Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:36])[C@H:31]([CH2:33][CH2:34][CH3:35])[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:30](=[O:36])[C@H:31]([CH2:33][CH2:34][CH3:35])[NH2:32])=[O:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CCC[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Yield: 146.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (155 mg, 0.53 mmol, 1.0 eq), L-norvaline N-benzylamide (220 mg, 1.07 mmol, 2.0 eq) and dichloromethane (1.0 mL), was treated with triethylamine (446 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (680 uL, 1.07 mL, 2.0 eq), to provide 372 mg (70%) of L-norvaline, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](CC#N)[CH:5]=[C:6]([O:8]C)[CH:7]=1.Br.[C:14]([OH:17])(=[O:16])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C:14]([OH:17])=[O:16])[CH:5]=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(Br)cc(CC#N)c1
Reactant: CC(=O)O
Agent: Br
Product: O=C(O)Cc1cc(O)cc(Br)c1
Temperature: 100 °C

Procedure:
The product of step (iv) (4.5 g), in glacial acetic acid (30 ml) was treated with 48% aqueous HBr (30 ml) and heated at 100° C. for 24 h. The reaction mixture was partitioned between water and ethyl acetate, the organics were separated then dried (MgSO4) and evaporated under reduced pressure to give a tan solid which was triturated with ether/isohexane (4.24 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1OCCOCCOCCOCCOCCOC1.[CH:37]1(Br)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CS(C)=O.O>[CH:37]1([O:7][N:8]2[C:9](=[O:18])[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:13])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrC1CCCCC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
Solid potassium carbonate (6.91 g, 50.0 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) and 18-crown-6 (661 mg, 2.5 mmol) in dimethyl sulfoxide (62 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture cyclohexyl bromide (12.3 mL, 100.0 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-cyclohexyloxy-isoindole-1,3-dione (5.67 g, 93%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15]O>C1COCC1.O.[O-2].[O-2].[Mn+4]>[CH:4]1[CH:3]=[CH:2][C:1]([C@H:7]2[O:15][C@@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: OO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
In a 25 mL scintillation vial equipped with a magnetic stirrer, trans-stilbene (1.80 g, 10 mmol) was placed followed by addition of 2.8 mL THF.6 To this solution was added BTSP (2.8 g, 15 mmol). The vial was immersed into ice/water bath. After 5 minutes Re2O7 (24 mg, 0.05 mmol) was added dropwise as a solution in 1.2 mL THF.7 The reaction turned yellow and was allowed to warm up to room temperature and stirred for 10 h. Upon completion, water (3 drops) was added followed by manganese dioxide (ca. 5 mg) in order to decompose the remaining H2O2. The destruction of H2O2 was evident by the disappearance of yellow color. The mixture was then dried over Na2SO4. Concentration afforded trans-stilbene oxide (1.88 g, 96% yield) of as an off-yellow solid.
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].CN(C)C=O>O>[C:17]([O:20][CH:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]=[C:10]([C:13]#[N:14])[C:9](=[O:15])[C:8]=2[CH:16]=1)[CH3:3])(=[O:19])[CH3:18]
Reactant: CC(Br)c1ccc2occ(C#N)c(=O)c2c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)c1ccc2occ(C#N)c(=O)c2c1
Temperature: 70 °C
Reaction time: 0.83 h

Procedure:
A mixture of 5.56 parts of 6-(1-bromoethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile, 1.640 parts of anhydrous sodium acetate and 8 parts by volume of dimethylformamide is heated at 70° C under stirring for 50 minutes. After cooling, the reaction mixture is poured into 100 parts by volume of water to give precipitates, which are collected and recrystallized from ethanol and subsequently ethyl acetate. The procedure yields 2.90 parts of 6-(1-acetoxy-ethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile. Melting point: 148°-149° C
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][CH:14]([C:17](O)=[O:18])[CH2:15][O:16][C:11]=2[CH:10]=1>>[OH:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][CH:14]([C:17]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:18])[CH2:15][O:16][C:11]=2[CH:10]=1
Reactant: O=C(O)C1COc2cc(O)ccc2O1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)C1COc2cc(O)ccc2O1
Yield: 75 %

Procedure:
That compound is obtained in a yield of 75% starting frown aniline and 6-hydroxy-2,3-dihydro -1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)(=[O:28])=[O:29])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc3ccc(S(=O)(=O)N4CCOCC4)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 14.7 %

