Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH:19]=O)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[OH:25][CH:26]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]1.C(O)(=O)C.[Na]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][N:28]2[CH2:29][CH2:30][CH2:31][CH:26]([OH:25])[CH2:27]2)=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: OC1CCCNC1
Reactant: O=CCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCN1CCCC(O)C1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of 5-((3,5-dichloropyridin-4-yl)thio)-4-nitro-N-(3-oxopropyl)thiophene-2-carboxamide (0.13 g, 0.32 mmol) and 3-hydroxy-piperidine (89.0 mg, 0.38 mmol) in tetrahydrofuran (3.0 mL) under nitrogen, was added acetic acid (0.2 mL). The resulting mixture was stirred at ambient temperature for 30 minutes. Then sodium triacetoxyboronhydride was added and the reaction mixture was stirred at ambient temperature for additional 4 hours. After this time, the reaction mixture was diluted with water and extracted with ethylacetate. The organic layer was separated, dried (Na2SO4) and concentrated. The crude residue was purified by silica gel chromatography using a 90:10 mixture of dichloromethane and methanol as eluent to afford the title product as a solid (14.0 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.83 (1H, m), 8.41 (1H, s), 4.58 (1H, m), 3.19 (2H, m), 2.80 (1H, m), 2.61 (1H, m), 2.27 (2H, m), 1.76 (2H, m), 1.61 (3H, m), 1.38 (1H, m), 1.23 (1H, m), 1.06 (1H, m). MS m/z: 491.11, 493.13 [M+H]+.
Reaction SMILES: O[C:2]1[C:3]([OH:18])=[C:4](O)[C:5](O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+].C1([O-:27])C=CC=CC=1.[Na+].[Na+].C1([O-])C=CC=CC=1.ClC([SiH2]OC)Cl>>[OH:18][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:27])=[CH:11][CH:10]=2)=[O:8])=[CH:15][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc(O)c(O)c(O)c1O
Reactant: [O-]c1ccccc1
Agent: CO[SiH2]C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccc(O)cc1)c1ccc(O)cc1

Procedure:
Synthesis I: A solution of tetrahydroxybenzophenone (Aldrich Chemical) is treated with sufficient caustic, i.e. sodium hydroxide, to prepare a disodium phenolate salt. This salt solution is mixed at a two to one molar ratio with dichloromethylmethoxysilane (Aldrich, United Chemicals) to yield 2,2′ di-(dimethoxymethylsilyoxy), 4,4′dihydroxy-benzophenone having the structure shown in FIG. 8(a).
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.[Al+3].[Cl-].[Cl-].[Cl-].[C:26](Cl)(=[O:28])[CH3:27]>C(OCC)(=O)C>[C:26]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]2[CH2:8][CH2:9][C@H:10]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:11][CH2:12]2)=[CH:2][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H]1CC[C@H](c2ccc(C(C)=O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A 500 mL round bottom flask with a stir bar was charged with the product of Example 1B (3 g, 12.2 mmol) and 60 mL of dichloromethane. The reaction solution was cooled to 0° C. and AlCl3 (4.86 g, 36.5 mmol) was added in portions. The mixture was allowed to stir for 20 min, and then acetyl chloride (954 μL, 13.4 mmol) was added dropwise. After stirring for 15 minutes, the reaction mixture was slowly pored into a beaker with ice water and diluted with 120 mL of ethyl acetate. The layers were separated and the organic layer washed with 1 N NaHCO3 (×2) brine (×2), dried over Na2SO4, and filtered. Evaporation of the solvents afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.17 (m, 2 H), 1.18 (t, 3 H), 1.39-1.62 (m, 3 H), 1.68-1.88 (m, 5 H), 2.17-2.26 (m, 2 H), 2.52-2.57 (s, 3 H), 4.07 (q, J=7.12 Hz, 2 H), 7.25-7.46 (m, 2 H), 7.77-7.94 (m, 2 H) MS (ESI) m/z 247 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])#[N:2].[CH3:16][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([O:8][CH3:16])=[O:7])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To 3-cyano-4-isopropoxybenzoic acid (0.3 g, 1.462 mmol) in a mixture of dichloromethane (4 mL) and MeOH (1.00 mL) was added trimethylsilyldiazomethane (0.950 mL, 1.9 mmol) dropwise over a period of 3 min at 0° C. The pale yellow solution was allowed to come to room temperature over a period of 15 min. and stirred at room temperature for 1.5 h. Excess trimethylsilyldiazomethane was quenched by the slow addition of acetic acid (˜0.5 ml) at room temperature until the yellow color was discharged. The reaction mixture was concentrated and partitioned between ether (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate and concentrated. The resulting oil was azeotroped with THF (5 mL) and dried under high vacuum to yield methyl 3-cyano-4-isopropoxybenzoate (0.32 g, 1.460 mmol, 100% yield) as an oil. LC/MS M+1=219.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][NH2:10].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:21](=[O:20])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][NH:10]1
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2c(Cl)cccc2Cl)c1=O
Yield: 72.2 %

