Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][NH2:14].O>C1(C)C=CC=CC=1>[CH3:10][O:11][CH:12]([O:15][CH3:16])[CH2:13][N:14]1[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]1=[O:8]
Reactant: COC(CN)OC
Reactant: CC1=C(C)C(=O)OC1=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(CN1C(=O)C(C)=C(C)C1=O)OC

Procedure:
84 g (0.66 mol) of dimethylmaleic anhydride are dissolved in 150 ml of toluene, and 70 g (0.66 mol) of aminoacetaldehyde dimethyl acetal are added. The solution is heated to the boil, and the water formed is separated off by means of a water separator. When the reaction is complete, the solvent is removed by distillation, and the residue is distilled, giving 127 g (90% of theory) of the product of boiling point 160° C. at 0.03 mbar which is a single product according to TLC and GC. NMR data: 2.97 (s) 6-methyl protons, 3.34 ppm (s) 6 methoxy protons, 3.61 ppm (d) 2 methyl protons, 4.66 ppm (t) 1 acetal proton.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]1[N:12]1[CH:20]=[N:19][C:18]2[C:13]1=[N:14][CH:15]=[N:16][C:17]=2[NH2:21].O.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38](ON3C(=O)CCC3=O)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:1][C@@H:2]3[C@@H:7]([OH:8])[C@H:6]([OH:9])[C@@H:5]([CH2:10][OH:11])[O:4][C@H:3]3[N:12]3[CH:20]=[N:19][C:18]4[C:13]3=[N:14][CH:15]=[N:16][C:17]=4[NH2:21])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
To 0.69 g (2.33 mmol) of 9-(2-amino-2-deoxy-β-D-glucopyranosyl)adenine was added 3.45 mL of H2O. To this solution was added a 28 mL 1,4-dioxane solution of 0.94 g (2.80 mmol) of N-(9-fluorenylmethoxycarbonyloxy)succinimide. This resulted in a cloudy mixture. To this system was added 0.13 g (1.50 mmol) of NaHCO3. This mixture was stirred for 12 h at room temperature. At this time, TLC indicated the consumption of starting material and the mixture was concentrated in vacuo to a dry residue. This residue was stirred for 18 h in 250 mL of Et2O and 250 ml of H2O. The suspension was then filtered and the solid dried in a vacuum oven for 2 days. Thus was obtained 1.0 g (82%) of the desired 9-[2-deoxy-2-[[(9H-fluoren-9-ylmethoxy)carbonyl]-amino]-β-D-glucopyranosyl]adenine 1H NMR: (DMSO-d6): adenine aromatic 8.19 (s, 1H), adenine aromatic 8.17 (s, 1H), anomeric H-1 6.60 (d, 1H), Fmoc-methine 4.17 (m, 1H). FAB-MS: m/z 519 for (M+1)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:39](=[O:38])[CH2:40][OH:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C.[CH:27]([Mg]Cl)([CH3:29])[CH3:28]>C1COCC1>[CH3:28][CH:27]([CH3:29])[C:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([C:14]2[CH:15]=[N:16][C:17]3[NH:8][CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:23]=1)([OH:26])[CH3:25]
Reactant: CC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(=O)OC(C)(C)C)c1
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1cncc(-c2cnc3c(c2)CCCN3)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of 6-(5-acetyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (125 mg, 0.35 mmol) in THF (2 mL) is added a solution of isopropylmagnesium chloride in THF (1.3M, 816 μL, 1.1 mmol). The resultant mixture is stirred warming to room temperature for 1 h. The reaction is quenched with saturated aqueous ammonium chloride solution and is extracted with EtOAc. The combined organic extracts are washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure. The residue is taken up in MeOH (3 mL) and 4N HCl in 1,4-dioxane (3 mL) is added. The reaction is stirred at room temperature for 16 h and is concentrated to provide 3-methyl-2-[5-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-butan-2-ol (131 mg) as the dihydrochloride salt.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[N:13]=1)=[N:7]2.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:30][C:31]1[N:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:23][O:22][C:14]1[N:13]=[C:12]([C:6]2[N:7]=[C:8]3[C:3]([C:2]([NH:30][C:31]4[N:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][N:36]=4)=[CH:11][CH:10]=[N:9]3)=[CH:4][CH:5]=2)[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=1
Reactant: COc1ccc(C(F)(F)F)c(-c2ccc3c(Cl)ccnc3n2)n1
Reactant: Nc1ncc(C(F)(F)F)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(F)(F)F)c(-c2ccc3c(Nc4ncc(C(F)(F)F)cn4)ccnc3n2)n1
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a de-gassed mixture of 5-chloro-2-(6-methoxy-3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (68 mg, 0.2 mmol), cesium carbonate (98 mg, 0.3 mmol), 2-amino-5-trifluoromethylpyrimidine (37 mg, 0.22 mmol) in dioxane (5 mL) under nitrogen, add Pd2 dba3 (12 mg) and xantphos (8 mg). Stir the mixture at 100° C. for 14 hours, cool, add water (20 mL) and extract with EtOAc. Dry the combined extracts over Na2SO4, and concentrate under vacuum. Purify by chromatography eluting with DCM/MeOH/ammonium hydroxide mixture to give the title compound. 1H NMR δ (CDCl3) 9.14 (1H, d), 8.81 (2H, s), 8.56 (2H, d), 8.40 (1H, brs), 7.99 (2H, dd), 7.26 (1H, s), 6.92 (1H, d), 4.01 (3H, s). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:34])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=3)[CH2:23][C:22](=[O:34])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(C2=Nc3ccc(-c4ccccc4F)cc3NC(=O)C2)ccn1