Procedure:
The product was obtained using the same synthetic methods as Example 54, using 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (350 mg, 0.83 mmol, 1.00 equiv) and morpholine (1.44 g, 16.53 mmol, 20.00 equiv) as reactants. Purification by Prep-HPLC afforded 60 mg (34%) of 2,3-bis(4-methoxyphenyl)-6-(morpholinosulfonyl)quinoxaline as a white solid.
Reaction SMILES: [CH2:1]([SH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([O-:22])=[O:21].N1C=CC=CC=1>C(#N)C>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:31])[S:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: CCCCCCCCCCCCCCCCCCS
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCSC(=O)Nc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
In a three necked flask equipped with a dropping funnel, a thermometer and a reflux condenser, n-octadecanethiol (183 g) was dissolved in acetonitrile (1000 ml) in a nitrogen atmosphere. To the solution, p-nitrophenyl isocyanate (100 g) was gradually added, and then pyridine (4 ml) was added dropwise, the mixture was stirred at room temperature for 10 minutes and then heat-refluxed for 30 minutes. When the reaction mixture was cooled to room temperature, crystals precipitated. The crystals were collected by filtering and washed with acetonitrile. S-n-octadecyl p-nitrophenylthiocarbamate (272 g) was obtained at a yield of 99%.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCCC1>C(O)C>[CH3:1][N:2]1[C:7](/[CH:8]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:6]([N+:9]([O-:11])=[O:10])[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C)c(=O)n1C
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c(/C=C/c2ccccc2)c([N+](=O)[O-])c(=O)n(C)c1=O
Yield: 60.3 %

Procedure:
A mixture of 1,3,6-trimethyl-5-nitro-1H-pyrimidine-2,4dione (3.00 g, 15.06 mmol), benzaldehyde (1.58 ml, 15.56 mmol), piperidine (1.41 ml, 15.56 mmol) and a 3 Å molecular sieve (6.00 g) in ethanol (70 ml) was refluxed for 4 hours, filtered and the solid was treated with a mixture of chloroform and methanol. The resulting suspension was filtered again and the filtrates were evaporated. The residue was triturated with diethyl ether and the precipitate collected by filtration and dried under vacuum to yield 1,3-dimethyl-5-nitro-6-((E)styryl)-1H-pyrimidine-2,4-dione (2.61 g, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)c(OC)c1-c1cccnc1
Product: COc1ccc(-c2ccccc2)c(OC)c1-c1cccnc1

Procedure:
This compound was prepared by the same procedure as used in EXAMPLE 3 using 1,3-dimethoxy-2-(pyrid-3-yl)-4-bromobenzene 30 and phenyl boronic acid to yield 31.
Reaction SMILES: [Mg].Br[CH:3]([CH3:8])[CH2:4][CH2:5][CH:6]=[CH2:7].[CH2:9]1[O:12][C@H:10]1[CH3:11]>C1COCC1.[Cu](Br)Br.II>[CH3:7][CH:6]([CH2:5][CH2:4][CH:3]=[CH2:8])[CH2:9][C@@H:10]([OH:12])[CH3:11]
Reactant: C[C@H]1CO1
Reactant: C=CCCC(C)Br
Agent: Br[Cu]Br
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC(C)C[C@H](C)O
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To magnesium turnings (7.44 g, 0.020 moles) in dry THF (100 mL) and was added a iodine (100 mg) at room temperature. To this reaction mass was added a solution of 5-bromohex-1-ene (50 g, 362 mmoles) in THF (200 mL). The reaction mass was heated with hot air gun to initiate the reaction. Upon completion of the reaction the solution was transferred by cannula to a solution of (S)-propylene oxide (14 g, 241 mmol) and copper bromide (3.45 g, 24 mmol) in THF (100 mL) at −78° C. The reaction mass was allowed to come to room temperature and was stirred overnight. The reaction mass was quenched with saturated aq. ammonium chloride solution and extracted with diethyl ether (200 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated at room temperature to get crude compound. The crude compound was purified by column chromotography (Silica gel, 10% TBME in pet ether) to get (2S)-4-methyloct-7-en-2-ol (12.4 g, 30%) as an oil. 1H NMR (400 MHz, CDCl3): δ ppm 5.84-5.77 (m, 1H), 5.02-4.92 (m, 2H), 4.05-3.85 (sb, 1H), 2.08-2.06 (m, 2H), 1.29-1.20 (m, 2H), 1.19-1.16 (m, 4H), 0.97-0.87 (m, 6H).
Reaction SMILES: O[C@H](CCCC1C=CC(OC)=CC=1)C(O)=O.[OH:17][CH:18]([CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[OH:17][C@H:18]([CH2:24][CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(O)CCCc1ccc(OC)cc1
Agent: COc1ccc(CCC[C@@H](O)C(=O)O)cc1
Product: CCOC(=O)[C@H](O)CCCc1ccc(OC)cc1

