Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CN(C=O)C.C(OCC)C>[Si:13]([O:1][C@H:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1OCC[C@@H]1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCOC1=O
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of (S)-3-hydroxydihydrofuran-2(3H)-one (91a, 5 g, 49 mmol) in anhydrous DMF (40 mL) was added imidazole (6.7 g, 98 mmol) and TBDMS-chloride (8.1 g, 54 mmol) and the reaction is stirred for 3 h. The reaction was diluted with diethyl ether and washed with 1N HCl×3. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed in vacuo to yield (S)-3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (91b) as a clear oil (10.6 g, 49 mmol). 1H NMR (400 MHz, CHLOROFORM-d) δ 0.15 (s, 3H), 0.18 (s, 3H), 0.86-0.99 (m, 9H), 2.23 (dq, J=12.63, 8.67 Hz, 1H), 2.46 (dddd, J=12.63, 7.58, 6.57, 3.28 Hz, 1H), 2.84-3.01 (m, 1H), 4.20 (td, J=9.16, 6.44 Hz, 1H), 4.33-4.47 (m, 2H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].C([Sn](CCCC)(CCCC)[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1)CCC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[CH:44]=[N:43][CH:42]=[CH:41][N:40]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnccn2)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Tris(dibenzylidene-acetone)dipalladium(0) (1 mg) was added to 5-iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoro-methyl)phenyl]-1,2-dihydropyridine-3-carboxamide (Example 1 (d), 20 mg, 0.034 mmol), 2-(tributylstannyl)pyrazine (25 mg, 0.068 mmol) and triphenylphosphine (1.6 mg, 0.006 mmol) in toluene (1.5 ml) under argon and the mixture was stirred in a sealed vial at 100° C. overnight. After cooling, the mixture was filtered through celite and evaporated. The residue was dissolved in toluene and ether was added. The precipitate was filtered off and dried in vacuo (5 mg, 27%).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:35])[NH:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30](O)[CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:17])([CH3:16])[CH3:15].O1CCOC1CC1C=CC(CO)=CC=1.OC1C=C(C=CC=1)C(C1C=CC=CC=1)=O>>[C:1]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:35])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCCO)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(O)c1
Agent: O=C(c1ccccc1)c1cccc(O)c1
Agent: OCc1ccc(CC2OCCO2)cc1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCCCOC(=O)c2ccccc2)c1

Procedure:
The title compound was prepared as described in Example 22 Step 3 with 3-hydroxypropyl benzoate (prepared as outlined in Organic & Biomolecular Chemistry, 8(24), 5505-5510; 2010, which is incorporated herein by reference in its entirety) and tert-butyl((3-hydroxyphenyl)(phenyl)methyl)carbamate (derived from the second eluting isomer Chiral Example 1 Step 4) replacing (4-((1,3-dioxolan-2-yl)methyl)phenyl)methanol and 3-hydroxybenzophenone respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:19]I>O1CCCC1.[Cl-].[Na+].O>[Si:10]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][CH3:19])[N:7]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(N)n1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNc1nccc(CO[Si](C)(C)C(C)(C)C)n1
Reaction time: 0.25 h
Yield: 20 %

Procedure:
Under a nitrogen atmosphere, a solution of 2-amino-4-(tert-butyldimethylsilyloxymethyl)pyrimidine (200 mg, 0.84 mmol, Reference Compound No. 5-1) in anhydrous tetrahydrofuran (4.0 mL) was added dropwise to a suspension of sodium hydride (60%, 37 mg, 0.92 mmol) in anhydrous tetrahydrofuran (1.0 mL) under ice-cooling. The mixture was stirred for 15 minutes under ice-cooling, then methyl iodide (57 μL, 0.92 mmol) was added thereto, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into brine (30 mL), then extracted with ethyl acetate (30 mL). The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 43 mg of the title Reference Compound as a colorless oil (Yield: 20%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:20](=[O:24])[CH2:21][CH2:22][CH3:23]>>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][N:12]=[C:11]([CH:14]([CH:20]([OH:24])[CH2:21][CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nsc(NC(=O)OC(C)(C)C)n1
Reactant: CCCC=O
Product: CCCC(O)C(C(=O)OCC)c1nsc(NC(=O)OC(C)(C)C)n1