Procedure:
Prepared from {3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K64) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a green solid (40 mg).
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C1CO[C:13]2([C:19]3[CH:20]=[CH:21][C:22]([CH2:24][C:25]([OH:27])=[O:26])=[CH:23][C:18]=3[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]2=3)[O:12]1>CC(C)=O.CCCCCC>[CH:23]1[C:18]2[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=3[C:13](=[O:12])[C:19]=2[CH:20]=[CH:21][C:22]=1[CH2:24][C:25]([OH:27])=[O:26]
Reactant: O=C(O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is dissolved in 20 ml. of acetone and to the solution is added 20 ml. of N-hydrochloric acid. The mixture is refluxed for 1 hour, then cooled, diluted with water, and extracted with ethyl acetate. The extract is washed, dried and evaporated to give a 90% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][CH:12]([NH:14][C:15]3[C:16]([CH3:27])=[N:17][O:18][C:19]=3[C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)[CH3:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B1OC(C)(C)C(C)(C)O1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:23]1[CH:24]=[CH:25][C:20]([C:19]2[O:18][N:17]=[C:16]([CH3:27])[C:15]=2[NH:14][CH:12]([CH3:13])[CH2:11][CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[CH:21][CH:22]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(C)CCc2ccc3c(c2)OCO3)cc1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using (3-benzo[1,3]dioxol-5-yl-1-methyl-propyl)-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-amine and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: CNC1C=CC=CC=1C(N)=O.[CH3:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([N:18]=C=S)=[O:17]>CCOCC>[CH3:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([NH2:18])=[O:17]
Reactant: Cc1cccc(C(=O)N=C=S)c1
Agent: CNc1ccccc1C(N)=O
Solvent: CCOCC
Product: Cc1cccc(C(N)=O)c1