Procedure:
Using (2R)-2-hydroxy-5-(4-methoxyphenyl)pentanoic acid (80% e.e.), ethyl 2-hydroxy-5-(4-methoxyphenyl)pentanoate was quantitatively obtained (80% e.e.) by a process similar to the process described in Reference Example 27. The optical purity analysis conditions are as follows: Column: AD-H (Chiralcel, DAICEL Chemical Industries Ltd.)
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH3:26][Si:27](Cl)([CH3:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:27]([CH3:34])([CH3:26])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Reactant: C[Si](C)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC1(CO[Si](C)(C)c2ccccc2)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 92.4 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath, and 1 ml of triethyl amine (7 mmol) was added thereto. After stirring for 5 minutes, 1 ml of dimethylphenylsilyl chloride (6.2 mmol) was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the remainder was purified through column chromatography to give 1.44 g of concentrate (yield 92.4%).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:11][N:10]=[C:9]([NH2:12])[CH:8]=2)=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23].CN(C=O)C>O>[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:21]=1[C:22]([NH:24][C:25]([NH:12][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:2][CH:3]=2)[O:11][N:10]=1)=[O:26])=[O:23]
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Reactant: Nc1cc(-c2ccc(-c3ccccc3)cc2)on1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2ccc(-c3ccccc3)cc2)on1

Procedure:
5-(4-Biphenylyl)-3-aminoisoxazole (450 mg.) was mixed with excess 2,6-dichlorobenzoyl isocyanate in 50 ml. of DMF and the reaction mixture stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and recrystallized from ethanol, m.p. 225°-227° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+]=[N-])[CH2:10][C@H:9]1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CP(C)C>C1COCC1>[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:13])[CH2:10][C@H:9]1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)=[O:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)CC1
Agent: CP(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N)CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S,4S)-1-Boc-4-azido-2-[(4-methylpiperazin-1-yl)carbonyl]pyrrolidine (11.67 g, 34.48 mmol) obtained in Step B was dissolved in THF (30 mL). Trimethyl phosphine (3.40 mL, 38.37 mmol) was added dropwise thereto at 0-5° C. The reaction solution was stirred for 2 hours at room temperature, concentrated in vacuo and basified with saturated NaHCO3 aqueous solution. The solution was extracted with EtOAc two times and concentrated in vacuo to give the title compound in oil form (10.61 g, 98.5%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2([C:27]([O:29]CC)=[O:28])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH-].[Na+].C1COCC1>CO>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C:14]([CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=2)([C:27]([OH:29])=[O:28])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC#CCOc1ccc(SCC2(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(SCC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 893.4 %

Procedure:
A mixture of 0.288 g (0.0643 mmol) of 1-(tert-butyl) 4-ethyl 4-({[4-(2-butynyloxy) phenyl]sulfanyl}methyl)-1,4-piperidinedicarboxylate, 3.25 mL of 1N NaOH 3.25 mL of THF and 3.25 mL of MeOH was heated to reflux for 3 h. The organics were removed and the residue was diluted with H2O, acidified and extracted with EtOAC. The organics were washed with H2O, brine, dried over mgSO4, filtered and concentrated in vacuo to provide 0.241 g (89%) of the desired product as an off white gum. Electrospray Mass Spec: 464.3 (M+FA−H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=[O:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([O:56][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:67])[CH3:2].C1C=CN=CC=1.F>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=[O:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a stirred solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(3"-methoxy-4"-oxocyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,18-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10, 16-tetraone from Example 23 (870 mg) in tetrahydrofuran (20 ml) contained in a polypropylene vial is added 4 ml of an HF-pyridine solution in tetrahydrofuran and the mixture was stirred at room temperature. The reaction mixture is quenched with sat'd aqueous sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate three times. Combined organic layers are washed (sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography, gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].[CH:12]([NH:14][NH:15][CH:16]=O)=O.[Si](Cl)(C)(C)C.CCN(CC)CC>N1C=CC=CC=1>[F:1][C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[N:4]1[CH:16]=[N:15][N:14]=[CH:12]1
Reactant: O=CNNC=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(F)c(-n2cnnc2)c1
Temperature: 100 °C
Yield: 37.4 %

