Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9]N=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)[S:13][C:6]=12.[CH3:27]CN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[C:6]2[S:13][C:12]([C:14]3[CH2:15][CH2:16][N:17]([C:36](=[O:38])[CH3:37])[CH2:18][CH:19]=3)=[CH:11][C:7]=2[CH:27]=[CH:9][CH:10]=1
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cc3cccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of 4-(7-(2-fluoro-4-nitrophenoxy)benzo[b]thiophen-2-yl)-1,2,3,6-tetrahydropyridine 268 (400 mg, 1.08 mmol) and DIPEA (0.207 mL, 1.19 mmol) in DCM was added acetyl chloride (0.15 mL, 2.16 mmol) at room temperature and the mixture (that turned homogeneous soon after) was stirred for 1 h. The crude mixture was concentrated under reduced pressure and the residue purified by flash chromatography (5% MeOH to 10% MeOH in DCM) affording 269 (358.2 mg, 0.87 mmol, 80% yield) as a white solid. MS (m/z): (M+1) 414.4 (100%).
Reaction SMILES: COC1C=CC=CC=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15]C(C)(C)C=C2CSC(=O)C.Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[O:44][CH3:45])[CH:36]=2)[NH:31][C:30]([CH3:47])([CH3:46])[CH:29]=1.C(O)(=S)C.C(N(CC)CC)C>C(Cl)Cl>[CH3:45][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30]([CH3:47])([CH3:46])[CH:29]=[C:28]2[CH2:27][NH:15][C:16]1[CH:17]=[CH:18][CH:9]=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSC(C)=O)=CC(C)(C)N2
Agent: CC(O)=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
Thioacetic acid S-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl] ester 776 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline in 16 mL of methylene chloride was treated with 155 μL of thioacetic acid and 303 μL of triethylamine to give 100 mg of the title compound as a foam.
Reaction SMILES: CI.C(=O)([O-])[O-].[K+].[K+].O1CCOC[CH2:10]1.[F:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[NH:18][N:17]=1>C(OCC)(=O)C>[F:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=2)[N:18]([CH3:10])[N:17]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(F)c2c1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1nc(F)c2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Methyl iodide (41 μl) and potassium carbonate (114 mg) were added to a 1,4-dioxane (2.5 ml) solution containing 3-fluoro-5-nitro-1H-indazole (100 mg), followed by stirring at 100° C. for 2 hours. Ethyl acetate was added to the reaction solution. An insoluble precipitate was removed by filtration, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1). 3-Fluoro-1-methyl-5-nitro-1H-indazole was thus obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:22])[C:14]([N:16]([CH3:21])[N:17]=C(C)C)=[O:15])[CH3:2].C(O)C.Cl.CCCCCC>C(OCC)(=O)C>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:22])[C:14]([N:16]([CH3:21])[NH2:17])=[O:15])[CH3:2]
Reactant: CCc1cc(CC)c(C(=O)C(=O)N(C)N=C(C)C)c(CC)c1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc(CC)c(C(=O)C(=O)N(C)N)c(CC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.2 %

Procedure:
To a 100 ml volume four-necked flask, 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylethylidene)hydrazine (18-b) (21.41 g) and ethanol (35 ml) were added under a nitrogen atmosphere, 10 w/w % of hydrochloric acid (14.54 g) was added and stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. To the residue, saturated brine was added and extracted with chloroform (120 ml×1, 60 ml×2). The organic layers were combined, and dried over anhydrous magnesium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure to give 19.08 g of a crude product. The crude product was subjected to column chromatography (hexane:ethyl acetate=2:1 to 1:1) to give 3.008 g of 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-40).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH2:34])=[CH:23][CH:22]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:43][C:44](ON1C(=O)CCC1=O)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.ON1C2C=CC=CC=2N=N1.C(OCC)(=O)C>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH2:33][NH:34][C:44]([O:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:45])=[CH:25][CH:26]=2)[C:10]1=[O:35])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(=O)OCc3ccccc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
A solution of 64 mg (0.14 mmol) of 3(R)-t-butoxycarbonylamino-2,3,4,5-tetrahydro-1-[[2'-aminomethyl[1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-2-one (Example 59, Step C) in 1 mL of methylene chloride at room temperature was treated with 1 drop of triethylamine followed by 36 mg (0.14 mmol, 1 eq.) of N-(benzyloxycarbonyloxy)succinimide and 5 mg of N-hydroxybenzotriazole. The mixture was stirred at room temperature for 1 hour then added to 10 mL of ethyl acetate and washed with 5% aqueous citric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was removed, dried over magnesium sulfate, filtered and solvents removed under vacuum. The residue was purified by medium pressure liquid chromatography on silica, eluting with ethyl acetate/hexanes (2:1), to give 68 mg (0.11 mmol, 83%) of the product as a white, crusty foam. 1H NMR (400 MHz, CDCl3): δ 1.38 (s, 9H), 1.89 (m, 1H), 2.40-2.60 (m, 3H), 4.27 (m, 3H), 4.75 (br t, 1H), 4.92 (d, 15 Hz, 1H), 5.05 (s, 2H), 5.18 (d, 15 Hz, 1H), 5.44 (br d, 7 Hz, 1H), 7.10-7.35 (m, 11H), 7.40 (d, 8 Hz, 1H). FAB-MS: calculated for C37H39N3O5 605; found 606 (M+H, 2%), 506 (M-BOC, 100%).