Procedure:
To a stirred mixture of 7.97 g of 2-methylaminobenzamide and 200 ml of ether was added dropwise, a solution of 10 g of 3-methylbenzoyl isothiocyanate in ether over 10 minutes. After 48 hours the solid was collected, giving 15.5 g of N-[[[2-aminocarbonyl)phenyl]methylamino]thioxomethyl]-3-methylbenzamide.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)[C:16]3=[N:15][CH:14]=2)=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:17]3[CH:18]=[CH:19][N:20]=[C:21]([NH:22][CH2:23][C:24]4[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=4)[C:16]3=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: COc1ccc(-c2cnc3c(NCc4cccc(S(N)(=O)=O)c4)nccn23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(CNc2nccn3c(-c4ccc(O)cc4)cnc23)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
BBr3 (2.81 mL, 1.0M in DCM, 2.81 mmol) is added to a suspension of 3-{[3-(4-Methoxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide (0.115 g, 0.281 mmol) in DCM (3 mL) at −78° C. under nitrogen atmosphere. The reaction is allowed to warm to r.t and monitored by analytical HPLC. After 2 h the reaction is complete and is cooled to −78° C., quenched with a solution of saturated aqueous K2CO3. The reaction is diluted with AcOEt, washed with water, dried with MgSO4 anh., filtered and evaporated to give 0.058 g of 3-{[3-(4-Hydroxy-phenyl)-imidazo[1,2-a]pyrazin-8-ylamino]-methyl}-benzenesulfonamide as a brown oil (52%). No further purification was required. LC-MS m/z 396 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9](Br)[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O)[CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:10]=[C:9]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[O:18][CH2:16][CH3:17])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(Br)c([N+](=O)[O-])cc1O
Reactant: CCOc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(C(C)(C)C)c(O)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 97.2 %

Procedure:
To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30 mmol) in DMF (90 mL) was added 2-ethoxyphenyl boronic acid (5.48 g, 33 mmol), potassium carbonate (4.56 g, 33 mmol), water (10 ml) and Pd(PPh3)4 (1.73 g, 1.5 mmol). The mixture was heated at 90° C. for 3 h under nitrogen. The solvent was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried and purified by column chromatography (petroleum ether-ethyl acetate, 10:1) to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (9.2 g, 92%). 1HNMR (DMSO-d6) δ 10.38 (s, 1H), 7.36 (s, 1H), 7.28 (m, 2H), 7.08 (s, 1H), 6.99 (t, 1H, J=7.35 Hz), 6.92 (d, 1H, J=8.1 Hz), 3.84 (q, 2H, J=6.6 Hz), 1.35 (s, 9H), 1.09 (t, 3H, J=6.6 Hz); ESI-MS 314.3 m/z (MH+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([O:14]CC)=O.C(N(CC)CC)C.[C:24]1([NH:30][NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC1C=CC=CC=1C>[C:24]1([N:30]2[C:12](=[O:14])[C:3]3=[CH:4][NH:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]3=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=c1c2c[nH]c3ccccc3c-2nn1-c1ccccc1

