Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C@@H:2]1[C@H:6]([NH2:7])[C@@H:5]([CH2:8][O:9]C(=O)C2C=CC=CC=2)[O:4][C@H:3]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].[CH3:26][O:27][C:28]1[CH:47]=[CH:46][C:31]([C:32](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[F:1][C@@H:2]1[C@H:6]([NH:7][C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:47][CH:46]=2)[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:18]1[CH:25]=[CH:24][C:22](=[O:23])[NH:21][C:19]1=[O:20]
Reactant: N[C@H]1[C@@H](F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(=O)c1ccccc1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(C(N[C@H]2[C@@H](F)[C@H](n3ccc(=O)[nH]c3=O)O[C@@H]2CO)(c2ccccc2)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
2'-fluoro-3'-(4-methoxytrityl)amino-2',3'-dideoxyuridine (compound 12, FIG. 2) was prepared as follows: To 1.0 g (2.9 mmol) of 11 in 50 mL anhydrous pyridine was added 1.0 g (3.2 mmol) 4-methoxytrityl chloride. The mixture was stirred overnight, 5 mL saturated aqueous NaHCO3 was added, and the mixture concentrated in vacuo to an oil. The oil was dissolved in 125 mL ethyl acetate, which was washed with water (3×100 mL) and reconcentrated in vacuo to 2.05 g of foam.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Pd].O1CCOCC1>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][CH:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)S(=O)(=O)NC1Cc2ccc(I)cc2C1
Reactant: OB(O)c1cccnc1F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NC1Cc2ccc(-c3cccnc3F)cc2C1
Yield: 36.5 %

Procedure:
A mixture of Intermediate 2 (65 mg, 0.18 mmol) and cesium carbonate (1.5 eq, 88 mg, 0.27 mmol) in a 3:1 mixture of 1,4-dioxan:water (4 ml) was degassed with argon for 5 minutes. Then the mixture was added to (2-fluoro-3-pyridinyl)boronic acid (1.1 eq, 28 mg, 0.20 mmol, Asymchem International Inc.). Palladium acetate (2 mg, 0.01 mmol—alternatively, solid supported palladium may be used), and triphenylphosphine (9 mg, 0.03 mmol) were then added and the whole mixture stirred at reflux for 16 h. The reaction mixture was allowed to cool and partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was separated, dried and evaporated. The resulting product was purified using mass directed preparative HPLC to give the title compound (22 mg, 37%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]([CH3:30])[CH3:29]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH:28]([CH3:30])[CH3:29])[CH2:19]1
Reactant: CC(C)I
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(C(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and 2-iodopropane.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:18][C:19]1[O:23][C:22]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)O)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:15]([CH:24]([C:22]1[O:23][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(C(O)C2CCOCC2)o1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(N=[N+]=[N-])C2CCOCC2)o1
Temperature: 0 °C
Reaction time: 22 h
Yield: 69.8 %

Procedure:
6.08 g (22 mmol, 1.1 eq) of diphenylphosphoryl azide were added dropwise to a solution of 4.43 g (20 mmol, 1 eq) of (5-methylfuran-2-yl)-(tetrahydropyran-4-yl)methanol at 89% in 60 ml of toluene. The reaction medium was cooled to 0° C. and then 3.3 ml (22 mmol, 1.1 eq) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added dropwise. The reaction medium was stirred at ambient temperature for 22 hours. The reaction medium was separated by settling out and the organic phase was washed with water and then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (column Analogix SF40-240 g, Spot II) eluted with heptane/ethyl acetate (95/5). 3.09 g of 4-[azido-(5-methylfuran-2-yl)methyl]tetrahydropyran were obtained. Yield=70%.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH3:29])[CH:12]([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)[S:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=1>CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([CH3:29])[CH:12]([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)[S:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(SC(C(C)c2ccccc2OC)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1C(C)C(Sc1ccc(C(=O)O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
4.7 ml of a 1N aqueous solution of sodium hydroxide were added to 450 mg of methyl 4-[2-(2-methoxyphenyl)-1-(imidazol-1-yl)propylthio]benzoate prepared as described in Example 43) in 4.7 ml of methanol, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then treated and purified by the same method as described in Example 28, to give 300 mg of the title compound as a powder, melting at 118°-124° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14](Br)=[C:13]([CH3:19])[N:12]=1.C([O-])([O-])=O.[K+].[K+].Cl>C(O)CO.O>[NH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([S:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=2)=[C:13]([CH3:19])[N:12]=1
Reactant: OCc1ccc(S)cc1
Reactant: Cc1nc(N)nc(O)c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: Cc1nc(N)nc(O)c1Sc1ccc(CO)cc1
Temperature: 155 °C

