Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]>C(O)(C)(C)C>[CH3:16][O:17][C:18]([CH:20]1[CH2:25][N:24]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:5]=[CH:4][N:3]=2)[CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:19]
Reactant: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Solvent: CC(C)(C)O
Product: COC(=O)C1CN(c2cc(-c3ccc(Cl)c(Cl)c3)ncn2)CCN1C(=O)OC(C)(C)C
Temperature: 150 °C
Yield: 192.6 %

Procedure:
4-Chloro-6-(3,4-dichloro-phenyl)-pyrimidine (0.11 g, 0.4 mmol) was added in one portion to a suspension of piperazine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.21 g, 0.85 mmol) and in tert-butanol (2 ml) in a microwave reactor tube. The tube was sealed and heated to 150° C. in a microwave for 40 minutes at a pressure of 250 psi. After this time the reaction mixture was cooled to room temperature and the solvent was removed. The resulting residue was purified by flash column chromatography (elution: 20% EtOAc, 80% Heptane) to give the title compound (0.36 g, 75% yield) as a colourless oil. δH (500 MHz, DMSO) 8.59 (s, 1H) 8.43 (d, J=2.05 Hz, 1H) 8.17 (dd, J=8.51, 2.05 Hz, 1H) 7.74-7.81 (m, 1H) 7.42 (d, J=7.88 Hz, 1H) 4.88-5.09 (m, 1H) 4.60-4.76 (m, 1H) 4.24-4.46 (m, 1H) 3.76-3.88 (m, 1H) 3.56 (d, J=13.08 Hz, 3H) 3.38-3.51 (m, 1H) 3.10-3.28 (m, 2H) 1.31-1.47 (m, 9H). Tr=3.71 min m/z (ES+) (M+H+) 283, 285.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][CH2:16][C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1.[OH-].[Li+].[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH2:16][F:15])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(CF)nn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(CF)nn2-c2cccc3ncccc23)cc1
Temperature: 85 °C
Yield: 4.3 %

Procedure:
To a mixture of 4-t-butylbenzenesulfonyl chloride (0.085 g, 0.37 mmol), 3-(fluoromethyl)-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.05 g, 0.21 mmol), and DMAP (0.025 g, 0.19 mmol) in pyridine (1.0 mL) was heated at 85° C. for 2 h with stirring. After cooling to room temperature, 1 M aqueous lithium hydroxide (1 mL) and 1 M aqueous sodium hydroxide (1 mL) were added to the reaction mixture and heated at 75° C. for 1 h. After cooling to room temperature, the reaction mixture was neutralized with 1 N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.004 g, 0.009 mmol, 4%). 1H NMR (400 MHz, CD3OD) δ 8.86 (dd, J=1.2, 4.0 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.4, 8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.43-7.37 (m, 4H), 6.24 (s, 1H), 5.34 (s, 1H), 5.22 (s, 1H), 1.35 (s, 9H); MS: (ES) m/z calculated for C23H24FN4O2S [M+H]+ 439.2. found 439.1.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[N:13]=1)=[O:11])([CH2:7][CH3:8])[CH2:5][CH3:6].O.[OH-].[Li+].[OH-].[Na+]>C1COCC1.O>[CH:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:10]([NH:9][C:4]([CH2:7][CH3:8])([CH2:5][CH3:6])[C:3]([OH:28])=[O:2])=[O:11])=[N:13][C:14]=2[O:21][CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][O:24]2)[CH2:20][CH2:19]1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)OC
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CCCO2)n1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
Methyl 2-(5-cyclopropyl-6-((tetrahydrofuran-2-yl)methoxy)picolinamido)-2-ethylbutanoate (60 mg, 154 μmol, Example 233) and lithium hydroxide hydrate (7.74 mg, 184 μmol) were dissolved in a mixture of THF (600 μL) and water (150 μL). The reaction mixture was stirred for 48 h at ambient temp. Additional sodium hydroxide (24.6 mg, 614 μmol) was added and stirring was continued at 70° C. for additional 3 d. The mixture was poured onto ice water/brine/1N HCl (25 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with ice water/brine (25 mL) and dried over Na2SO4. Concentration in vacuo afforded the title compound (49 mg, 85%) as a light yellow waxy solid. MS: 375.3 [M−H]−.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][N:13]1C(=O)C2=CC=CC=C2C1=O.NN>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][NH2:13]
