Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:24][CH2:23][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:22])[C:11]=2[CH:12]=1)(=[O:5])=[O:4].[OH-].[Na+].Br[CH2:30][C:31]1[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1>CN(C)C=O.C(OCC)(=O)C>[F:26][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:24][CH2:23][C:13]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]([CH2:30][C:31]4[O:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)[C:14]3=[O:22])[C:11]=2[CH:12]=1)(=[O:5])=[O:4]
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: O=C1Nc2ccccc2C12COc1ccc(OS(=O)(=O)C(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C12COc1ccc(OS(=O)(=O)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
To a mixture of 2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indol]-5-yl trifluoromethanesulfonate (0.42 g, 1.10 mmol) and sodium hydroxide (0.07 g, 1.65 mmol) in N,N-dimethylformamide (5.00 mL) was added 2-(bromomethyl)-5-(trifluoromethyl)furan (0.50 g, 2.20 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and diluted with ethyl acetate (200 mL). After washing with aqueous saturated sodium chloride (2×20.0 mL), the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/3) to give the title compound (0.47 g, 80%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.34 (t, 1H), 7.18-6.94 (m, 5H), 6.74 (dd, 1H), 6.55 (dd, 1H), 6.40 (d, 1H), 5.09-4.72 (m, 4H); MS (ES+) m/z 534.4 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.O1CCCCC1[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>CN(C)C=O>[OH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH3:3])=[C:5]1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Reactant: BrCCCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-n2ccnc2)n(CCCCCCCCO)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3.0 g of 50% sodium hydride in mineral oil in 40 ml of dimethylformamide under nitrogen at 0°-5° is added dropwise over 20 minutes a solution of 10.0 g of 3-methyl-2-(1-imidazolyl)indole in 60 ml of dimethylformamide. The mixture is stirred for 0.5 hour at 0°-5° followed by the dropwise addition of 17.5 g of 1-tetrahydropyranyloxy-8-bromooctane in 50 ml of dimethylformamide. After stirring at 0°-10° for 1 hour and at room temperature for 0.5 hour, the reaction mixture is poured into ice-water and extracted with ether. The ether extract is washed with water, dried over MgSO4 and evaporated to dryness. The residue is dissolved in 100 ml of 3N hydrochloric acid, the resulting mixture is kept at room temperature for 0.5 hour, washed with ether, basified with aqueous 3N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride solution is evaporated to dryness to give 1-(8-hydroxyoctyl)-2-(1-imidazolyl)-3-methylindole.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12](O)=[O:13].B.C1COCC1.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:12][OH:13]
Reactant: O=C(O)c1cccc2cc(Cl)ncc12
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cccc2cc(Cl)ncc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroisoquinoline-8-carboxylic acid (0.5 g, 1.803 mmol) in THF (18.03 ml) at 0° C. was treated with BH3.THF (5.41 ml, 5.41 mmol). After stirring for 2 hours at 0° C., 1N NaOH was added. The reaction was stirred for 30 minutes then diluted with EtOAc and the layers were separated. Aqueous layer was washed with EtOAc three times. All combined organic layers were washed with brine, then dried with sodium sulfate. Filtered and concentrated in vacuo. Purified by silica gel chromatography (0-100% EtOAc in hexane) to yield (3-chloroisoquinolin-8-yl)methanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.C1(S([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:18]2)(=O)=O)C=CC=CC=1>>[O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:28]2[N:27]=[C:26]([C:19]3[C:20]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:17][CH:18]=3)[CH:31]=[CH:30][N:29]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: NC1CCOCC1
Product: c1cnc2[nH]cc(-c3ccnc(NC4CCOCC4)n3)c2c1
Yield: 83.7 %

Procedure:
Using the procedure of example 1, tetrahydropyran-4-ylamine (0.8 g) was reacted with compound 1f (1.8 g) to provide compound 60 (1.2 g, 42%). 1H NMR (400 MHz, DMSO) δ 12.20 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.30 (d, 1H), 8.15 (d, 1H), 7.20 (m, 1 H), 7.06 (d, 1H), 7.04 (d, 1H), 4.00 (m, 1H), 3.90 (m, 2H), 3.45 (m, 2H), 1.90 (m, 2 H), 1.55 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:28]([CH2:35][C:36](Cl)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:36](=[O:37])[CH2:35][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)COc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and phenoxyacetyl chloride.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8].[Cl:16][C:17]1[N:18]=[C:19]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:20]2[S:25][C:24]([CH:26]=O)=[CH:23][C:21]=2[N:22]=1>>[Cl:16][C:17]1[N:18]=[C:19]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:20]2[S:25][C:24]([CH2:26][N:13]3[CH2:14][CH2:15][CH:10]([S:7]([C:3]4[S:2][CH:6]=[CH:5][N:4]=4)(=[O:9])=[O:8])[CH2:11][CH2:12]3)=[CH:23][C:21]=2[N:22]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: O=S(=O)(c1nccs1)C1CCNCC1
Agent: Cl
Product: O=S(=O)(c1nccs1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 31.9 %