Procedure:
A suspension of ethyl 4-chloro-quinoline-3-carboxylate (3a) (2.35 g, 0.01 M) in 20 mL of o-xylene was refluxed with triethylamine (2.0 mL, 0.02 M) and phenyl hydrazine (2.89 g, 0.02 M) overnight. The crude product was obtained by filtration followed by washing the solid with cold methanol.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[NH2:9][CH2:10][CH:11]1[O:15][CH2:14][CH:13]([S:16][C:17]2[CH:23]([CH3:24])[CH:22]3[N:19]([C:20](=[O:28])[CH:21]3[CH:25]([OH:27])[CH3:26])[C:18]=2[C:29]([OH:31])=[O:30])[CH2:12]1.C(O[CH:36](OC(C)C)[N:37]([CH3:39])[CH3:38])(C)C>>[CH3:36][N:37]([CH:39]=[N:9][CH2:10][CH:11]1[O:15][CH2:14][CH:13]([S:16][C:17]2[CH:23]([CH3:24])[CH:22]3[N:19]([C:20](=[O:28])[CH:21]3[CH:25]([OH:27])[CH3:26])[C:18]=2[C:29]([OH:31])=[O:30])[CH2:12]1)[CH3:38]
Reactant: CC(C)OC(OC(C)C)N(C)C
Reactant: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN=CN(C)C)C3)C(C)C12
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
Three ml of sodium phosphate buffer, pH 7, is cooled to 0° C. and 0.052 g of product from Example 46 is added. To this cooled solution is added, dropwise, 159 μl of N,N-dimethylformamide diisopropyl acetal, while maintaining the pH below 8.5. The reaction mixture is stirred at 0° C. for 35 minutes, pH adjusted to 7.0 and freeze-dried. The residue is purified by chromatography (C18 reverse phase tlc plates: 75% aqueous ethyl alcohol) to give 0.031 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH2:25])[CH3:21].[BH4-].[Na+]>CO>[CH2:20]([CH:22]([CH2:26][CH3:27])[CH2:23][CH2:24][NH:25][CH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=2)=[C:2]([F:1])[CH:17]=1)[CH3:21]
Reactant: CCC(CC)CCN
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)CCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 3-ethylpentylamine (Example 733, Part B) (0.317 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 10% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.516 g, 58%): TOF MS ES+ 360.2 (M+H)+, HRMS calcd for C20H27N3O2F 360.2087 (M+H)+, found 360.2086, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.3 min, 100% purity.
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].C(N(CC)CC)C.[CH2:36]([O:43][C:44]([NH:46][C@H:47]([C:55](O)=[O:56])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O.O1CCCC1>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:55](=[O:56])[C@H:47]([CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[NH:46][C:44]([O:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:45])[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O)OCc1ccccc1
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (384 mg) prepared in Example 1 and triethylamine (0.19 ml) in water (10 ml) was added a solution of N-hydroxysuccinimide ester of N-benzyloxycarbonyl-L-phenylalanine (635 mg) in tetrahydrofuran (10 ml) at room temperature under stirring, which was continued overnight. The mixture was evaporated to remove tetrahydrofuran, acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was triturated in diethyl ether to give 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-(N-benzyloxycarbonyl-L-phenylalanylamino)-β-D-ribofuranuronic acid (521 mg), mp. 145°-150° C. (dec.).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][C:11]3[C:12](=[N:13][CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=3)[N:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>[Pd].C(O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][C:11]3[C:12](=[N:13][CH:14]=[C:15]([NH2:17])[CH:16]=3)[N:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCn2c1nc1cc([N+](=O)[O-])cnc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC1CCn2c1nc1cc(N)cnc12

Procedure:
A suspension of 0.25 g (0.95 mmol) of 3-nitro-7,8-dihydro-6H-pyrrolo[2′,1′:2,3]imidazo[4,5-b]pyridin-6-yl acetate, obtained in the preceding step, and 0.21 g of 10% palladium on carbon in 60 ml of ethanol is stirred at 20° C. for 3 hours under five atmospheres of hydrogen. After this time the mixture is filtered on a bed of celite and then concentrated under reduced pressure. This gives 0.22 g of the expected product, which will be used as it is in the remainder of the synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:17])=[C:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[H][H]>[Pd].C(O)(=O)C.CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH3:17])[CH:12]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2=C(C)c3ccc(OC)cc3C3CCCCC23)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C2C(C)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 92.5 %

Procedure:
Combine 6-methoxy-10-(4-methoxy-phenyl)-9-methyl-1,2,3,4,4a,10a-hexahydro-phenanthrene (0.116 g, 0.347 mmol), Pd-Black (14.7 mg, 0.139 mmol) and acetic acid/methanol/tetrahydrofuran (1.0 mL, 10.0 mL, 3.0 mL) at 50 psi Hydrogen pressure. After 18 hours, filter off the Pd catalyst over celite eluting with ethyl acetate. Concentrate and flash chromatograph with 0% to 10% ethyl acetate/hexanes to yield the titled compound (0.108 g, 93%) as a clear oil. TLC Rf=0.30 in 5:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.26 (d, 1H, J=8.4 Hz), 7.03 (m, 3H), 6.83 (m, 3H), 3.90 (s, 3H), 3.83 (s, 3H), 3.36 (m, 2H), 3.12 (m, 1H), 2.52 (m, 1H), 2.35 (m, 1H), 1.87 (m, 1H), 1.51 (m, 4H), 1.30 (m, 2H), 1.18 (d, 3H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[F:25][C:2]([F:1])([F:24])[C:3]1[N:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1cnc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2N3)cn1
Reaction time: 8 h

Procedure:
To the intermediate of Example 181 Step A (100 mg, 0.3 mmol) in DCM (3 mL) was added 4M HCl in dioxane (0.8 mL). The reaction was allowed to proceed overnight then concentrated neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step A that was used without further purification.