Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.I[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(I)cc1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 33.5 %

Procedure:
Following the procedure of Example 1(c), but reacting 1.5 g (3.6 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 500 mg (1.9 mmol) of methyl 4-iodobenzoate, 320 mg (33%) of the compound were obtained, which compound had a melting point of 170°-3° C.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH:19](=[C:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH:19](=[C:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCC=C1CCNCC1
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 87.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.612 g, 1.69 mmol) and 4-butylidenepiperidine (0.212 g, 1.5 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF39) (0.489 g, 77%). 1H NMR (CDCl3) δ 6.90 (d, J=8.4 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 6.50 (dd, J=8.4 Hz, J=2.8 Hz, 1H), 5.11 (t, J=7.6 Hz, 1H), 4.54 (q, J=14.4 Hz, 2H), 3.97-3.94 (d, J=6.8 Hz, 2H), 3.78 (s, 3H), 2.48-2.41 (m, 2H), 2.33-2.23 (m, 5H), 2.20-2.13 (m, 4H), 1.96 (q, J=7.4 Hz, 2H), 1.40-1.29 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.3, 155.5, 139.8, 136.5, 129.8, 122.5, 117.2, 107.0, 103.4, 68.1, 63.8, 56.5, 56.0, 55.7, 45.5, 36.2, 29.3, 29.2, 28.4, 23.3, 16.9, 13.9; HPLC-MS; (ammonium acetate) [M+H]+=373.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][C:14]3[N:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[C:16](=[O:25])[C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[N:9]=[C:10]([CH2:11]O)[C:3]=12.C(N(S(F)(F)[F:39])CC)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:13][C:14]3[N:15]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])[C:16](=[O:25])[C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:24])[N:9]=[C:10]([CH2:11][F:39])[C:3]=12
Reactant: Cc1ccccc1-n1c(Cn2nc(CO)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-n1c(Cn2nc(CF)c3c(N)ncnc32)cc2cccc(C)c2c1=O
Reaction time: 5 h
Yield: 20 %

Procedure:
To a stirred suspension of 3-((4-amino-3-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (compound 4503) (50 mg, 0.12 mmol) in anhydrous DCM (2 mL) at 0° C. under an argon atmosphere, diethylaminosulfur trifluoride (DAST, 77 μL, 0.59 mmol) was slowly added and the resulting mixture was stirred from 0° C. to room temperature for 5 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC plate (7% MeOH/DCM) to afford the desired product, 3-((4-amino-3-(fluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-8-methyl-2-o-tolylisoquinolin-1(2H)-one (4504, compound 310 in Table 4) (10.3 mg, 20% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[O:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2)[CH3:23]>>[CH3:23][O:22][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: COc1ccc2c(c1)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: COc1ccc2c(c1)C(=Cc1[nH]c3c(c1C)C(=O)N(CCN1CCCCC1)CC3)C(=O)N2
Yield: 39.9 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (17 mg, 39.9%) as an orange solid.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3](OCC)=[O:4].C[O-].[Na+].[O:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.Cl>C1COCC1>[F:1][CH:2]([F:8])[C:3](=[O:4])[CH2:25][C:24]([C:21]1[CH:20]=[CH:19][C:18]([N:15]2[CH2:14][CH2:13][O:12][CH2:17][CH2:16]2)=[CH:23][CH:22]=1)=[O:26]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(N2CCOCC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)F)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 15.8 h
Yield: 91.6 %

Procedure:
Ethyl difluoroacetate (2.30 g, 18.5 mmol) was placed in a 100 mL round bottom flask and dissolved in THF (25 mL). To the stirred solution was added 25 weight % sodium methoxide (4.90 g, 22.6 mmol) followed by 4'-morpholinoacetophenone (3.45 g, 16.8 mmol). The reaction was stirred at room temperature overnight (15.8 hours), then treated with 3N HCl (13 mL). The reaction was extracted with ethyl acetate (20 mL), washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo to give a green solid (4.36 g) which was recrystallized from methylene chloride/isooctane to give the diketone as a yellow solid (3.27 g, mp 102°-3° C., 69%). 1H NMR (CDCl3) 300 MHz 15.80 (br s, 1H), 7.86 (d, J=9.1 Hz, 2H), 6.90 (d, J=9.1 Hz 2H), 6.46 (s, 1H), 5.99 (t, J=54.4 Hz, 1H), 3.84 (m,4H), 3.36 (m, 4H); 19F NMR (CDCl3) 300 MHz: -126.75 (d); M+283.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=2)[CH:18]=1>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[N:17]([CH:19]=[C:20]([C:22]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)=[O:23])[N:21]=2)[CH:18]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate I, using 4-(trifluoromethyl)aniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CCNC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 87.4 %