Procedure:
4-(Thiazole-2-sulfonyl)-piperidine HCl salt (124 mg) was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]ppimidine-6-carbaldehyde 10 (130 mg) using standard reductive amination conditions. Aqueous work-up, purification on silica and trituration with hot ethyl acetate yielded 2-chloro-4-morpholin-4-yl-6-[4(thiazole-2-sulfonyl)-piperidin-1-ylmethyl]-thieno[3,2-d]pyrimidine (73 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 415. NMR (CDCl3): 2.03-2.18 (4H, m), 2.18-2.22 (2H, m), 3.12-3.16 (2H, m), 3.39-3.46 (1H, m), 3.84 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 5.20 (2H, br), 7.26 (1H, s), 7.79 (1H, d, J=3.0), 8.11 (1H, d, J=3.0), 9.29 (2H, s) MS (ESI+): MH+ 559.13 (100%)
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[N:13](S(C3C=CC=CC=3)(=O)=O)[CH:12]=[C:11]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].O1CCCC1.[OH-].[Na+]>CO>[C:1]([C:3]1[C:8]([C:9]2[NH:13][CH:12]=[C:11]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[C:10]=2[F:33])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
To a mixture of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (5.43 g), tetrahydrofuran (50 mL), and methanol (13 mL) was added a 8 mol/L aqueous sodium hydroxide solution (2 mL) at 0° C., and the mixture was stirred at the same temperature for 30 min. The reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=1:1), and further by silica gel column chromatography (eluent: hexane:ethyl acetate=1:1) to give the title compound as a yellow oil (yield 2.18 g, 57%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:25]3[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=3[N:17]=[CH:16]2)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:45](O)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:25]3[N:24]=[C:22]([NH2:23])[N:21]=[C:19]([O:20][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:18]=3[N:17]=[CH:16]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1OC(C)=O
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(OCc4ccccc4)nc(N)nc32)C[C@@H]1OC(C)=O
Temperature: 85 °C

Procedure:
3′,5′-Di-O-acetyl-O6-benzyl-2′-deoxyguanosine (4) was prepared following the method of Zajc et al., Tet. Lett. 1992, 33, 3409-3412. To a mixture of 3′,5′-di-O-acetyl-2′-deoxyguanosine (5.71 g, 16.3 mmol), triphenylphosphine (5.91 g, 22.5 mmol) and benzyl alcohol (2.5 mL, 24.1 mmol) in 100 mL 1,4-dioxane under argon was slowly added diisopropylazodicarboxylate (4.5 mL, 22.8 mmol). The mixture was heated to 85° C. for two hr and was then cooled and concentrated to a thick paste on a rotary evaporator. The product was isolated as a light brown solid (1.78 g, 24.8%) following silica gel column chromatography with 10% ethyl acetate/chloroform. 1H-NMRδH(DMSO-d6) 8.09 (s, 1H, H-8), 7.51-7.35 (m, 5H, Ar), 6.54 (s, 2H, N2H2, exchange with D2O), 6.24 (dd, J=6.0, J′=8.5, 1H, H-1′), 5.50 (s, 2H, OCH2Ar), 5.33-5.32 (m, 1H, H-3′), 4.32-4.27 (m, 1H, H-4′), 4.22-4.18 (m, 2H, H-5′), 3.06-2.98 (m, 1H, H-2′α), 2.50-2.44 (m, 1H, H-2′β), 2.09 (s, 3H, COCH3), 2.02 (s, 3H, COCH3); MS, m/z 442.1 [M+H]+, 464.1 [M+Na]+; Anal. Calcd. for C21H23N5O6: C, 57.14; H, 5.25; N, 15.86.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][N:30]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(S(C)(=O)=O)CC3)c12

Procedure:
3-(3-Chloro-phenyl)-1-(1-methanesulfonyl-piperidin-4-yl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (47 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and methanesulfonyl chloride. LCMS: m/z 515 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.56 (s, 1H), 7.58 (m, 1H), 7.48 (m, 1H), 7.38 (m, 1H), 7.24 (m, 1H), 7.09-7.18 (m, 2H), 6.48 (m, 1H), 5.06 (m, 1H), 4.10 (s, 3H), 4.02 (m, 2H), 3.80-3.92 (m, 7H), 1.84 (m, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([NH:1][C:38](=[O:40])[CH3:39])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:12])=[O:13])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)Cl
Reactant: COc1cccc(-c2c(N)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(-c2c(NC(C)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.3 %