Procedure:
A stirred mixture of (4-mercaptophenyl)methanol (6.72 g), 2-amino-5-bromo-6-methylpyrimidin-4-ol (10.76 g) and K2CO3 (7.29 g) in ethylene glycol (120 ml) was heated at 155° C. for 9 h. After cooling the mixture was poured into water (500 ml) and neutralised with conc. HCl. The precipitate was filtered, washed with water then 50% EtOH/ether and dried to give the subtitle compound as a solid, 6.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=3[C:13](=[CH:14][C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=3[C:13](=[CH:14][C:15]3[CH:16]=[C:17]([NH:21][S:27]([CH3:26])(=[O:29])=[O:28])[CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1OCc1ccccc1C2=Cc1cccc(N)c1
Solvent: Cc1ccccc1
Product: COc1cccc2c1OCc1ccccc1C2=Cc1cccc(NS(C)(=O)=O)c1

Procedure:
Following procedures essentially as described in Example 90, the title compound is prepared from 3-(4-Methoxy-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-phenylamine and methanesulfonyl chloride. Flash chromatography eluting with 5 to 10 to 20% ethyl acetate:toluene provides 198 mg product (60% yield) of the title final product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:5][N:4]=1.[OH:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:17](O)=[O:18].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C.C([O-])(O)=O.[Na+]>[OH:15][CH:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:17]([NH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[N:5][N:4]=1)=[O:18]
Reactant: NCc1nnc(-c2ccc(O)cc2)s1
Reactant: O=C(O)C(O)CCCCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1nnc(-c2ccc(O)cc2)s1)C(O)CCCCCCc1ccccc1

Procedure:
A solution of 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (1.74 mmol), 2-hydroxy-8-phenyloctanoic acid (1.74 mmol), HOBt (2.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.1 mmol) and DIPEA (6.94 mmol) in DMF (4 mL) was stirred at room temperature overnight. The resulting mixture was diluted with NaHCO3 (saturated) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The resulting residue was purified by chromatography (silica gel, methanol-CH2Cl2) to yield 2-hydroxy-N-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)-8-phenyloctanamide. A solution of 2-hydroxy-N-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)-8-phenyloctanamide (0.18 mmol), 4-bromomethypyridine hydrochloride (0.26 mmol), and potassium carbonate (0.53 mmol) in DMF (4 mL) was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyl-N-((5-(4-(pyridin-4-ylmethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)octanamide, which was used in the next step without purification. To a solution of 2-hydroxy-8-phenyl-N-((5-(4-(pyridin-4-ylmethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)octanamide (0.16 mmol) in CH2Cl2 (5 mL) was added the Dess-Martin periodinane (0.23 mmol). The resulting mixture was stirred overnight, then quenched with an excess of a solution of sodium thiosulfate in saturated NaHCO3 (aqueous). The mixture was then extracted twice with ethyl acetate and the combined extracts were washed with brine, dried (Na2SO4) and concentrated. The resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:23][OH:24])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]2=[O:22])=[C:4](O)[CH:3]=1.ClC1C=CC(Cl)=C2C=1C(C1C(O)=CC3OCOC=3C=1)(CO)C(=O)N2CCCCC>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]3([CH2:23][O:24][C:6]=2[CH:7]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22]
Reactant: CCCCCN1C(=O)C(CO)(c2ccc(Br)cc2O)c2ccccc21
Agent: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Cl)ccc(Cl)c21
Product: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Yield: 82 %

Procedure:
Following the procedure as described in EXAMPLE 1.22, and making non-critical variations using 3-(4-bromo-2-hydroxyphenyl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 4,7-dichloro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 82% yield as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.33 (td, 1H), 7.15-7.14 (m, 2H), 7.04 (dd, 1H), 6.96-6.90 (m, 2H), 6.56 (d, 1H), 4.95 (d, 1H), 4.69 (d, 1H), 3.89-3.64 (m, 2H), 1.80-1.68 (m, 2H), 1.43-1.34 (m, 4H), 0.92 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.6, 161.6, 142.5, 132.1, 129.1, 128.4, 124.4, 123.9, 123.3, 122.8, 114.1, 108.8, 80.4, 57.6, 40.4, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 386.3 (M+1), 388.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH3:20])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[CH:13]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=1[O:33][CH3:34]>O1CCOCC1.C(OCC)(=O)C.[Ag-]=O>[CH:1]1([CH2:6][N:7]([CH3:20])[C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[CH:14]=[C:13]3[CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]=2[O:33][CH3:34])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(CC1CCCC1)C(=O)c1ccc2c(ccn2C)c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(=O)N(C)CC4CCCC4)cc23)c(OC)c1
Yield: 13.2 %

