Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]3[CH2:15][O:14]3)=[CH:7][C:5]=2[N:6]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)C>[OH:14][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:15][N:19]1[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1nc2cc(OCC3CO3)ccc2s1
Solvent: CCO
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To 2-methyl-5-(oxiran-2-ylmethoxy) benzothiazole (2.21 g, 10 mmol), a compound of formula (3), was added tert-butyl 1-piperazinecarboxylate (1.86 g, 10 mmol), a compound of formula (4), and ethanol (30 ml). The resulting solution was heated to 85° C. and stirred for 8 hours. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:15][C:16]([C:17]([NH:19][C@@H:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:21]([OH:23])=[O:22])=[O:18])=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O/[N:56]=[C:57](\[NH2:59])/[CH3:58]>CN(C=O)C.O>[NH2:59]/[C:57](=[N:56]\[O:22][C:21](=[O:23])[C@@H:20]([NH:19][C:17]([C:16]1[N:15]=[C:14]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=12)=[O:18])[C:24]([CH3:26])([CH3:27])[CH3:25])/[CH3:58]
Reactant: CC(C)(C)OC(=O)N1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)O)C(C)(C)C)c2C1
Reactant: C/C(N)=N/O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: C/C(N)=N/OC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C
Reaction time: 0.5 h

Procedure:
Intermediate 22B (0.25 g, 0.55 mmol) was dissolved in DMF and EDCI (0.17 g, 0.87 mmol) was added, followed by HOBt (0.12 g, 0.87 mmol). The resulting mixture was stirred for 30 min and (Z)-N′-hydroxy-acetimidamide (0.06 g, 0.82 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed successively with water, 2N Na2CO3 solution and brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used in the next step without purification. LCMS (+ESI) m/z 1025.2 [2M+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4](NC1CC1)=[O:5].[C:13]1([CH2:23][NH2:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[NH2:1][C@@H:2]([CH2:11][CH3:12])[C@H:3]([OH:10])[C:4]([NH:24][CH2:23][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)=[O:5]
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Reactant: NCc1cccc2ccccc12
Product: CC[C@H](N)[C@H](O)C(=O)NCc1cccc2ccccc12

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide, Representative Procedure B, using naphthalen-1-ylmethanamine in the seventh step (step B7).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:9][C@H:10]([C:14]([OH:16])=O)[CH:11]([CH3:13])[CH3:12].[CH3:17][Si](Cl)(C)C>CO>[CH3:17][O:7][C:6](=[O:8])[C@H:2]([CH:3]([CH3:5])[CH3:4])[NH:1][C:14](=[O:16])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH2:9]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C

Procedure:
The title compound is prepared by the procedure of Example 7 using 0.50 g of L-valine-L-valine, 10 ml of methyl alcohol and 0.689 ml of trimethylsilyl chloride to give 0,657 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc2[nH]c(=O)[nH]c2c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2[nH]c(Cl)nc2c1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 5-methyl-1,3-dihydrobenzimidazol-2-one (2) (24.4 g) and phosphoryl chloride (245 mL) was stirred at 90° C. for 5 hr. After cooling to room temperature, chloroform (250 mL) was added to the reaction mixture. After stirring at room temperature, the resulting precipitate was collected by filtration, and washed 5 times with chloroform (100 mL). To the precipitate was added a mixture of ethyl acetate and saturated sodium hydrogen carbonate solution. After stirring at room temperature, the organic phase was successively washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was powdered with hexane and diisopropyl ether to give 2-chloro-5-methyl-1H-benzimidazole (3) (20.4 g).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[NH:16]2)=[CH:11][CH:10]=1>[OH-].[Na+]>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23](=[O:24])[C:22]3[C@@H:21]4[C:25]([CH3:27])([CH3:26])[C@@:18]([CH3:28])([CH2:19][CH2:20]4)[C:17]=3[N:16]2[CH3:5])=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(Cl)cc3)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c2c(c(=O)n1-c1ccc(Cl)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.8 %