Procedure:
In the same manner as in Reference Example 63 and using (2,6-dichlorophenyl)hydrazine•hydrochloride (4.8 g, 23 mmol), water (100 mL), potassium carbonate (6.9 g, 50 mmol) and diethyl ethoxymethylenemalonate (5.9 g, 27 mmol) as starting materials, the title compound (5.0 g, 73%) was obtained as a pale-yellow solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:31]5[CH:30]=[CH:29][N:28]=[CH:27][C:26]=5[N:25]=[C:24]4[CH3:32])=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1>O1CCCC1.CO.[Pd]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:31]5[CH:30]=[CH:29][N:28]=[CH:27][C:26]=5[N:25]=[C:24]4[CH3:32])=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=Cc2ccc(-n3c(C)nc4cnccc43)cc2)cc1OC1CCCC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CCc2ccc(-n3c(C)nc4cnccc43)cc2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.3 %

Procedure:
A cis and trans mixture of 1-[4-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-ethenyl]phenyl]-2-methyl-1H-imidazo[4,5-c]pyridine (300 mg, 0.705 mmol 1.0 eq) and 300 mg of 10% Pd/C in 10 ml of tetrahydrofuran and 10 ml of methanol was placed on a Parr hydrogenation apparatus and shaken under 50 psi H2 at room temperature for 6 hours. The reaction mixture was filtered through celite, concentrated, and chromatographed on a silica gel column eluting with 5% CH3OH-CH2Cl2 to give 230 mg of clear oil. Recrystallization from ether-hexane gave 239 mg, 79%, of white crystals. M.P.: 123°-125° C. Elemental Analysis Calc'd for C27 H28N3O2 : Calc'd: C, 75.85; H, 6.84; N, 9.83. Found: C, 75.83; H, 6.74; N, 9.65.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:35][CH:36]([CH3:40])[CH2:37][O:38][CH3:39].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:35][CH:36]([CH3:40])[CH2:37][O:38][CH3:39])=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: COCC(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCC(C)NC(=O)/C=C/c1c(C#N)c2c(C)cc(C)nc2n1[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 2-amino-1-methoxypropane (0.171 ml, 1.62 mmol), triethylamine (0.451 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective product as a solid material.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:3]1>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CCCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Reaction time: 1 h
Yield: 103.5 %

Procedure:
A mixture of tert-butyl 6-[[4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazin-6-yl]oxy]hexanoate (0.80 g, 1.8 mmol) and trifluoroacetic acid (10 ml) was stirred under ice cooling condition for 1 hr. The reaction mixture was concentrated under reduced pressure and crystallized from diisopropyl ether to give the titled compound (0.69 g, ca. 100%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:33])[NH:10][C@@H:11]([CH2:27][C:28]2[N:29]=[CH:30][S:31][CH:32]=2)[C:12]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@H:8]3[O:7][C@@H:6]3[C:4]([OH:5])=[O:3])=[O:33])[CH2:27][C:28]3[N:29]=[CH:30][S:31][CH:32]=3)[S:16][CH:17]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)Nc1nc(-c2ccc(F)cc2)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1nc(-c2ccc(F)cc2)cs1)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 74.1 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 19b (974 mg, 2.0 mmol); LiOH (47.5 mg, 2.0 mmol); THF/MeOH/H2O (25 mL: 5 mL: 2 mL); yielded 33 as a white solid (685 mg, 74.6%). 1H NMR (MeOD-d4, 400 MHz): δ 8.99-8.98 (d, 1H, J=1.67 Hz); 7.94-7.91 (q, 2H); 7.37 (s, 1H); 7.36 (s, 1H); 7.15-7.10 (t, 2H); 5.06-5.02 (q, 1H); 3.64-3.63 (d, 1H, J=1.57 Hz): 3.49-3.45 (m, 3H). 13C NMR (MeOD-d4, 100 MHz): 170.05, 169.01, 166.19, 163.43, 158.19, 154.25, 152.66, 148.36, 131.30, 128.18, 116.63, 116.15, 115.93, 108.62, 53.12, 53.05, 52.21, 33.09. ESI-HRMS (m/z): [M+H+] calcd. for C19H15FN4O5S2: 463.0541, observed: 463.0545; HPLC method 2: Rt=23.3 min; purity=96.3%.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: BrCC1CCCCO1
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCCCO3)c2n1
Temperature: 25 °C
Yield: 85 %