Procedure:
A solution of 2-fluoro-5-nitroaniline (415 mg, 2.7 mmol) in pyridine (15 mL) was treated with N′-formylformohydrazide (703 mg, 7.98 mmol), and TMS-Cl (5.10 mL, 39.9 mmol) was then added dropwise. After the addition, Et3N (2.60 mL, 18.6 mmol) was added, and the reaction mixture was heated to 100° C. for 4 hours. The reaction mixture was then cooled to room temperature and concentrated to dryness. The resulting solid was suspended in H2O (25 mL) and filtered. The filtrate was extracted with EtOAc (4×20 mL), and the organics were dried (Na2SO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM and purified by flash chromatography (SiO2, hexanes to 100% EtOAc, 40 g column, 40 min. gradient) to afford Intermediate 28A (210 mg, 37.9%). HPLC: Rt=1.497 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=209.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, s), 9.05 (1H, s), 8.72 (1H, dd, J=6.55, 2.77 Hz), 8.39-8.45 (1H, m), 7.85 (1H, t, J=9.57 Hz).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.C1(C)C=CC=CC=1.[NH2:30][C:31]1[C:32]2[C:57]([CH3:64])([C:58]([NH:60][NH:61][CH:62]=O)=O)[C:56](=[O:65])[NH:55][C:33]=2[N:34]=[C:35]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])[N:38]=2)[N:36]=1>C1COCC1>[NH2:30][C:31]1[C:32]2[C:57]([CH3:64])([C:58]3[S:10][CH:62]=[N:61][N:60]=3)[C:56](=[O:65])[NH:55][C:33]=2[N:34]=[C:35]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][C:48]([F:54])([F:53])[C:49]([F:52])([F:51])[F:50])[N:38]=2)[N:36]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C(=O)NNC=O)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(c2nncs2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 100 °C

Procedure:
Lawesson's reagent (133 mg, 0.328 mmol) was added to a toluene (5 mL) solution of the intermediate from Step B (170 mg, 0.298 mmol). THF (0.5 mL) was added to improve solubility and the reaction was heated to 100° C. for 1 hour in a screw cap vial. The reaction was then cooled and concentrated in vacuo. The crude product was purified by silica gel column chromatography using a hexanes/EtOAc gradient to give the title compound. Chiral separation using SFC on a Chiralcel OD column provided both enantiomers of the title compound. 1H NMR (600 MHz, CD3OD): δ 9.45 (s, 1H); 9.04 (dd, J=7.8, 1.2 Hz, 1H); 8.60 (dd, J=4.2, 1.2 Hz, 1H); 7.36 (dd, J=7.8, 4.2 Hz, 1H); 4.94 (t, J=8.4 Hz, 2H); 4.56 (bs, 2H), 3.01-2.92 (m, 2H); 1.98 (s, 3H). m/z=511.95 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)=[C:4]([N:22]=[N+:23]=[N-:24])[N:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2cnc3c(N=[N+]=[N-])nc(N)nc32)CO1
Temperature: 105 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (0.47 g, 1.5 mmol) in dry N,N-dimethylformamide (5 ml), sodium azide (0.20 g, 3.0 mmol) was added and the mixture was stirred at 100-110° C. for 4 hours. The solvent was removed and the residue washed with water to leave 2-amino-6-azido-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a crystalline solid (0.36 g, 75%), m.p. decomposed at 200° C.; λmax (MeOH) 272 (ε 8,210) and 301 (ε 10,100) nm; νmax (KBr) 1670, 1625, and 1560 cm−1; δH (CDCl3—CD3OD) 1.44 (6H, s, C(CH3)2), 1.6-2.2 (3H, m, CHCH2CH2), 3.5-3.8 (2H, dd (ABX), J 7 Hz and J 11 Hz, 2×Hax), 3.85-4.15 (2H, dd (ABX), J 4 Hz and J 11 Hz, 2×Heq), 4.29 (2H, t, J 7 Hz, CH2N), and 7.93 (1H, s, 8-H) (Found: C, 48.96; H, 5.66; N, 35.15%; M+ 318.1553. C13H18N8O2 requires C, 49.05; H, 5.07; N, 35.20%; M+ 318.1546).