Procedure:
To a stirred solution of N-{2-amino-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Description 85) (40 mg, 0.087 mmol) in DCM (3 mL) was added triethylamine (0.036 mL, 0.261 mmol) and acetyl chloride (7.42 ul, 0.104 mmol) and the mixture stirred at RT for ca. 1 h. NaHCO3 solution (25 mL) was then added and the mixture extracted with DCM (20 mL×3) and the combined organics dried and concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in DCM and was then further purified by MDAP (acidic conditions), to give the title compound (5.8 mg). LCMS (A) m/z: 502 [M+1]+, Rt 1.05 min (acidic).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1.[NH2:20][CH2:21][C@@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[Si:24]([O:23][C@H:22]([C:31]1[CH:40]=[CH:39][C:38]([OH:41])=[C:37]2[C:32]=1[CH:33]=[CH:34][C:35](=[O:42])[NH:36]2)[CH2:21][NH:20][CH2:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: O=C(Nc1ccc(C#CCCCBr)cc1)C(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCC#Cc1ccc(NC(=O)C(F)(F)F)cc1)c1ccc(O)c2[nH]c(=O)ccc12
Temperature: 55 °C
Yield: 90.2 %

Procedure:
A mixture of Intermediate 26 (0.33 g, 1.0 mmol) and Intermediate 2 (0.40 g, 1.2 mmol) in DMF (5 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.25 mL, 1.5 mmol) and catalytic potassium iodide. The mixture was heated overnight in a 55° C. oil bath. The mixture was concentrated under reduced pressure and purified via automated flash silica gel chromatography, using a 12 g Isco RediSep flash column (dichloromethane/methanol/ammonium hydroxide). Concentration of the desired fractions under reduced pressure provided the title compound (0.53 g, 90%). ES/MS calcd. for C30H37F3N3O4Si+588.3. found m/z=588.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[N:15]2[CH3:18])=[C:11]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:10]=1.[CH:36]1([C:39](O)=O)[CH2:38][CH2:37]1>>[CH:36]1([C:39]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([CH2:19][N:20]5[CH2:21][CH2:22][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:24][CH2:25]5)[N:15]4[CH3:18])=[C:11]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[N:10]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:38][CH2:37]1
Reactant: O=C(O)C1CC1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Nc3ccccc3N)nc21
Product: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21

Procedure:
Following the procedures for 178, 2-(1-((2-(2-aminophenylamino)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and cyclopropanecarboxylic acid were reacted to give 159. LCMS: M+H+=531.3. 1H-NMR (400 MHz, DMSO-d6): δ 7.93 (m, 1H), 7.53 (m, 1H), 7.22 (m, 2H), 4.26 (s, br, 4H), 4.08 (m, 2H), 4.03 (s, 1H), 3.82 (s, 3H), 3.77 (m, 4H), 3.74 (s, 2H), 3.17 (d, 2H), 2.84-2.96 (m, 3H), 1.99 (m, 2H), 1.67 (m, 2H), 1.04-1.29 (m, 3H), 1.02 (s, 6H)
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>O1CCOCC1.C1COCC1>[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([O:10][C:9](=[O:11])[C@@H:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:46]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Cc1ccccc1)Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)[C@H](Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a solution of 3-phenyl-2-(phenylamino)propanoic acid (I21) (1.21 g, 5.01 mmol) in dioxane, a 4M solution of HCl in dioxane (5 mL) is added and the reaction is allowed to stir at RT for 1 hour; the solvent is evaporated under reduced pressure to obtain a white solid which is dissolved in dry THF (70 mL). DCC (1.22 g, 6.01 mmol), HOBt (0.8 g, 6.0 mmol) and 3(R)-quinuclidinol (1.31 g, 10.1 mmol) are added to the resulting solution and the mixture stirred for 24 hours at RT under nitrogen flowstream (LC-MS monitoring: complete conversion). The solvent is evaporated. 1N HCl (20 mL) is added to the resulting crude and the aqueous layer is washed with EtOAc (2×50 mL); NaHCO3 is added to the aqueous layer (pH=7-8) and the product is extracted with DCM and dried over Na2SO4, to obtain 530 mg (35% yield) of diastereoisomer 1 of C22, which is further purified by preparative LC-MS to get the titled product as a brown oil (mixture of diastereoisomers that contains 20% of diastereoisomer 2 of C22, TFA salt).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:17])[C:4]([OH:6])=[O:5].[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:2][CH:3]([CH2:7][CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:17])[C:4]([OH:6])=[O:5])=[O:24])=[CH:21][CH:20]=1
Reactant: NC(CC1C(=O)Nc2ccccc21)C(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC(CC1C(=O)Nc2ccccc21)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.25 Grams of 2-amino-3-(oxindol-3-yl)propionic acid hydrochloride prepared in reference example 1, and 1.3 g of N-hydroxysuccinimide ester of p-chlorobenzoic acid were dissolved in 50 ml of dimethylformamide. To this solution was added 1.2 g of triethylamine, and the whole mixture was stirred at a room temperature for 3 hours. Dimethylformamide was removed by evaporation, then water was added to the resultant residue, the crystals formed were collected by filtration to obtain 0.68 g of 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionic acid 1/4-hydrate. Melting point: 133°-135° C. (decomp.) [α]D25 -50.3° (C=1, methanol)
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]2=[O:32])=[CH:5][C:3]=1[NH2:4].C(O[C:36]1[CH2:40][C:39](=[O:41])[N:38]([C:42]2[C:47]([Cl:48])=[CH:46][C:45]([Cl:49])=[CH:44][C:43]=2[Cl:50])[N:37]=1)C.CS(O)(=O)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:10]2=[O:32])=[CH:5][C:3]=1[NH:4][C:36]1[CH2:40][C:39](=[O:41])[N:38]([C:42]2[C:47]([Cl:48])=[CH:46][C:45]([Cl:49])=[CH:44][C:43]=2[Cl:50])[N:37]=1
Reactant: CCCCCCCCCCCCCCCCCCN1CCN(c2ccc(Cl)c(N)c2)C1=O
Reactant: CCOC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCCCN1CCN(c2ccc(Cl)c(NC3=NN(c4c(Cl)cc(Cl)cc4Cl)C(=O)C3)c2)C1=O
Temperature: 150 °C
Reaction time: 6 h