Procedure:
1.0 g (3.5 mMol) of product from Example 28 were reacted with 0.9 ml (~10 mMol) of n-butanal for 5 days in the manner described in Example 29 and then purified by chromatography on silica gel. Yield 0.17 g (14% of theory).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH:26]=O)=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:4])=[O:3].[CH2:36]([NH:38][CH2:39][CH2:40][CH3:41])[CH3:37].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:18]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:26][N:38]([CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37])=[CH:21][CH:20]=3)=[C:11]2[C:7]=1[CH2:8][NH:9][C:10]2=[O:35])(=[O:3])=[O:4]
Reactant: COc1cc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Reactant: CCCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCN(CC)Cc1ccc2c(c1)cc(-c1cc(OC)c(OS(C)(=O)=O)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C
Yield: 59.8 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (100 mg, 0.200 mmol) was dissolved in acetonitrile (5.8 mL), and the solution was treated with N-ethyl-1-propylamine (0.242 mL, 2.00 mmol), acetic acid (0.229 mL, 4.00 mmol) and sodium triacetoxyborohydride (253 mg, 1.19 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-methanesulfonyloxy-5-methoxy-7-[1-(tert-butoxycarbonyl)-5-(N-ethyl-1-propylaminomethyl)indol-2-yl]isoindolinone (68.4 mg, yield 60%).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[CH:14]=[C:15]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=3)(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=2)[CH2:9]1
Reactant: O=S(=O)(Nc1cccc([C@@H]2CCN(Cc3ccccc3)C2)c1)c1cccc(OC(F)(F)F)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1cccc([C@@H]2CCNC2)c1)c1cccc(OC(F)(F)F)c1
Reaction time: 5 h
Yield: 44.4 %

Procedure:
N-[3-((S)-1-Benzyl-pyrrolidin-3-yl)-phenyl]-3-trifluoromethoxy-benzene sulfonamide (0.5 g, 1.05 mmol) was dissolved in glacial acetic acid and 10% Pd on charcoal was added under a nitrogen atmosphere. The reaction mixture was then hydrogenated for 5 h at 70° C. Subsequently, the catalyst was removed by filtration over celite. The filtrate was concentrated under reduced pressure. The residue was treated with water and the pH adjusted to alkaline pH with 1 N aqueous NaOH. The aqueous layer was extracted twice with ethyl acetate and once with dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered and evaporated. The remaining white solid was tritiurated with 10 ml diethylether, and the precipitate was filtered and dried to yield 0.18 g of the title compound.
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:34](Cl)(=[O:36])[CH3:35].CS(C)=O>C1C=CC=CC=1>[C:34]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:36])[CH3:35]
Reactant: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: CS(C)=O
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCN(C(C)=O)C(c1ccccc1)c1ccccc1
Yield: 99.6 %

Procedure:
Analogously to Example 19, 8 g of ethyl 6-benzhydrylaminocaproate and 3.5 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 2.1 g of acetyl chloride. As reaction product one obtains 9 g of ethyl N-acetyl-6-benzhydrylaminocaproate as a viscous non-distillable oil. The saponification of this ester gives 7.3 g (87.5%) of N-acetyl-6-benzhydrylaminocaproic acid (M.P. 119° to 120°).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].N1(CO)C2C=CC=C[C:25]=2N=N1.[BH4-].[Na+]>C(O)C.CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:25])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: OCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC)c3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
N1-Methyl-5-(2-aminopyridin-4-yl)oxy-1H-1-indolecarboxamide (5.00 g, 17.7 mmol, Production example 5-1) was dissolved in ethanol (170 ml) and N,N-dimethylformamide (40 ml); 1H-benzotriazole-1-methanol (2.64 g, 17.7 mmol) was added thereto; and the reaction mixture was heated to reflux for 2 hours. After allowing to be cooled to room temperature, sodium borohydride (1.49 g, 35.4 mmol) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia BW-300, hexane-ethyl acetate-methanol system). The obtained crystals were suspended in acetone:diethyl ether=1:3, filtered off, washed with hexane, and dried to yield the title compound (1.05 g, 3.55 mmol, 20.1%) as pale yellow crystals.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]([CH2:28][CH2:29][CH3:30])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[C:19]=1[C:35]([O:37][CH3:38])=[O:36])[CH2:16][CH3:17]>C1C=CC=CC=1>[CH2:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][CH3:30])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[C:19]=1[C:35]([O:37][CH3:38])=[O:36])[CH2:16][CH3:17]
Reactant: CCCc1c2c(c(CCC)c(C(=O)OC)c1C(=O)OC)CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCCc1c(C(=O)OC)c(C(=O)OC)c(CCC)c2ccccc12
Yield: 70.6 %