Reaction SMILES: [S:1]=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4]([O:6]CC)=O.C[O-].[K+].Cl[CH2:16][C:17]#[N:18]>CO>[C:17]([C:16]1[S:1][C:2]([CH2:9][CH2:10][CH3:11])=[CH:3][C:4]=1[OH:6])#[N:18]
Reactant: N#CCCl
Reactant: CCCC(=S)CC(=O)OCC
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CCCc1cc(O)c(C#N)s1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 4.6 %

Procedure:
A mixture of 77 g of ethyl 3-thioxo-hexanoate, 300 ml of methanol and 28 g of potassium methylate was stirred at 20° C. for 15 minutes and after the addition of 30.2 g of chloroacetonitrile thereto, the mixture was stirred for another 15 minutes at 20° C. The mixture was refluxed for 4 hours and the solvent was then evaporated. The residue was dissolved in ether and the ether phase was washed with methylene chloride, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The solution was then treated with activated carbon, was dried and evaporated to dryness. The residue was dissolved in toluene and the solution was iced and vacuum filtered. The recovered crystals were crystallized from a 3-1 petroleum ether-benzene mixture to obtain 3.1 g of 2-cyano-3-hydroxy-5-n-propyl-thiophene melting at 78° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=2[O:17][CH2:16][C:15]1=[O:26].C(N(CC)CC)C>ClCCl>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]2[O:17][CH2:16][C:15](=[O:26])[N:14]([CH2:13][CH:12]=[O:11])[C:19]=2[CH:20]=1
Reactant: COc1ccc2c(c1)N(CCO)C(=O)CO2
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)N(CC=O)C(=O)CO2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in dichloromethane (10 mL) at −70° C. was added a solution of dimethyl sulfoxide (DMSO, 0.426 mL, 6.0 mmol) in dichloromethane (10 mL). After thirty minutes a solution of 4-(2-hydroxyethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 126, 550 mg, 2.5 mmol) in dichloromethane (3.5 mL) was added dropwise and it was stirred for 90 minutes. Triethyl amine (1.74 ml, 12.5 mmol) was added it was stirred at −70° C. for another 45 minutes. The reaction was quenched with water and warmed to 0° C. It was diluted with dichloromethane, the aqueous phase was extracted with dichloromethane (3×25 mL) and the combined organic phases were washed with 1N HCl (2×25 mL), water (25 mL), 1M sodium carbonate solution (2×25 mL), water, brine, dried over magnesium sulfate and concentrated at reduced pressure. Chromatography on silica gel with dichloromethane/methanol (96:4) gave the product as a yellow oil, 292 mg (53%).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][C:7]3[O:8][CH2:9][CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[N:3]=[CH:2]1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24](Cl)[CH:23]=[CH:22]2>CN1CCCC1=O>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([N:1]1[C:5]3=[CH:6][C:7]4[O:8][CH2:9][CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[N:3]=[CH:2]1)[CH:23]=[CH:22]2
Reactant: c1nc2cc3c(cc2[nH]1)OCCO3
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Brc1cccc2ccc(-n3cnc4cc5c(cc43)OCCO5)nc12
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 135 %

Procedure:
6,7-Dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene 81B (600 mg, 3,4 mMol) was dissolved in 15 mL of 1-methyl-2-pyrrolidinone under an atmosphere of dry N2. To this solution was added 60% sodium hydride in oil (136 mg, 3.40 mMol) and the reaction mixture was stirred for 15 minutes. 8-Bromo-2-chloro-quinoline 81A (750 mg, 3.10 mMol) was then added to the reaction mixture which was subsequently heated to 65° C. and reacted at this temperature overnight. The reaction mixture was then cooled to ambient temperature, partitioned between DCM and saturated aqueous NaHCO3, washed again with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to give 1.60 g of an orange solid. The solid was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (0.5/99.5) to give 700 mg of the title compound 81C as a light yellow solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[CH3:13][O:14][C:15]1[C:16](OC)=[C:17]([O:21][CH3:22])[CH:18]=[CH:19][CH:20]=1.[C:25](OCC)(=[O:27])C>ClCCCl>[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:16]1[C:17]([O:21][CH3:22])=[CH:18][C:19]([O:27][CH3:25])=[CH:20][C:15]=1[O:14][CH3:13])=[O:11]