Procedure:
Silver(I) oxide (0.30 g) was added to a solution of 5-[N-(cyclopentylmethyl)-N-methylcarbamoyl]-1-methylindole (G) (0.35 g) in dioxane (2 ml). The mixture was protected from light, stirred, and heated to reflux under an atmosphere of nitrogen for 2 hours. A solution of methyl 4-bromomethyl-3-methoxybenzoate (B) (0.33 g) in dioxane (1 ml) was added and the mixture was heated to reflux for an additional 18 hours. The mixture was then diluted with ethyl acetate and filtered. The filtrate was evaporated to give an amber gum which was purified by flash chromatography on silica gel (223 ml), eluting with chloroform to give the title compound (75.2 mg, 13%) as a white foam; partial nmr (80 MHz, CDCl3): 3.01(s, 3H, CONCH3), 3.51(br d, 2H, NCH2), 3.74(s, 3H, NCH3), 3.89(s, 3H, OCH3), 3.92(s, 3H, OCH3), 4.10(s, 2H, ArCH2), 6.81(s, 1H, H2 -indole).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14](=[O:15])[CH:16]=[C:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C(C)(C)C)CC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
4-tert-Butylcyclohexanone (8.62 g, 56 mmol) was dissolved in toluene (200 ml). Methoxycarbonylmethylenetriphenylphosphorane (56.1 g, 168 mmol) was added with stirring and the reaction mixture was heated under reflux for 3 days. The solvent was removed in vacua. The residue was dissolved in hot hexanes (100 ml) and cooled to room temperature. The precipitate was filtered off and the filtrate was evaporated in vacuo to afford a yellow oil which was then purified by chromatography (silica gel, hexane/ethyl acetate, 2:1 as eluant) to give the title compound as an oil (10.78 g, 92%). 1H-NMR; δ (CDCl3) 5.60 (1H, s), 3.87 (1H, m), 3.69 (3H, s), 2.38-2.10 (2H, m), 2.03-1.77 (3H, m), 1.36-1.02 (3H, m) and 0.87 (9H, s).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH3:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C@H:6]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH3:7]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1=NCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1=NCCO1
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
In a small vial, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4,5-dihydro-oxazol-2-yl)-ethyl]-amide (85 mg, 0.16 mmol) was dissolved in tetrabutylammonium fluoride (1.0 M in THF, 1.6 ml, 1.6 mmol). The yellow reaction mixture was stirred at 60° C. overnight then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-5% MeOH) to afford 27 mg (40%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4,5-dihydro-oxazol-2-yl)-ethyl]-amide as an off-white solid. MS: (M+Na)+=430; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.93 (br. s., 1H), 9.14 (s, 1H), 8.69 (dd, J=9.1, 5.3 Hz, 1H), 8.57 (d, J=8.3 Hz, 1H), 8.49 (s, 1H), 7.69 (dd, J=9.8, 1.9 Hz, 1H), 7.14 (td, J=9.1, 2.3 Hz, 1H), 4.97 (quin, J=7.5 Hz, 1H), 4.27-4.39 (m, 2H), 4.16 (s, 3H), 3.79 (td, J=9.3, 4.3 Hz, 2H), 1.50 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24][OH:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>C(Cl)Cl.CS(C)=O.CCN(CC)CC.[Cl-].[Na+].O>[CH2:1]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH:23]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH:24]=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccccc1CC(CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccccc1CC(C=O)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of the alcohol from Step B (135 mg, 0.29 mmol) in CH2Cl2, (1.0 ml), DMSO, (1.0 ml) and Et3N (0.2 ml) at room temperature under argon was added pyridine-SO3 complex (185 mg, 1.17 mmol). The mixture was stirred for 3 hrs and then poured into brine, and extracted with EtOAc. The organic extracts were combined, washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[C:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)C=C1CCc2cc(OC)ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1CCc2cc(OC)ccc2C1
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of (6-methoxy-3,4-dihydro-1H-napthalen-2-ylidene)-acetic acid ethyl ester (4.4 g, 18 mmol) in ethyl acetate (35 mL) was hydrogenated over 10% Pd—C (0.9 g) at 50 psi and left overnight. The reaction mixture was filtered through diatomaceous earth and washed with ethyl acetate (200 mL). The filtrate was concentrated to give the title compound (4.0 g, 91% yield) as a clear, colorless oil.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Cl.[C:20]1([S:26]([N:29]2[C:33]3=[N:34][CH:35]=[C:36]([N+:45]([O-:47])=[O:46])[C:37]([NH:38][CH:39]4[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]4)=[C:32]3[CH:31]=[CH:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH:16]1[C:17]2[CH:5]([CH2:4][O:3][C:1]([N:41]3[CH2:42][CH2:43][CH2:44][CH:39]([NH:38][C:37]4[C:36]([N+:45]([O-:47])=[O:46])=[CH:35][N:34]=[C:33]5[N:29]([S:26]([C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=6)(=[O:28])=[O:27])[CH:30]=[CH:31][C:32]=45)[CH2:40]3)=[O:2])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Fmoc-Cl (3.16 g, 12.2 mmol) was added to a solution of crude (1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-yl)-piperidin-3-yl-amine hydrochloride (5.34 g, 12.2 mmol) and diisopropylethylamine (5.31 ml, 30.5 mmol) in CH2Cl2 (100 ml) at 0° C. The reaction mixture was warmed to 25° C. and stirred for 18 h, then was partitioned between half-saturated NaHCO3 (225 ml) and CH2Cl2 (2×200 ml). The combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (gradient: 0 to 70% EtOAc in heptanes) to afford 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (7.09 g, 93%) as a yellow solid. This material was used in the next step below without additional characterization or purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][CH:5]=1.Cl[C:37]1[S:38][C:39]2[C:44]([Cl:45])=[N:43][C:42]([CH:46]3[CH2:48][CH2:47]3)=[N:41][C:40]=2[N:49]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:37]3[S:38][C:39]4[C:44]([Cl:45])=[N:43][C:42]([CH:46]5[CH2:47][CH2:48]5)=[N:41][C:40]=4[N:49]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[O:11])=[CH:32][CH:33]=1
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Reactant: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a mixed solution of the compound (0.94 g) obtained in Example 783, the compound (0.48 g) obtained in Step 5 and chloroform (2.8 ml) was added N,N-diisopropylethylamine (0.30 ml) at room temperature. The mixture was stirred at room temperature for 30 min, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:chloroform=1:2) to give the title compound (1.3 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:14][CH3:13])[CH:8]=2)[N:3]=[CH:2][CH:11]=1
Reactant: C[O-]
Reactant: Clc1cc(Cl)c2ccccc2n1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2nccc(Cl)c2c1
Temperature: 25 °C
Yield: 85.7 %