Procedure:
2-Butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (0.20 g) was heated with anhydrous potassium carbonate (0.315 g) in dry DMF (5 mL) at 60° C. for 1 hour and cooled to room temperature. 2-(Bromomethyl) tetrahydro-2H-pyran (73 uL) was added and the reaction mixture heated at 50° C., overnight. The reaction mixture was quenched into water (50 mL) and extracted into ethyl acetate (25 mL, 3 times). The combined organic layers were separated and passed through a hydrophobic frit to dry, then stripped to dryness and the pale yellow gum (145 mg), which turned to a white solid when triturated with methanol, was purified by MDAP to give the title compound (6 mg) (˜85% pure).
Reaction SMILES: [I:1][C:2]1[C:10]([C:11]([Cl:13])=[O:12])=[C:9]([I:14])[C:8]([NH:15][CH3:16])=[C:7]([I:17])[C:3]=1[C:4]([Cl:6])=[O:5].[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:13][C:11]([C:10]1[C:9]([I:14])=[C:8]([N:15]([CH3:16])[C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24])[C:7]([I:17])=[C:3]([C:4]([Cl:6])=[O:5])[C:2]=1[I:1])=[O:12]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CNc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(=O)N(C)c1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
2,4,6-Triiodo-5-methylamino-isophthaloyl dichloride (20 g, 32.8 mmol) was dissolved in DMA (60 ml) and acetoxyacetyl chloride (15.32 ml, 142 mmol) was added. The reaction was stirred overnight at room temperature with nitrogen bubbling through the reaction mixture. The reaction mixture was poured slowly onto ice-water (300 ml) and a white solid was isolated by filtration. The solid was dissolved in ethyl acetate and washed with water. The ethyl acetate was collected, dried over MgSO4, filtered and evaporated to give a white solid. This was purified by silica column chromatography eluting with petrol:ethyl acetate to give acetic acid [(3,5-bis-chlorocarbonyl-2,4,6-triiodo-phenyl)-methyl-carbamoyl]-methyl ester (16.25 g, 22.9 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.[NH2:13][OH:14].Cl.C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[N:13][OH:14]
Reactant: NO
Reactant: COc1cccc2c1CCC2=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cccc2c1CCC2=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
To a solution of 4-methoxy-2,3-dihydro-1H-inden-1-one (1.0 g, 1.0 eq.) in 25 ml MeOH was added NH2OH.HCl (0.493 g, 1.15 eq.) and sodium acetate (0.597 g, 1.18 eq.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with 100 ml ice-water. The white precipitate was collected by filtration, washed with 3×20 ml water and dried in vacuo to afford 1.08 g (yield 99%) 4-methoxy-2,3-dihydro-1H-inden-1-one oxime which was used to next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=O)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:23])=[O:22])[CH2:25][CH2:26]3)[N:8]2[CH3:11])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: Cn1c(C=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Solvent: CC(Cl)Cl
Product: Cn1c(CN2CCN(S(C)(=O)=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-Chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde was treated with 1.1 eq 1-(methylsulfonyl)piperazine, 7 eq trimethylorthoformate, 1 eq of acetic acid in 2 mL of dichloroethane for 6 hours upon which 1.1 eq of sodium triacetoxyborohydride was added to the reaction mixture. The reaction mixture was extracted with dichloromethane and water to give crude intermediate 4-(2-chloro-9-methyl-8-((4 (methylsulfonyl)piperazin-1-yl)methyl)-9H-purin-6-yl)morpholine which was then reacted with 1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole via General Procedure A and purified via reverse phase HPLC to give 41.8 mg 138 as a white solid. MS (Q1) 512.2 (M)+.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:26])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][C:14]=2[OH:25])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[C:33]([OH:36])=[N:34][O:35][C:31]=2[CH:30]=1.O.[OH-].[Na+].Cl>CO>[CH:20]1([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:12]([C:10]3[CH:9]=[CH:8][C:7]([O:27][CH2:28][C:29]4[CH:38]=[CH:37][C:32]5[C:33]([OH:36])=[N:34][O:35][C:31]=5[CH:30]=4)=[C:6]([CH2:5][CH2:4][C:3]([OH:39])=[O:2])[CH:11]=3)=[O:26])=[C:14]([OH:25])[CH:15]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1cc(C(=O)c2ccc(OC3CCCC3)cc2O)ccc1OCc1ccc2c(O)noc2c1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
In 182 mL of methanol, 26.0 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid methyl ester was suspended. After dropping 78 mL of water of 10.5 g of sodium hydroxide at room temperature, the result was stirred for 30 minutes at the same temperature. The reaction mixture was added to water. After adjusting to pH 1.5 with a 6 mol/L hydrochloric acid, solids were filtered. The obtained solids were dissolved in a mixture solution of chloroform and methanol. After washing with water, solvent was distilled off under reduced pressure to obtain 22.5 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid in the form of a light yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.CCN=C=NCCCN(C)C.[CH3:29][C:30]1[N:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[N:38][C:30]=3[CH3:29])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: Cc1ncccc1C(=O)O
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)c1cccnc1C
Temperature: 80 °C
Yield: 50 %