Procedure:
A solution of benzyl 4-oxopiperidin-1-carboxylate (10 g), β-alanine methyl ester monohydrochloride (5.99 g), acetic acid (4 mL) and sodium triacetoxyborohydride (10.9 g) in dichloroethane (400 mL) was stirred overnight. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (12.0 g, 87%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[NH:29][CH2:28][C:27]2[CH:30]=[C:31]([Cl:32])[C:24](=[C:25]([Cl:33])[CH:26]=2)[NH:23][C:22](=[O:34])[CH2:21][NH:20][CH2:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14][C:13]2[CH:35]=[CH:36][C:10](=[CH:11][CH:12]=2)[C:9]2[C:5](=[C:6]([CH3:37])[S:7][N:8]=2)[C:4](=[O:38])[N:3]=1.NC1NCC2C=C(Cl)C(=C(Cl)C=2)NC(=O)CNCCC=CCOC2C=CC(=CC=2)C2C(=C(C)SN=2)C(=O)N=1>>[NH2:1][C:2]1[NH:29][CH2:28][C:27]2[CH:30]=[C:31]([Cl:32])[C:24](=[C:25]([Cl:33])[CH:26]=2)[NH:23][C:22](=[O:34])[CH2:21][NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]2[CH:12]=[CH:11][C:10](=[CH:36][CH:35]=2)[C:9]2[C:5](=[C:6]([CH3:37])[S:7][N:8]=2)[C:4](=[O:38])[N:3]=1
Reactant: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCCC=CCOc1ccc-2cc1
Agent: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCC/C=C/COc1ccc-2cc1
Agent: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCC/C=C\COc1ccc-2cc1
Product: Cc1snc2c1C(=O)N=C(N)NCc1cc(Cl)c(c(Cl)c1)NC(=O)CNCCCCCOc1ccc-2cc1

Procedure:
Utilizing a mixture of (22Z)-9-amino-14,31-dichloro-5-methyl-25-oxa-4-thia-3,8,10,16,19-pentaazatetracyclo[24.2.2.212,15.02,6]dotriaconta-1(28),2,5,8,12,14,22,26,29,31-decaene-7,17-dione and (22E-9-amino-14,31-dichloro-5-methyl-25-oxa-4-thia-3,8,10,16,19-pentaazatetracyclo[24.2.2.212,15.02,6]-dotriaconta-1(28),2,5,8,12,14,22,26,29,31-decaene-7,17-dione (Example 8) in place of tert-butyl 9-((tert-butoxycarbonyl)amino)-14,32-dichloro-5-methyl-7,17-dioxo-26-oxa-4-thia-3,8,10,16,19-pentaazatetracyclo[25.2.2.212,15.02,6]tritriaconta-1(29),2,5,8,12,14,23,27,30,32-decaene-19-carboxylate (Example 4, Step (C)), the title compound was synthesized by analogy to Example 5.
Reaction SMILES: COC(=O)C1C=CC=C([Cl:10])C=1OC.I[C:15]1[CH:20]=[CH:19][C:18]([C:21](C)([CH3:28])[CH2:22][C:23](=[O:27])[C:24]([OH:26])=[O:25])=[C:17]([O:30][CH3:31])[CH:16]=1>>[Cl:10][C:16]1[C:17]([O:30][CH3:31])=[C:18]([CH:21]([CH3:28])[CH2:22][C:23](=[O:27])[C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:15]=1
Reactant: COC(=O)c1cccc(Cl)c1OC
Reactant: COc1cc(I)ccc1C(C)(C)CC(=O)C(=O)O
Product: COc1c(Cl)cccc1C(C)CC(=O)C(=O)O