Procedure:
Dimethyl sulfate (84 μL, 0.92 mmol) was added to a solution of (4S,7R)-2-(4-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 11; 252 mg, 0.83 mmol) in 1 M NaOH (3 mL) and the resulting solution was stirred at room temperature overnight. The aqueous supernatant was decanted away from the red gum, and the gum was dissolved in ethyl acetate. This solution was washed with water, dried (sodium sulfate), filtered, evaporated, and purified by chromatography using a Waters Sep-Pak® column, eluting with 20% ethyl acetate/hexanes to elute 2-(4-chloro-phenyl)-3-methoxy-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole, and then a step gradient of 50% ethyl acetate/hexanes, 66% ethyl acetate/hexanes, and finally 4% methanol/ethyl acetate to give (4S,7R)-2-(4-chloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (18 mg, 7%). ES(+)-MS (M+H) 317.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([F:25])=[CH:23][C:22]([N+:26]([O-])=O)=[CH:21][C:10]=1[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:26][C:22]1[CH:23]=[C:24]([F:25])[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([CH:21]=1)[CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cc(N)cc(F)c1OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 17E (2.789 g, 7.14 mmol) in methanol (40 mL) and THF (10 mL) was added zinc (dust) (4.67 g, 71.4 mmol) and ammonium chloride (7.64 g, 143 mmol). The resulting solution was stirred at rt for 30 min, then at 40° C. overnight. MeOH was removed under reduced pressure, Na2CO3 (aq, 100 mL) and EtOAc (150 mL) were added, and the suspension was stirred vigorously for 10 min. The mixture was filtered though glass frit, solid residue was washed with EtOAc (3×150 mL). Combined EtOAc fractions were washed with sat. Na2CO3 (aq, 2×50 mL), water (2×50 mL), brine (1×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-100% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 17F (2.566 g, 7.12 mmol, 100% yield) as a yellowish oil, which solidified upon standing. MS (ESI) m/z: 361.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.30-7.46 (5H, m), 6.37 (1H, dd, J=12.55, 2.76 Hz), 6.11-6.30 (1H, m), 4.94 (2H, s), 4.20-4.39 (2H, m), 3.58 (2H, s), 2.70 (3H, d, J=7.53 Hz), 1.36-1.54 (9H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31]Cl)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH3:35][NH:36][CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31][N:36]([CH3:37])[CH3:35])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NC(=O)CCl)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CC(=O)N=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-chloroacetyl sulfoximide (100 mg, 0.185 mmol, Example 6) in DMF (0.2 mL) was added 50% aqueous dimethylamine solution (164 mg, 0.162 mmol) followed by catalytic amount of KI. The reaction mixture was stirred at 25-30° C. for 12 hr and then diluted with water (5 mL). Filtration and drying afforded 50 mg of titled compound in 49% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[CH3:21][C:22]1[N:30]2[C:25]([C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]2)=[C:24]([CH2:32][N+](C)(C)C)[CH:23]=1.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:32][C:24]2[CH:23]=[C:22]([CH3:21])[N:30]3[C:25]=2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cccn2c(C)cc(C[N+](C)(C)C)c12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(C)n3cccc(C)c23)c2ccccc21
Yield: 26 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide, CAS: (3,8-Dimethyl-indolizin-1-ylmethyl)-trimethyl-ammonium; iodide (93.4 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(3,8-Dimethyl-indolizin-1-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (20 mg, 26%) as a colorless foam.
Reaction SMILES: C([O-])(O)=O.[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][C:12](Cl)=[O:13].[C:15]1([S:21][CH2:22][CH2:23][S:24][C:25]2[C:30]([NH2:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC>O1CCOCC1>[C:15]1([S:21][CH2:22][CH2:23][S:24][C:25]2[C:30]([NH:31][C:12](=[O:13])[CH2:11][C:7]3[S:6][CH:10]=[CH:9][CH:8]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Nc1cccnc1SCCSc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: O=C(Cc1cccs1)Nc1cccnc1SCCSc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
420 mg (5.0 mmol) NaHCO3 and 402 mg (2.5 mmol) 2-(thiophen-2-yl)acetic acid chloride were added to a solution of 262 mg (1.0 mmol) [2-(2-phenylsulfanyl-ethylsulfanyl)-pyridin-3-yl]amine (VPF-006) in dioxane (25 ml) at 0° C. and then the mixture was stirred for 16 h at RT. Then it was diluted with EE and washed with water and brine. The organic phase was dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 9:1) of the residue yielded 186 mg (0.5 mmol, 48%) N-[2-(2-phenylsulfanyl-ethylsulfanyl)-pyridin-3-yl]-2-thiophen-2-yl acetamide. MS: m/z 387.1 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[S:10][C:9]2[C:11]3[C:16]([CH2:17][C:8]=2[C:7]=1[C:18]([NH2:20])=[O:19])=[CH:15][CH:14]=[CH:13][CH:12]=3.C(OCC)C>N1C=CC=CC=1>[C:1]([NH:5][C:6]1[S:10][C:9]2[C:11]3[C:16]([CH2:17][C:8]=2[C:7]=1[C:18]([NH2:20])=[O:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)Nc1sc2c(c1C(N)=O)Cc1ccccc1-2
Reaction time: 2 h
Yield: 87 %