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc2ccccc2n1
Agent: NN
Solvent: CCO
Product: NOCc1ccc2ccccc2n1
Reaction time: 5 h
Yield: 103.9 %

Procedure:
N-(2-quinolyl)methoxy phthalimide (1.53 g) was suspended in 95% EtOH and hydrazine (0.30 mL) was added. The reaction mixture was stirred for 5 h and then filtered. The filtrate was concentrated under reduced pressure and then taken up in a small amount of dichloromethane. The small amount of remaining phthalhydrazide was then removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.91 g) as a yellow oil. MS(CI) m/e 175 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[CH:14]=[CH:15][CH:16]([OH:21])[CH2:17][C:18](=[O:20])[CH3:19].N1C=CC=CC=1>CCOCC>[Br:1][CH2:2][C:3]([O:21][CH:16]([CH:15]=[CH:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[Cl:6])[CH2:17][C:18](=[O:20])[CH3:19])=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(=O)CC(O)C=Cc1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(=O)CC(C=Cc1ccc(Cl)cc1Cl)OC(=O)CBr
Temperature: 20 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Bromoacetyl bromide (1.1 ml, 13.2 mmole) was added dropwise to a stirred solution of 6-(2,4-dichloro-phenyl)-4-hydroxy-5-hexene-2-one (3.4 g, 13.1 mmole) and pyridine (1.07 ml, 13.2 mmole) in ether (100 ml) at 0° C. The ice bath was removed and the reaction mixture was stirred at 20° C. for 2 hours and then diluted with H2O (100 ml). The organic layer was separated and washed with 1N HCl (100 ml), H2O (2×100 ml) and brine, dried over MgSO4, filtered and evaporated. The residual oil was chromatographed on a 60 mm column with 15 cm of silica gel (230-400 mesh) Elution with methylene chloride-acetone (99:1; v:v; 1.9 L) provided the title compound (2.8 g, 56%); pmr (CDCl3)δ2.2 (3H, s), 2.92 (2H, t), 3.85 (2H, s), 5.9 (H, m), 6.15 (H, m) 6.95-7.5 (4H, m).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[F:9].[Mg].C[O:12][B:13](OC)[O:14]C.C(O)(=O)C>O1CCCC1.C(OCC)C.O>[OH:12][B:13]([OH:14])[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[F:9]
Reactant: COB(OC)OC
Reactant: Fc1ccc(Br)cc1Br
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Br)ccc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2,4-dibromofluorobenzene (12.7 g, containing 30% 3,4-dibromofluorobenzene) in dry tetrahydrofuran (THF) (10 ml) is added over 5 min to a stirred suspension of magnesium turnings (1.15 g) in dry THF (50 ml) under an atmosphere of nitrogen and cooled in a water bath. After 1 hour, when all the magnesium has reacted, this reagent is added over 20 min to a stirred solution of trimethoxyborane (7 ml) in dry diethyl ether (80 ml) under an atmosphere of nitrogen and cooled at -78° C. The mixture is stirred at -78° C. for a further 15 min. and glacial acetic acid (6 ml) added followed by water (50 ml). The mixture is warmed to room temperature, extracted with diethyl ether (x3), washed with water, dried and the solvent evaporated under reduced pressure. The residue is stirred with carbon tetrachloride (30 ml) and then cooled at 0° C. The crystals of dihydroxy-(5-bromo-2-fluorophenyl)-borane are filtered off and washed with a little carbon tetrachloride. Yield 2.8 g m.pt. 173°-174° C.