Procedure:
2,3-Dichloro-5,6-dicyanobenzoquinone (1.362 g, 6.0 mmols) was added to a solution of dimethyl 1,4-dipropyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate (0.665 g, 2.0 mmols) in benzene (20 ml). The mixture was then refluxed for 24 hours. After filtration, the solvent in the mixture was removed in vacuum. By column chromatography (ethyl acetate/hexane, 1/20) using silica gel, 0.464 g of the title compound was obtained as colorless crystals. The GC yield was 87% and the isolation yield was 71%.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[OH:13])([O-])=O.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@H:24](O)[CH3:25])=[N:22][N:23]=2)[N:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>Cl.[Fe].CCO.C1COCC1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([C@@H:24]([O:13][C:5]3[C:6]4[O:12][CH:11]=[CH:10][C:7]=4[CH:8]=[N:9][C:4]=3[NH2:1])[CH3:25])=[N:22][N:23]=2)[N:20]=1
Reactant: C[C@@H](O)c1nnc2ccc(Cl)nn12
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Agent: [Fe]
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Temperature: 40 °C

Procedure:
To a mixture of 6-nitrofuro[3,2-c]pyridin-7-ol (50.0 mg, 0.278 mmol), (R)-1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (110 mg, 0.555 mmol), triphenylphosphine (191 mg, 1.11 mmol) and THF (10 mL) under nitrogen at rt was added diisopropyl azodicarboxylate (0.219 mL, 1.11 mmol) dropwise. The solution was heated to 40° C. for 2 h. The solvent was removed in vacuo, and EtOH (20 mL), iron powder (200 mg, 3 mmol) and conc. HCl (8 drops) were added. The mixture was heated to 75° C. for 1 h. The material was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo to afford the title compound as a dark orange solid, and was used in the next step without further purification. MS (ES+): m/z 331.04 (100) [MH+]. HPLC: tR=1.93 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.C(O)C.C[O-].[Na+].Br[CH2:27][C:28]([OH:30])=[O:29]>O.C(Cl)(Cl)Cl.CO.CC(O)=O>[C:28]([CH2:27][N:7]1[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[C:5]1=[O:6])([OH:30])=[O:29]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C(O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CC(=O)O)c1=O
Reaction time: 8 h

Procedure:
A mixture of 560 mg AZT, 15 ml absolute ethanol, 2 ml sodium methoxide solution (4.4M NaOMe in MeOH) and 500 mg bromoacetic acid was refluxed for 5.5 hours, then allowed to stand overnight at room temperature. The next morning, 1 ml NaOMe solution was added followed by 300 mg bromoacetic acid and the mixture refluxed for one hour, at which time the reaction was shown to be complete by TLC on silica gel-F 250 um using the solvent system CHCl3 /MeOH/HOAc (85+15+1). The reaction mixture was diluted with five volumes of deionized water and extracted with CHCl3. The aqueous phase was acidified with 1N HCl, and extracted into EtOAc. The EtOAc extract was concentrated under reduced pressure and chromatographed by preparative TLC on silica gel-F 1000 um using the solvent system CHCl3 /MeOH/HOAc (85+15+1). The product band (Rf =0.25) was scraped, eluted with MeOH and concentrated to a syrup which was flashed repeatedly with CHCl3, MeCl2 and THF until the odor of HOAc was no longer detectable. The oil was stored in vacuo over sodium hydroxide pellets. The product was homogeneous on TLC and its UV spectrum resembled that of AZT-3-VA (Example 2) and 3-methylthymidine. The product was subsequently shown to have immunological activity with antisera to AZT by FPIA.
Reaction SMILES: Br[CH:2]1[CH:6]2[O:7][C:8](=[O:11])[CH:9]3[CH2:10][CH:3]1[CH2:4][CH:5]23.[OH-:12].[Na+].Cl>O>[O:12]=[C:6]1[CH:5]2[CH2:4][CH:3]([CH2:10][CH:9]2[C:8]([OH:7])=[O:11])[CH2:2]1
Reactant: [OH-]
Reactant: O=C1OC2C(Br)C3CC1C2C3
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CC2CC(=O)C1C2

Procedure:
6-bromohexahydro-2H-3,5-methanocyclopenta[b]furan-2-one, 72a, (28.0 g, 129.0 mmol) was treated with NaOH (258.0 mL of 2 M solution, 516.0 mmol) in H2O (350 mL) for 2 hour at room temperature. The reaction mixture was acidified with conc. HCl, extracted with Et2O. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2 gradient) to provide 16 g of 6-oxonorbornane-2-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][NH2:23])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)(C)c1ccc(CC(=O)c2ccc(Cl)cc2)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(CC(=NN)c2ccc(Cl)cc2)cc1
Yield: 96 %