Procedure:
This ester is reacted analogously to the process that is described for 4-(4-iodo-2-methoxyphenyl)-4-methyl-2-oxo-valeric acid. 8 g of the title compound is obtained as a light yellow oil.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH2:13])=[O:5])[CH3:2].CCN(CC)CC.[C:23](Cl)(=[O:25])[CH3:24].C(OCC)(=O)C.CCCCC>C(Cl)Cl>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]([O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:12]=1[NH:13][C:23](=[O:25])[CH3:24])=[O:5])[CH3:15]
Reactant: CCN(CC)C(=O)Oc1cnccc1N
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cnccc1NC(C)=O
Reaction time: 0.25 h

Procedure:
4-Amino-3-pyridinol N,N-diethylcarbamate (4.18 g) was dissolved in CH2Cl2 (75 mL) containing Et3N (2.22 g). The reaction mixture was chilled in an ice-water bath and then acetyl chloride (1.57 g) was added dropwise. After stirring in the cold bath for 15 minutes, the mixture was concentrated under reduced pressure to a volume of ca. 20 mL. This suspension was applied directly to a flash chromatography column and eluted with 5% Et3N/ethyl acetate. The product-containing fractions were concentrated to give 3.76 g of chromatographically pure product. An analytically pure material was obtained by recrystallization from ethyl acetate/pentane, m.p. 102°-104° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CC(F)(F)F)CC3)c2)c2ccc(F)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 277 mg; 0.63 mmol), Et3N (0.40 mL; 2.87 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (147 mg; 0.63 mmol) in toluene (40 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase flash chromatography to afford 275 mg (84%) of the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[C:29]([S:35](=[O:40])(=[O:39])[N:36]([CH3:38])[CH3:37])[CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])=[C:29]([S:35](=[O:39])(=[O:40])[N:36]([CH3:38])[CH3:37])[CH:28]=1
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Agent: Cl
Product: CC(C)N1CCn2c1nc(C(=O)NCc1ccc(F)cc1S(=O)(=O)N(C)C)c(OCc1ccccc1)c2=O
Yield: 77.7 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.150 g, 0.45 mmol) and 4-fluoro-2-(N,N-dimethylsulfamoyl)benzylamine hydrochloride (0.147 g, 0.55 mmol) as described for the synthesis of intermediate 3 gave 0.190 g (75% yield) of the title amide as white crystals; mp 161-163° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.9 Hz, 2×CH3), 2.85 (6H, s, 2×NCH3), 3.65 (2H, t, J=9 Hz, CH2),4.12 (2H, t, J=9 Hz, CH2),4.40 (1H, m, CH), 4.81 (2H, d, J=6.6 Hz, NCH2), 5.13 (2H, s, OCH2), 7.22 (1H, m, aromatic), 7.28-7.34 (3H, m, aromatics), 7.49-7.52 (2H, m, aromatics), 7.55 (1H, dd, J=2.6 Hz and J=8.6 Hz, aromatic), 7.71 (1H, dd, J=5.6 Hz and J=8.6 Hz, aromatic), 8.26 (1H, broad t, NH). Anal. Calcd for C26H30FN5O5S: C, 57.44; H, 5.56; N, 12.88. Found: C, 57.40; H, 5.46; N, 12.85.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)OB([C:26]2[C:27]([O:32][C:33]3[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=3)=[N:28][CH:29]=[CH:30][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.O.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][C:27]2[C:26]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[CH:10][C:3]=34)=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2cccnc2Oc2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)n1ccc2c(Cl)ccnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2c(-c3cccnc3Oc3ccc(N)cc3)ccnc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In an argon-purged sealed tube, tert-butyl 4-chloro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (2.77 g, 11.0 mmol), 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yloxy)benzenamine (5.14 g, 16.5 mmol), sodium carbonate (3.49 g, 32.9 mmol), 1,4-dioxane (32.3 ml, 11.0 mmol), and water (11.7 ml, 11.0 mmol) were added. The tube was sealed, and the reaction was stirred at RT for 5 min. Palladium acetate (0.246 g, 1.10 mmol) and tri-t-butylphosphonium tetrafluororoborate (0.637 g, 2.19 mmol) were added, and the tube was sealed and heated to 100° C. After ˜105 min, heating was stopped, the reaction mixture was cooled to RT and passed through a pad of celite with an aid of EtOAc. The filtrate was dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography on 120 g silica gel column using DCM and 95:05 DCM:(90:10:1 DCM:MeOH:NH4OH) to flush out the nonpolar spots, then 80:20 DCM:(90:10:1 DCM:MeOH:NH4OH) to collect the Boc-product. A viscous brown oil was obtained. After setting the oil at RT for several hours, crystals were formed. The oil was cooled to 0° C. and light yellow solid precipitated out after adding small amounts of hexanes and a little bit of ether in addition to scratching the wall of the flash with a spatula. The light yellow solid was filtered, washed with cold hexanes, and dried under vacuum. This solid, tert-butyl 4-(2-(4-aminophenoxy)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate was mainly the product according to 1H NMR. MS Calcd for C23H22N4O3: [M]+=402. Found: [M+H]+=403.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36](O)=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C[N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+].N.CO>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:30])[S:24]([CH:27]3[CH2:29][CH2:28]3)(=[O:25])=[O:26])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([NH2:40])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC[C@@H](CN(C)S(=O)(=O)C1CC1)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
A solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid (0.055 g, 0.095 mmol; Example 141) in DMF (2.0 mL) was treated with HBTU (0.072 g, 0.189 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.036 g, 0.189 mmol) and sodium hydrogencarbonate (0.016 g, 0.189 mmol) successively. Let it stir for 0.5 h. 7.0M ammonia in methanol (0.135 mL, 0.946 mmol) was added dropwise. After being stirred at room temperature for 18 h, the reaction was diluted with water, extracted (2×EtOAc), and washed (1×saturated NaHCO3, and 2×sat. aq. NaCl solution). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to give the title compound as a white solid after lyophilization.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[C:5]([OH:12])[CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([OH:12])[CH:4]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)cc1O
Reaction time: 24 h
Yield: 99.3 %