Reaction SMILES: C([NH:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]1[O:21]C(C)(C)C(C)(C)[O:18]1)[C:6](NC(C)(C)C)=[O:7])(=O)C.[ClH:39].[OH2:40]>>[ClH:39].[ClH:39].[NH2:4][C:5]([C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:27]1)([CH2:13][CH2:14][CH2:15][CH2:16][B:17]([OH:21])[OH:18])[C:6]([OH:7])=[O:40]
Reactant: O
Reactant: CC(=O)NC(CCCCB1OC(C)(C)C(C)(C)O1)(C(=O)NC(C)(C)C)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Agent: Cl
Product: NC(CCCCB(O)O)(C(=O)O)[C@@H]1CCN(Cc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
An aqueous solution of 2-acetamido-N-tert-butyl-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanamide (0.280 g, 0.527 mmol) in 6M hydrogen chloride (10 mL, 60 mmol) was heated under reflux overnight. The reaction was cooled to room temperature, diluted with 20 mL of water, and washed with ethyl acetate (20 mL). The aqueous layer was purified by HPLC (3 injections) using a 5-20% acetonitrile in water. The fractions corresponding to the desired product were concentrated and lyophilized to give 2-amino-6-borono-2-((R)-1-(4-fluorobenzyl)pyrrolidin-3-yl)hexanoic acid dihydrochloride as white powder, which became oily upon exposure to air (hydroscopic). (0.003 g, 2%). 1H NMR (400 MHz, CDCl3, Mixture of diastereoisomers) δ 7.41 (dd, J1=8.1 Hz, J2=6.5 Hz, 2H), 7.12 (t, J=8.1 Hz, 2H), 4.35-4.25 (br, m, 2H), 3.77-3.09 (br. m, 3H), 2.99-2.60 (br. m, 1H), 2.39-1.57 (br. m, 4H), 1.34-1.18 (br. m, 2H), 1.15-1.03 (br. m, 1H), 0.70-0.61 (m, 2H),; ESI MS found for C17H26BFN2O4 m/z 335.3 (M+H-water)+; 351.4 (M−H)−; 333.4 (M−H-water)−.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>>[C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5])(=[O:16])[CH2:14][C:13]([CH3:12])=[O:17]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: C=C1CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Reaction time: 2.5 h

Procedure:
L-aspartic acid, 13.3 parts, was added to 100 parts by volume of 2N aqueous sodium hydroxide and the resulting solution was cooled to 0°-10° C. in an ice bath. Diketene, 8.4 parts, was added and the resulting two phase mixture was stirred for 2.5 hours at 0°-10° C. The homogeneous solution was washed twice with 100 parts by volume of ether and the aqueous layer was acidified with 16.6 parts by volume of concentrated hydrochloric acid. This solution was extracted three times with 100 parts by volume of ethyl acetate, the combined extracts were dried over sodium sulfate, filtered and the solvent evaporated under vacuum at 25°-30° C. to give 2.3 parts of N-acetoacetyl-L-aspartic acid, mp 127°-129.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NS(=O)(=O)c1cccnc1Cl
Reactant: CN
Product: CNc1ncccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
10 g of 2-chloropyridine-3-sulfonamide (obtained in Stage A of Preparation 6) are dissolved in 100 cm3 of 40% aqueous methylamine solution and the solution is introduced into a sealed tube. The tube is placed at 150° C. for 18 hours. After cooling, the reaction mixture is concentrated under vacuum (rotary evaporator) to a volume of 30 cm3. The crystalline precipitate corresponding to the title compound is collected on a filter, washed with water and dried.
Reaction SMILES: [OH-:1].[Na+].Br[O-].[Na+].[C:6]([C:9]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:16][CH:17]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:8])C.Cl>O.BrBr.O1CCOCC1>[CH2:22]([C:15]1[CH:14]=[C:13]2[C:18]([C:19]3[CH:20]=[CH:21][C:9]([C:6]([OH:1])=[O:8])=[CH:10][C:11]=3[CH2:12]2)=[CH:17][CH:16]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: [OH-]
Reactant: CCCCCCCCc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCc1ccc2c(c1)Cc1cc(C(=O)O)ccc1-2
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 79.5 %

Procedure:
To a solution of 1.30 g (32.5 mM) of sodium hydroxide in 8.8 ml of water, 0.54 ml (10.5 mM) of bromine was added dropwise at -2° to -0.5° C. under cooling on an ice-common salt bath. After the addition, 3.4 ml of dioxane was added to the mixture to prepare a sodium hypobromite solution. The sodium hypobromite solution was added dropwise to a solution of 1.00 g (3.12 mM) of 2-acetyl-7-octylfluorene in a mixture solvent of 28 ml of dioxane and 2 ml of water at about 5.5° C. under cooling on an ice bath. After the addition, the ice bath was removed and 10 ml of dioxane was added to the resultant mixture, followed by stirring for 1 hour and 50 minutes. After the reaction, the reaction mixture was poured into 200 ml of ice water and acidified with 2.3 ml of hydrochloric acid so as to indicate pH=1 to precipitate a crystal. The crystal was recovered by filtration and recrystallized from acetone to obtain 0.80 g of 7-octyl-2-fluorenecarboxylic acid (Yield: 79.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C([Si](C)(C)Cl)(C)(C)C.[Cl-].[CH3:29][O:30][C:31](=[O:41])[C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:29][O:30][C:31]([C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:37])=[CH:34][CH:33]=1)=[O:41]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 63.9 %

Procedure:
To a solution of 4-aminobenzoic acid (500 mg, 3.65 mmol) in anhydrous THF (20 mL) were added DIEA (1.36 mL, 8.02 mmol) and tert-butyldimethylchlorosilane (4 mL, 1M in THF). The resulting mixture was allowed to stir at rt for 45 min. A solution of terephtalic acid monomethyl ester chloride (800 mg, 4 mmol) in THF (5 mL) was added and the resulting mixture was stirred for 90 min at rt until the disappearance of the starting material and finally TBAF (4 mL, 1M in THF) was added. After 25 min at rt, the reaction was quenched with a solution of 0.1N HCl (100 mL). Extraction with EtOAc (3×200 mL), drying over sodium sulfate and evaporation under vacuo gave a pale yellow solid. Washing with hot EtOH (50 mL) gave the tilte compound as a white solid (698 mg, 64%) in a 84% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][C:13]1[CH:14]=[C:15]([C:19]23[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH2:29][CH2:30][OH:31])([CH2:23][CH2:24]2)[CH2:21][O:20]3)[CH:16]=[CH:17][CH:18]=1>C(Cl)Cl>[CH3:1][S:2]([O:31][CH2:30][CH2:29][CH2:28][CH2:27][C:22]12[CH2:23][CH2:24][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH:7]4[CH2:8][CH2:9][CH2:10][CH2:11][O:6]4)[CH:14]=3)([CH2:26][CH2:25]1)[O:20][CH2:21]2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
MsCl (0.036 ml, 0.462 mmol) was added to a solution of 4-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2] octan-4-yl)butan-1-ol (111 mg, 0.31 mmol) and TEA (0.129 ml, 0.92 mmol) in DCM (2 mL) at 0° C. The reaction was then stirred at rt for 2 h and concentrated in vacuo. The residue was dissolved in EtOAc (5 mL), washed with water (4×5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 (gradient from 0 to 50% EtOAc: hexanes) to afford the title compound (133 mg, 98% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.13-7.10 (m, 1H), 7.03-6.99 (m, 1H), 6.94 (ddd, J=8.2, 2.5, 0.8 Hz, 1H), 5.44 (t, J=3.2 Hz, 1H), 4.25 (t, J=6.5 Hz, 2H), 4.04-3.88 (m, 1H), 3.82 (s, 2H), 3.67-3.55 (m, 1H), 3.03 (s, 3H), 2.06-1.99 (m, 5H), 1.90-1.83 (m, 2H), 1.79-1.57 (m, 9H), 1.43-1.34 (m, 2H), 1.23-1.16 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH:19]C(=O)COC4C=CC=CC=4)[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH:35]C(=O)C)[CH3:31])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.CO>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([C@@H:12]2[N:16]3[C:17](=[O:30])[C@@H:18]([NH2:19])[C@H:15]3[S:14][C@:13]2([CH2:32][O:33][C:34](=[O:39])[NH2:35])[CH3:31])=[O:11])=[CH:40][CH:41]=1)([O-:3])=[O:2]
Reactant: CC(=O)NC(=O)OC[C@]1(C)S[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: C[C@@]1(COC(N)=O)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
A solution of (2R,3S,5R,6R) 2-(N-acetyl)carbamoyloxymethyl-2-methyl-6-phenoxyacetamidopenam-3-carboxylic acid p-nitrobenzyl ester (1.17 g, 2.0 mmol) in methylene chloride (10 ml) at -40° was charged with dimethylaniline (1.03 ml, 8.0 mmol) and phosphorous pentachloride (0.92 g, 4.4 mmol). The solution was stirred at -35° to -40° for 30 minutes and cold (~-35°) methanol (4.1 ml, 100 mmol) was added dropwise. The pale green solution was stirred at -35° to -40° for 2 hours and then quenched into ice-water (10 ml). The pH was adjusted to 1.7 with conc. ammonia and the layers were separated. The aqueous was washed with CH2Cl2 (5 ml), combined