Procedure:
0.7 of magnesium(scraped shape) and 100 mg of a chip of iodine were added to 5 ml of anhydrous diethyl ether. 10 ml of anhydrous diethyl ether solution of 5.6 g of p-bromochlorobenzene was dropwise added thereto under nitrogen stream at a rate that was just fast enough to maintain a gentle reflux. This solution was stirred at room temperature for 20 minutes to react them, a solution of 4.8 g of p-tert-butylphenyl acetonitrile in 5 ml of anhydrous diethyl ether was dropwise added thereto at a rate that was just fast enough to maintain a gentle reflux. The solution was further stirred for 30 minutes to react them. After completion of the reaction, a mixture solution of 10 g of ice and 130 ml of 6N-hydrochloric acid was added thereto and a reaction product was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The redisue was purified by silica gel column chromatography (developing solvent: ethyl acetate/n-hexane=1/9) to obtain 1.3 g of 4'-chloro-2-(4-tert-butylphenyl)acetophenone. (2) 1.3 g of (4.5 mmol) of 4'-chloro-2-(4-tert-butylphenyl)acetophenone was dissolved in 15 ml of ethanol, and 0.2 g (4.5 mmol) of hydrazine monohydrate was added thereto. The mixture was refluxed under heating for three hours. After completion of the reaction, ethanol was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain 1.3 g of [4'-chloro-2-(4-tert-butylphenyl)acetophenone]hydrazone as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH:21](OS(C)(=O)=O)[CH2:20][CH:19]=2)=[CH:14][C:13]=1[F:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C([O-])([O-])=O.[K+].[K+].CO>C(#N)C.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH2:23][CH2:22][CH:21]([N:32]3[CH2:33][CH2:34][CH2:35][C@@H:31]3[CH3:30])[CH2:20][CH:19]=2)=[CH:14][C:13]=1[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Reactant: C[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CCCN1C1CC=C(c2ccc(NC(=O)OCc3ccccc3)c(F)c2)CC1
Reaction time: 16 h

Procedure:
Methanesulfonic acid 4-(4-benzyloxycarbonylamino-3-fluoro-phenyl)-cyclohex-3-enyl ester (200 mg, 0.47 mmol, 1 equiv.) was dissolved in 5 mL of anhydrous acetonitrile. This solution was transferred into a flask containing (S)-2-methyl-pyrrolidine (159 mg, 1.88 mmol, 4 equiv.) and K2CO3 (285 mg, 2.07 mmol, 4.4 equiv.). The suspension was de-aerated by vacuum/nitrogen exchange 3 times, and then, heated on an oil bath set at 80° C. externally with stirring under nitrogen for 16 h. TLC (5% MeOH in DCM for SM) showed the reaction is complete. Acetonitrile was removed in vacuo. The residue was taken in water (5 mL) and DCM (10 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×10 mL). The combined extracts were washed with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered. The filtrate was concentrated in vacuo to obtain a crude product. The crude product was purified on a silica gel column, eluted with DCM, followed by 5% MeOH in DCM and 5% of 7N NH3-MeOH in DCM. The combined fractions containing the product were concentrated to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[F:20].[CH3:21]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:20][C:3]1[C:2]2[N:1]=[CH:21][O:11][C:10]=2[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F
Solvent: O
Solvent: COC(OC)OC
Product: O=C(O)c1cc2ocnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 1842.8 %

Procedure:
To a solution of 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxy benzoic acid (7.58 g, 27.08 mmol) in trimethyl orthoformate (50 mL) was added p-TsOH (233 mg, 1.35 mmol). The reaction mixture was stirred for 1 h and treated with water (300 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (7.22 g, 92% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.28 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.14 (m, 1H), 7.11 (m, 1H), 7.04 (m, 1H), 6.85 (m, 1H).
Reaction SMILES: [O:1]1[CH:7](C2C=CC=CC=2CCCCCCCCC2C=CC=CC=2)[CH:2]1[C:3]([O:5][CH3:6])=[O:4].[SH:28][C:29]1[N:33]([CH2:34][C:35]([O:37]CC)=[O:36])[N:32]=[N:31][N:30]=1.C(N(CC)CC)C>CO>[OH:1][CH:2]([CH2:7][S:28][C:29]1[N:33]([CH2:34][C:35]([OH:37])=[O:36])[N:32]=[N:31][N:30]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCOC(=O)Cn1nnnc1S
Reactant: COC(=O)C1OC1c1ccccc1CCCCCCCCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C(O)CSc1nnnn1CC(=O)O
Temperature: 25 °C

Procedure:
The methyl 2,3-epoxy-3-[2-(8-phenyloctyl)phenyl]propanoate (0.4 g) of Example 14(a) was dissolved in 5 ml of methanol containing 2% triethylamine under an argon atmosphere. The reaction mixture was cooled using an ice/methanol bath. A solution of 0.205 g of 5-mercapto-1-carbethoxymethyltetrazole and 0.61 ml of triethylamine in 5 ml of methanol containing 2% triethylamine was added. The bath was removed and the reaction was permitted to warm to room temperature. The reaction was concentrated and flash chromatographed on silica with 20% ethyl acetate/hexane as eluant to give the desired product.