Procedure:
6-chloro-7-methoxy-9H-β-carbolin-8-ylamine (100 mg, 0.4 mmol), EDCI (125 mg, 0.64 mmol) and 2-methyl nicotinic acid (66 mg, 0.48 mmol) were taken in a round-bottom flask and suspended in pyridine (2 ml). The resulting mixture was heated at 80° C. overnight. The pyridine was then removed by rotary evaporation and 5% Na2CO3 solution was added. The resulting solid that precipitated out was collected by filtration. Chromatographic purification gave the desired product in 50-70% yield.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.CC(S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.SCCO.[N-]=[N+]=[N-].[Na+].[NH2:60][C@H:61]([C:66]([O-:68])=[O:67])[CH2:62][C:63]([O-:65])=[O:64]>C(O)C(N)(CO)CO>[NH2:60][C@H:61]([C:66]([OH:68])=[O:67])[CH2:62][C:63](=[O:64])[OH:65]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NC(CO)(CO)CO
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The E. coli (XLI Blue strain) transformed with recombinant pHLASP or wild type pBluescript SK- phagemid were grown overnight in 15 ml of Luria broth containing glucose (0.1%) and ampicillin (50 μg/ml) in the absence or presence of 20 mM IPTG. The bacteria were harvested; treated with 500 μL of 0.05 mg/ml lysozyme in 25 mM Tris.Cl pH 8.0, 10 mM EDTA and 50 mM glucose for 10 min at ambient temperature. The treated bacteria were diluted with ice cold 1.5 ml of 50 mM Tris.Cl, pH 8.0, 0.01% β-mercaptoethanol and 0.01% sodium azide and sonicated by three 10 sec bursts in ice cold conditions. The protein concentration in the bacterial sonicates was determined48. Aspartoacylase assays were carried out in duplicate with 450 μg protein of bacterial sonicate under standard incubation conditions described elsewhere16. Controls lacking substrate or enzyme during the incubation were run simultaneously to account for background absorption in each assay. One mU of enzyme activity is defined as 1 nanomole of aspartate released/min of incubation time.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:19])[N:7]2[CH2:6][CH:2]=[O:1])=[N:12][CH:13]=1
Reactant: COc1cnc2ccc(=O)n(CC3OCCO3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2ccc(=O)n(CC=O)c2c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 120.2 %

Procedure:
To 0.11 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-1,5-naphthyridin-2(1H)-one, 6.0 mL of an 80% aqueous trifluoroacetic acid solution was added, and the mixture was stirred at 60 to 70° C. for 1 hour. Thereto was added 4.0 mL of an 80% aqueous trifluoroacetic acid solution, and the mixture was stirred at 60 to 70° C. for 1 hour. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. The resultant residue was charged with ethyl acetate and water and adjusted to pH 7.0 with a 1 mol/L aqueous sodium hydroxide solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined and the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.11 g of (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde as a light brown foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[CH:4][C:3]=1[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C1COCC1>[C:14]([NH:13][C:11]1[S:12][C:8]([C:5]2[CH:4]=[C:3]([N:18]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:21])[C:35](=[O:37])[CH3:36])[C:2]([Cl:1])=[N:7][CH:6]=2)=[C:9]([CH3:17])[N:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(NS(=O)(=O)c3ccccc3)c2)s1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N(C(C)=O)S(=O)(=O)c3ccccc3)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
N-{5-[6-Chloro-5-(phenylsulfonylamino)pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl)acetamide was dissolved in THF. Triethylamine (0.113 mL, 0.811 mmol) was added. The solution was placed in an ice-bath and acetyl chloride (0.058 mL, 0.81 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours and then evaporated. Water and ethyl acetate were added. The organic phase was dried with magnesium sulfate, filtered and evaporated. The reaction product was purified by preparative HPLC (Method A) to give the title product (retention time 9.2 minutes) in 91% yield; 1H NMR Spectrum: (DMSOd6) 12.33 (1H, s); 8.69 (1H, d); 8.24 (1H, d); 8.06-8.00 (2H, m); 7.82 (1H, t); 7.72-7.67 (2H); 2.42 (3H, s); 2.17 (3H, s); 1.96 (3H, s); Mass Spectrum: M+H+ 465 and 467.