Procedure:
A mixture of 13.9 g of 2-chloro-5-(3-octadecylimidazolidin-2-on-1-yl)aniline, 9.3 g of 3-ethoxy-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one and 1 g of methanesulfonic acid was heated at 150° C. under reduced pressure with stirring for 6 hours. After cooling, the reaction mixture was dissolved in ethyl acetate and washed three times with water. After distilling off the solvent, the residue was separated by a silica gel chromatography (using a solvent mixture of ethyl acetate and benzene as a spreading agent) to obtain the desired compound. By recrystallization from a solvent mixture of ethyl acetate and acetonitrile 10.5 g of the crystals having a melting point of 163° to 168° C. were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:14])[CH:13]=1)[CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])N.N([O-])=[O:16].[Na+]>OS(O)(=O)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][C@H:6]([OH:16])[C:8]([OH:10])=[O:9])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)Cc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A suspension of 1.6 g of (S)-3,5-difluoro-phenyalanine in 5.3 ml of H2SO4 (2.5N) is admixed dropwise at 0° C. with a solution of 0.829 g of sodium nitrite in 4.2 ml of H2O. The reaction mixture is stirred for 2 hours at 0° C. and then for 17 hours at ambient temperature. The reaction mixture is extracted with 2×100 ml of AcOEt. The combined organic phases are washed with 100 ml of saturated NaCl solution in H2O. Drying gives 1.197 g of yellow crystals. The acid obtained is used without further purification in the following step.
Reaction SMILES: [C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18]S(C)(=O)=O)[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Na+].[I-].[C:36]([O-])(O)=[O:37].[Na+].CCOC(C)=O>CN(C=O)C>[C:1]([O:6][C@@H:7]1[C@@H:15]([CH2:16][CH2:17][O:18][CH:36]=[O:37])[C:14](=[O:23])[O:13][CH2:12][C@H:11]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:10](=[O:32])[O:9][C@H:8]1[CH3:33])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOS(C)(=O)=O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CCOC=O
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution (3S,6S,7R,8R)-3-(tert-butoxycarbonylamino)-6-methyl-8-(2(methylsulfonyloxy)ethyl)-4,9-dioxo-1,5-dioxonan-7-yl isobutyrate (510 mg, 1.03 mmol) in DMF (3 mL) at room temperature (about 22° C.) was added NaI (1 g, 6.7 mmol). The resulting reaction mixture was heated to 80° C. and stirred for 48 h. After cooling to room temperature, saturated NaHCO3 solution (30 mL) and EtOAc (25 mL) were added. The phases were separated and the aqueous phase was extracted with EtOAc (2×25 mL). The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified via column chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (228 mg, 50%) as a white solid (228 mg, 50%): mp 103-104; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 5.43-5.15 (m, 2H), 5.06 (t, J=9.9 Hz, 1H), 4.93-4.77 (m, 2H), 4.19 (dt, J=11.1, 5.5 Hz, 1H), 4.05 (ddd, J=11.4, 8.9, 4.8 Hz, 1H), 3.60 (s, 1H), 2.71 (td, J=11.4, 2.8 Hz, 1H), 2.67-2.53 (m, 1H), 2.17-2.02 (m, 1H), 1.73 (dt, J=14.7, 7.4 Hz, 1H), 1.45 (s, J=15.6 Hz, 9H), 1.28 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.5 Hz, 6H); ESIMS m/z 468 ([M+Na]+).