Procedure:
Acetyl chloride (0.039 g, 0.5 mmol) was added dropwise to a stirred solution of 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide(0.115 g, 0.5 mmol) in dry pyridine (3 mL) at room temperature. The resulting reaction mixture was stirred under nitrogen for 2 h. Ethyl ether (20 mL) was then added to the reaction mixture. The reaction mixture was allowed to stir an additional 10 minutes. The reaction mixture was then filtered, washed with excess ethyl ether, air dried to give the title compound as light brown solid (0.082 g, 0.435 mmol, 60.3% yield). ESMS m/z: 273 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:10][CH2:11][C:12]#[CH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39](Cl)=[N:40][OH:41])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[CH:13]=[C:12]([CH2:11][NH:10][C:9]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[O:41][N:40]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Reactant: C#CCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
1-(2,3-bis(tert-butoxycarbonyl)guanidino)prop-2-yne (362 mg, 1.22 mmol) was added to the solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (473 mg, 1.53 mmol) in dry DCM (20 mL) at rt, followed by dropwise addition of TEA (0.16 g, 1.53 mmol). The mixture was stirred at rt for 2 hrs and then concentrated. The residue was purified by silica gel column chromatography (gradient elution 1:15 to 1:5 EtOAc/Hexanes) to give (2S,5R)-6-(benzyloxy)-2-(5-((2,3-bis(tert-butoxycarbonyl)guanidino)methyl)isoxazol-3-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (190 mg, 22% for two steps) as a white solid. ESI-MS (EI+, m/z): 571.2 [M+H]+. 1H NMR (500 MHz, CDCl3): δ 11.49 (s, 1H), 8.86 (bs, 1H), 7.47-7.34 (m, 5H), 6.32 (s, 1H), 5.09 (d, J=11.5 Hz, 1H), 4.93 (d, J=12.0 Hz, 1H), 4.87-4.76 (m, 2H), 4.59 (d, J=7.0 Hz, 1H), 3.36 (s, 1H), 2.87-2.85 (m, 1H), 2.70 (d, J=12 Hz, 1H), 2.35-2.30 (m, 1H), 2.24-2.18 (m, 1H), 2.10-2.05 (m, 1H), 1.81-1.78 (m, 1H), 1.50 (s, 18H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@H:9]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)/[CH:10]=[CH:11]/[C@@H:12]2[C@@H:19]3[C@@H:15]([O:16][C:17](=[O:20])[CH2:18]3)[CH2:14][C@H:13]2[O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C@H:9]([O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)/[CH:10]=[CH:11]/[C@@H:12]2[C@@H:19]3[C@@H:15]([O:16][CH:17]([OH:20])[CH2:18]3)[CH2:14][C@H:13]2[O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 128 %

Procedure:
(3aR,4R,5R,6aS)-hexahydro-4-((S,E)-5-phenyl-3-(tetrahydro-2H-pyran-2-yloxy)pent-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)cyclopenta[b]furan-2-one (14.0 g from Example 46) was dissolved in toluene (140 mL), followed by cooling to −70° C., and DIBAL (1.0M in Hexane, 45 mL) was added dropwisely. Then the reaction was quenched by adding saturated aqueous solution of ammonium chloride (10 mL) at −70° C. The resulting mixture was poured into 90 mL of a 2M sodium bisulfate aqueous solution at room temperature and stirring was continued for 30 minutes. After separation of the organic layers, 200 mL of toluene was added to the aqueous layer. The combined organic layers were concentrated under reduced pressure to give 18.0 g of crude title compound.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C([O-])([O-])=O.[K+].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]>CN(C=O)C.CCOC(C)=O>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of hydroquinone (3.2 g, 29.0 mmol) and K2CO3 (8.0 g, 54.0 mmol) in 40 mL of DMF was heated at 100° C. with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g, 19.3 mmol) with stirring for 24 hours. Cooled to room temperature and diluted with EtOAc. Washed with water and dried the organic layer over MgSO4. Filtered and concentrated under vacuum giving the title compound, which was purified by silica gel column chromatography eluting with 5% EtOAc/hexane giving an orange oil (1.89 g, 40%).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[NH2:8]/[C:9](/[CH3:16])=[CH:10]\[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:10](=[C:9](/[NH2:8])\[CH3:16])/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:7]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: C#CC(=O)OCC
Product: CCOC(=O)/C=C/C(C(=O)OCC)=C(\C)N
Temperature: 90 °C