Reactant: COc1cccc(OC)c1OC
Reactant: CCOC(C)=O
Reactant: O=C(Cl)CCCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc(OC)c(C(=O)CCCCCl)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
The following is the preparation of a compound of Formula 3 in which A mixture of aluminum chloride (22.6 g, 170 mmol), 5-chlorovaleryl chloride (26.4 g, 170 mmol), and 1,2-dichloroethane (200 mL) was stirred for 30 minutes, and then filtered. The filtrate was added to a solution of trimethoxybenzene (26.7 g, 158 mmol) in 1,2-dichloroethane (100 mL); with reaction mixture warming spontaneously to approximately 50° C. Thin layer chromatography of a water-quenched sample taken after four hours showed complete reaction. The reaction mixture was poured over ice, and ethyl acetate was added to extract the product. The ethyl acetate phase was washed twice with water and once with brine, then dried over anhydrous sodium sulfate. The solution was filtered and the solvent removed, then the resulting oil was dissolved in a warm 20% solution of ethyl acetate in hexane (250 mL). The solution was allowed to crystallize at room temperature for five hours, then at 4° C. for one hour. Filtration, washing the crystals with 10% ethyl acetate in hexane, and air-drying afforded 5-chloro-1-(2,4,6-trimethoxyphenyl)-1-pentanone, 34 g (83% yield), m.p. 53°-55° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.CO.BrBr.[NH2:13][C:14]([NH2:16])=[S:15]>O>[NH2:16][C:14]1[S:15][C:2]2[CH2:3][C:4](=[O:7])[CH2:5][CH2:6][C:1]=2[N:13]=1
Reactant: NC(N)=S
Reactant: O=C1CCC(=O)CC1
Agent: BrBr
Solvent: CO
Solvent: O
Product: Nc1nc2c(s1)CC(=O)CC2

Procedure:
8.8 g of 1,4-cyclohexanedione was dissolved with 40 mL of methanol. Solution was cooled to 10C and 4.2 mL of bromine was dropwise added at this temperature during 15 minutes. The temperature was kept at 10C for one hour and then allowed to rise to 20C. When bromine colour faded, 7.2 g of thiourea was added. The reaction mixture was then diluted with 20 mL of water and heated under reflux for 2 h. White precipitate was removed by filtration and filtrate was concentrated in vacuo and cooled. The crystals of product (6) were filtered off and washed with a cold water.
Reaction SMILES: N[C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH2:3][O:4][C:5](=[O:7])[CH3:6].C=O.[C:33]([BH3-])#[N:34].[Na+].[C:37](O)(=O)C>C(#N)C>[C:5]([O:4][CH2:3][C:2]([N:34]([CH3:33])[CH3:37])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:8][O:9][C:10](=[O:12])[CH3:11])(=[O:7])[CH3:6]
Reactant: [BH3-]C#N
Reactant: CCCCCCCCCCCCCCCCCCC(N)(COC(C)=O)COC(C)=O
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)N(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-1,3-diacetoxy-2-octadecylpropane (700 mg) was dissolved in 35 ml of acetonitrile and 1.38 g of 37% formaldehyde and 330 mg of sodium cyanoborohydride were added thereto. The mixture was stirred at room temperature for 1 hour. Acetic acid (0.265 ml) was added thereto and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by silica gel column chromatography using hexane-ethyl acetate (4:1→3:1) as an eluent to give 436 mg of colorless, oily 1,3-diacetoxy-2-(N,N-dimethylamino)-2-octadecylpropane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[NH:17][CH2:16]1)=[O:13])[CH2:7]2.[C:24]([O:28][C:29]([C@@H:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:32](O)=[O:33])=[O:30])([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N>[Cl:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([C:12]([O:14][C@@H:15]1[CH2:19][C@@H:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]([C:32](=[O:33])[C@@H:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:16]1)=[O:13])[CH2:7]2