Procedure:
2,4-Dichloroquinoline (2.5 g, 12.6 mmol) was dissolved in anhydrous toluene (20 ml), a suspension of sodium methoxide (2.5 g, 46.3 mmol) in anhydrous toluene (20 ml) was added and the mixture was heated under reflux for 16 hours. After cooling to room temperature the suspension was filtered, the filter cake washed once with toluene (50 ml), the combined filtrates were evaporated under reduced pressure to dryness to yield 2.1 g (10.8 mmol, 86%) of a red solid. MS (ES) m/z=193.1 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][C:16]([NH2:30])=[N:17][C:18]=2[O:22]CC1C=CC=CC=1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:12][N:13]1[CH:21]=[N:20][C:19]2[C:18](=[O:22])[NH:17][C:16]([NH2:30])=[N:15][C:14]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H]1CC=CC[C@@H]1Cn1cnc2c(OCc3ccccc3)nc(N)nc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H]1CCCC[C@@H]1Cn1cnc2c(=O)[nH]c(N)nc21

Procedure:
A suspension of 9-{[1(R)-acetoxymethyl-2(S)-cyclohex-4-enyl]methyl}2-amino-6-benzyloxypurine (0.75 mmol), ethanol (5 mL) and a catalytic amount of 10% Pd/C was stirred under a hydrogen balloon for 3 hours. The reaction was filtered and concentrated to yield the desired compound. 1HNMR (500 mHz, d6DMSO): 10.80 ppm (bs, 1H); 7.65 (s, 1H); 6.48 (s, 2H); 4.15-3.88 (m, 4H); 2.23 (bs, 1H); 2.01 (s, 3H); 1.92 (m, 1H); 1.68-1.15 (m, 8H).