80 (s, 1H), 7.45-7.40 (m, 3H), 7.35-7.31 (m, 2H), 6.90 (d, J=8.6 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.43 (bd, 4.0 Hz, 1H), 4.42 (t, J=5.8 Hz, 2H), 2.94 (d, J=4.8 Hz, 3H), 2.81 (t, J=5.6 Hz, 2H).
Reaction SMILES: OO.[CH3:3][S:4][C:5]1[C:6]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)=[N:9][CH:10]=1.CC(OC(C)=O)=[O:35]>C(Cl)Cl>[CH3:3][S:4]([C:5]1[C:6]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[N:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:26])[O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:15][CH:16]=2)=[N:9][CH:10]=1)=[O:35]
Reactant: CSc1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: ClCCl
Product: CS(=O)c1cnc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71 %

Procedure:
The H2O2 (0.32 ml, 3.13 mmole) solution was added to a stirred solution of phenyl 4-(5-(methylthio)-4-morpholinopyrimidin-2-yl)phenylcarbamate (0.54 g, 1.28 mmole), CH2Cl2 (7 ml), Ac2O (0.13 ml), and silica gel (230-400 mesh, 200 mg). The solution was stirred at room temperature for 2-3 hrs, and quenched with NaHSO3(aq) (70 ml), and NaHCO3(aq) (70 ml), the solvent was removed, the residue was chromatographed to give the product (71%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1.OS(O)(=O)=O.[CH3:17]O>>[Cl:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:17])=[O:10])[CH:3]=1
Reactant: O=C(O)c1c[nH]c(=O)c(Cl)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c[nH]c(=O)c(Cl)c1

Procedure:
A mixture of commercially available 5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid (4.000 g; 23.04 mmol) and concentrated H2SO4 (0.3 ml) in anh. MeOH (52 ml) was refluxed, under nitrogen, for 19 h. MeOH was removed under reduced pressure, and the residue was basified by addition of a solution of 10% aq. NaHCO3. The mixture was then extracted with DCM (5×), and the mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording methyl 5-chloro-6-oxo-1,6-dihydropyridine-3-carboxylate as a pale yellow solid. LC-MS (conditions D): tR=0.61 min.; [M+H]+: 187.93 g/mol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:20])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Yield: 87 %

Procedure:
1-Ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (15 g, 63.8 mmol) was dissolved in POCl3 (100 mL), and the resulting solution was heated at reflux for 4 h. The remaining POCl3 was removed via evaporation under reduced pressure. The residual light brown solid was recrystallized from EtOH-hexane to afford the title compound as a white solid (14 g, 55.3 mmol, 87%): HPLC (YMC S5 ODS 4.6×50 mm column, 4 minute gradient-0% B to 100% B, 4 mL/min flow, solvent A: 10% MeOH-90% H2O-0.2% H3PO4, solvent B: 90% MeOH-10% H2O-0.2% H3PO4) retention time 3.84 minutes showed a purity of 96%; LRMS (m/z) 254 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:16])=[C:13]([OH:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([CH3:27])=[CH2:26]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:16])=[C:13]([O:15][CH2:26][C:25]([CH3:27])=[CH2:24])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc(OCc2ccccc2)ccc1Br
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 5-(benzyloxy)-2-bromophenol (Simas, A. B. C., et al, Synthesis, (1999):1017-21) (8.15 g, 29.3 m mol) in DMF (150 mL) was added potassium carbonate (4.46 g, 32.2 mmol) slowly at 0° C. The mixture was stirred at ambient temperature for half an hour, followed by the addition of 3-bromo-2-methylpropene (3.35 mL, 32.2 mmol) during half an hour at 0° C. The mixture was stirred at ambient temperature overnight and quenched with saturated ammonium chloride (50 mL). The aqueous mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/20) to give the title compound (10.0 g, 94%): 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (m, 5H), 6.53 (d, 1H), 6.45 (dd, 1H), 5.15-4.94 (m, 4H), 4.43 (s, 2H), 1.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.1, 155.6, 140.1, 136.5, 133.1, 128.6, 128.1, 127.5, 112.9, 107.2, 103.3, 102.0, 72.4, 70.3, 19.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH:30]1[C:31]2[C:26](=[CH:25][C:24]([NH:23][C:11](=[O:13])[CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]3[CH:18]=[CH:17][S:16][CH:15]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][N:29]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)c1ccsc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(CC(=O)Nc1ccc2cnccc2c1)c1ccsc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To 3-(tert-butyoxcarbonylamino)-3-(thiophen-3-yl)propanoic acid (E4) in pyridine was added EDC, DMAP, and 6-aminoisoquinoline. The solution was stirred for 10 hours at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 5% MeOH/CH2Cl2) gave pure tert-butyl 3-(isoquinolin-6-ylamino)-3-oxo-1-(thiophen-3-yl)propylcarbamate (E5).