Procedure:
Ethyl propiolate (39.2 g, 41 mL, 400 mmol) was added to ethyl 3-aminocrotonate (51.75 g, 400 mmol) and the mixture heated at 90° C. for 90 minutes to give a dark red oil. The mixture was allowed to cool, to give the product as a dark orange solid, 87.0 g (96%).
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[C:18]2=[O:34])=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:23]=[CH:24][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:27]=3)[C:18]2=[O:34])=[CH:15][CH:16]=1)[CH3:10]
Reactant: COC(=O)CCc1ccc(C2CCN(c3ccc(C(C)NC(=O)OC(C)(C)C)cc3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCc1ccc(C2CCN(c3ccc(C(C)N)cc3)C2=O)cc1

Procedure:
Prepared from 1-[4-[1-[(tert.butyloxycarbonyl)-amino]ethyl]-phenyl]-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-pyrrolidin-2-one by stirring for 2 hours in a 1:1 mixture of methylene chloride and trifluoroacetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)([O-:3])=[O:2].C(O)C.[CH3:16][C:17]1([CH3:31])[CH2:22][CH2:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:16][C:17]1([CH3:31])[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:19][CH2:18]1
Reactant: CC1(C)CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=[N+]([O-])c1ccccc1B(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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-nitrophenylboronic acid (14.2 g, 85.19 mmol) in toluene (250 mL)-ethanol(125 mL) were added trifluoromethanesulfonic acid 4,4-dimethylcyclohex-1-enyl ester (20 g, 77.44 mmol) prepared in Example (1a), tetrakis(triphenylphosphine)palladium(0) (4.5 g, 3.87 mmol) and 2N aqueous sodium carbonate (128 mL, 256 mmol). The mixture was stirred at an external temperature of 100° C. for 1 hour and 45 minutes under a nitrogen atmosphere.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[C:14]3[NH:21][CH:20]=[C:19]([C:22]([OH:24])=O)[C:15]=3[N:16]=[CH:17][N:18]=2)[CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:22]([C:19]2[C:15]3[N:16]=[CH:17][N:18]=[C:13]([C:7]4[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:14]=3[NH:21][CH:20]=2)=[O:24])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A76) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: C([O:9][CH2:10][C@H:11]1[S:15][C@@H:14]([N:16]2[CH:31]=[CH:30][C:20]([NH:21]C(=O)C3C=CC=CC=3)=[N:19][C:17]2=[O:18])[CH2:13][O:12]1)(=O)C1C=CC=CC=1>N>[OH:9][CH2:10][C@H:11]1[S:15][C@@H:14]([N:16]2[CH:31]=[CH:30][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:13][O:12]1
Reactant: O=C(Nc1ccn([C@H]2CO[C@@H](COC(=O)c3ccccc3)S2)c(=O)n1)c1ccccc1
Agent: N
Product: Nc1ccn([C@H]2CO[C@@H](CO)S2)c(=O)n1
Reaction time: 8 h

Procedure:
2-(R)-benzoyloxymethyl-4-(R)—(N-benzoylcytosin-1-yl)-1,3-oxathiolane (15 g, 0.028 mol) was dissolved in a methanolic ammonia (approximately 2M) solution (250 mL). The initial slurry was stirred overnight. After overnight stirring, the resulting clear solution was filtered through celite, evaporated to dryness and slurried in acetone (100 mL). This yielded off-white powdery solid which was filtered and washed with acetone (2×25 mL), and dried to yield the product. 6.5 g (94%).
Reaction SMILES: C[O:2][C:3]1[N:4]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[C:10]([N:11]=1)=[C:9]([NH2:12])[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=2.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:12][C:9]1[N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:6]=[C:5]2[C:10]=1[NH:11][C:3](=[O:2])[N:4]2[CH2:19][CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: CCCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.7 %

Procedure:
To a solution of 8-methoxy-N2-pentyl-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (140 mg) in dry MeOH (15.7 mL) was added 4N HCl in 1,4-dioxane (2.65 mL). The reaction mixture was stirred at room temperature for 3 h and was then neutralised with 2M sodium hydroxide solution. The mixture was concentrated in vacuo and the residue was taken up into water (20 mL). The mixture was filtered under reduced pressure to give the title compound (95 mg) as an off-white solid.