with a water back-extract (5 ml), and stirred with CH2Cl2 (10 ml) during pH adjustment to 6.5 with ammonia. The organic phase was withdrawn, washed (5 ml, H2O), combined with a back-extract (CH2Cl2, 10 ml), dried (4A sieves), filtered, concentrated to 4 ml and diluted with heptane (10 ml). The suspension was concentrated to 8 ml and the liquids were decanted. The solids were treated with CH2Cl2 (4 ml) and heptane (10 ml) in the same fashion, and the product was washed with heptane and dried to an off-white solid (0.28 g) 34%; nmr 100 MHz CDCl3 -D2O δ8.24 (2, d, J=8.5 Hz, 1/2 pNB AB), 7.56 (2, d, J=8.5, pNB AB), 5.68 (1, brd J=4, C5 --H), 5.32 (2, s, benzyl CH2), 4.76 (1, s, C3 --H) 4.55 (HOD overlapping C6 -H d), 4.16 and 3.97 (2, ABq J=11.5 C2 -CH2 -O), 1.43 (3, s, C3 -CH3), with 2.36 (3/4, s, ##STR79## of impurity N-acetyl analog; ~25 mol %).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([N:10]([C:18]2[C:19]3[N:20]([C:30]([CH:33]=[O:34])=[CH:31][N:32]=3)[CH:21]=[C:22]([C:24]#[C:25][Si](C)(C)C)[N:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1>CO>[CH:7]1([N:10]([C:18]2[C:19]3[N:20]([C:30]([CH:33]=[O:34])=[CH:31][N:32]=3)[CH:21]=[C:22]([C:24]#[CH:25])[N:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N(c1nc(C#C[Si](C)(C)C)cn2c(C=O)cnc12)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cn2c(C=O)cnc2c(N(C(=O)OC(C)(C)C)C2CC2)n1
Reaction time: 2 h
Yield: 47.1 %

Procedure:
Potassium carbonate (86 mg, 0.63 mmol) was added to tert-butyl cyclopropyl(3-formyl-6-((trimethylsilyl)ethynyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (50 mg, 0.13 mmol) dissolved in methanol (2.5 mL). After 2 h, the volatiles were removed in vacuo. The residue was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous layer was further extracted with dichloromethane (2×10 mL). The organics were washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (30% EtOAc/hexanes) to provide tert-butyl cyclopropyl(6-ethynyl-3-formylimidazo[1,2-a]pyrazin-8-yl)carbamate (20 mg, 50%) as a yellow foamy solid. LCMS (ES): >95% pure, m/z 327 [M+1]+.
Reaction SMILES: C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:5](C)=O.[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][NH:33]2)=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCCl.C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][N:33]2[CH3:5])=[O:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CCCCN2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCCCC1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
0.54 ml of 37% aqueous formaldehyde and then 1.41 g of NaBH(OAc)3 are added to a solution of 0.99 g of the compound obtained in step 5.2, in 11 ml of DCE, and the medium is stirred at AT for 12 h. The medium is diluted in DCM and filtered through cotton wool. The organic phase is washed twice with a saturated NaHCO3 solution, and then with a saturated NaCl solution. After drying over MgSO4 and evaporation of the solvents, 0.84 g of the expected product is recovered.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:12]=[CH:11][N:10]([C@@H:13]3[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:14]3[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[NH2:43][NH2:44]>C(OCC)(=O)C>[NH:43]([C:2]1[C:3]2[CH:12]=[CH:11][N:10]([C@@H:13]3[O:33][C@H:32]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:14]3[O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[NH2:44]
Reactant: CSc1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: NN
Solvent: CCOC(C)=O
Product: CSc1nc(NN)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reaction time: 2 h

Procedure:
A mixture of 55 g of 4-chloro-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 500 ml of anhydrous hydrazine is heated under reflux and a nitrogen atmosphere for two hours, evaporated in vacuo, and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water and the aqueous layer reextracted with ethyl acetate. The dried ethyl acetate extracts are combined and evaporated in vacuo to provide 51 g of crude syrupy product. Chromatography of this material over silica gel and ethyl acetate provides 49 g of pure 4-hydrazino-2-methylmercapto-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow syrup.