Procedure:
1-(4-Methoxy-2-hydroxy-phenyl)-ethanone (11.0 g) was dissolved in MeOH (100 mL), treated with 10 wt % Pd/C (4.0 g, Degussa type) and stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to give the product as an oil (10.0 g). 1H NMR (300 MHz, CDCl3): δ 1.20 (t, J=7.85 Hz, 3 H) 2.60- (q, J=6.22 Hz 2 H), 3.75 (s, 3 H), 6.40 (dd, J=9.04 Hz, 2.64 Hz, 1 H), 6.45 (d, J=2.64 Hz, 1 H) 7.00 (d, J=8.29 Hz, 1 H), 12.90 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([OH:19])[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:17]([NH2:18])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:19][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:14]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCN1CCOCC1
Reactant: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Product: COc1cc2cc(C(=O)OC(C)(C)C)c(N)cc2cc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.8 %

Procedure:
To a solution of 0.72 g (2.49 mmol) of 3-amino-6-hydroxy-7-methoxy-naphthalene-2-carboxylic acid tert-butyl ester in 7.5 ml of tetrahydrofuran is added 0.46 mL (3.74 mmol) of 4-(2-hydroxyethyl)morpholine, followed by the addition of 1.34 g (4.98 mmol) of diphenyl-2-pyridylphosphine and 0.6 mL (3.87 mmol) of diethyl azadicarboxylate. The resulting mixture is stirred at room temperature for 1.5 hours, quenched with water, diluted with ethyl acetate and the two layers are separated. The organic layer is extracted with 0.2N hydrochloric acid. After neutralizing the aqueous layer with a saturated solution of sodium bicarbonate, it is extracted with ethyl acetate. The ethyl acetate extract is dried over anhydrous sodium sulfate, filtered and evaporated to yield a brown oil. The oil is purified by silica gel chromatography, utilizing a gradient of ethyl acetate/hexane (85:15 to 100:0), to give 0.7 g of 3-amino-7-methoxy-6-(2-morpholin-4-yl-ethoxy)-naphthalene-2-carboxylic acid tert-butyl ester as an orange solid, mp 125–127° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[NH2:14][C@@H:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17]([O:19][CH3:20])=[O:18])([O-:3])=[O:2]
Reactant: COC(=O)C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C[C@@H](Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccccc1

Procedure:
To a solution of 2,4-dinitrochlorobenzene (5.1 g, 25 mmol) in methanol (60 mL) was added methyl (3R)-3-amino-3-phenylpropanoate (3.75 g, 21 mmol, prepared according to Davies et. al., Tetrahedron Asymm., 1991, 183) and triethylamine (2.9 mL, 21 mmol). The mixture was brought to reflux, heating in total for 5 hours, and was then cooled and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (95:5), to afford the title compound, [LCMS (Method C, Mobile Phase I) RT=3.22 mins, MH+ 346].