Reactant: CC(C)(C)OC(=O)[C@H](C(=O)O)C(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2Cc3cccc(Cl)c3C2)CN1C(=O)[C@@H](C(=O)OC(C)(C)C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 200 mL round-bottomed flask was charged with (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-chloroisoindoline-2-carboxylate hydrochloride (1.20 g, 3.32 mmol), (S)-2-(tert-butoxycarbonyl)-3,3-dimethylbutanoic acid (807 mg, 3.49 mmol) and HATU (1.90 g, 4.98 mmol) in dry MeCN (30 mL). The solution was then cooled on an ethanol-ice bath and treated with DIEA (1.74 mL, 9.97 mmol) by dropwise addition. The mixture was stirred at 0° C. for 1 h, then allowed to warm up and stirred at room temperature for 16 h. The mixture was then concentrated and the residue dissolved in EtOAc (100 mL) and washed with iced 5% citric acid (aq.) (3×30 mL), 1M NaOH (3×30 mL), water (3×30 mL) and brine (3×30 mL). The organic layer was dried over MgSO4, filtered and concentrated to an oil. The oil was purified by chromatography (Biotage) eluting with 35% EtOAc-hexanes to give the product as a white foam, 1.27 g, 71%. MS m/e 438 (M+H)+−Boc. 1H NMR (400 MHz, d6-DMSO) δ 7.3-7.4 (m, 3H), 6.7-6.76 (m, 1H), 5.24 (bs, 1H), 4.4-4.76 (m, 4H), 4.12-4.2 (m, 1H), 3.96-4.3 (m, 1H), 3.7-3.78 (m, 1H), 3.64 (d, 3H), 2.38-2.48 (m, 1H), 2.07-2.16 (m, 1H), 1.14 (d, 9H), 0.98 (s, 9H).
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][OH:6])=[O:4].[CH3:19]I>[Ag]=O>[CH3:7][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:1])[C:3]([CH2:5][O:6][CH3:19])=[O:4]
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CO
Reactant: CI
Agent: O=[Ag]
Product: COCC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1

Procedure:
Methyl iodide (30 ml) and freshly prepared silver oxide (0.77 gm, 0.003 m) were added to N-(1',1'-dimethyl-3'-hydroxyacetonyl)-3,5-dichlorobenzamide (0.08 gm, 0.003 m) (Example 45) and the reaction mixture was refluxed for about 10 hours. Then fresh silver oxide (0.7 gm) was added and the mixture was refluxed for another 2 hours. The inorganic salts were removed by filtration, the filter cake was washed with ether and the solvents were stripped off to obtain 0.5 gm of product after recrystallization from ethylacetate and hexane.
Reaction SMILES: [CH2:1]([CH:5]1[O:9][C:8](=[O:10])[C:7]([OH:11])=[C:6]1[OH:12])[CH2:2][C:3]#[CH:4].I[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.OC1C(=O)OC(CCC#CC2C=CC=CC=2)C=1O>>[OH:11][C:7]1[C:8](=[O:10])[O:9][CH:5]([CH2:1][CH2:2][C:3]#[C:4][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:6]=1[OH:12]
Reactant: Ic1ccc2ccccc2c1
Reactant: C#CCCC1OC(=O)C(O)=C1O
Agent: O=C1OC(CCC#Cc2ccccc2)C(O)=C1O
Product: O=C1OC(CCC#Cc2ccc3ccccc3c2)C(O)=C1O
Yield: 78.2 %

Procedure:
5-(3-Butynyl)-3,4-dihydroxy-2(5H)-furanone (0.17 g, 1.0 mmol) and 300 μL (2.0 mmol) of 2-iodonaphthalene were coupled in an analogous fashion as described for the synthesis of 3,4-dihydroxy-5-[(4-phenyl)-3-butynyl]-2(5H)-furanone. The residue was purified over silica gel using CHCl3 /MeOH/AcOH (96/3/1) as eluant and dried at 0.05 mm Hg at 58° C. for 2 h to provide 230 mg (75%) of 3,4-dihydroxy-5-[4-(2-naphthyl)-3-butynyl]-2(5H)-furanone as a yellow wax: 1H NMR (acetone-d6) δ 8.4-8.3 (m, 1H), 7.96-7.88 (m, 2H), 7.70-7.43 (m, 4H), 4.98 (dd, J=3.4, 8.3 Hz, 1H), 2.82-2.75 (m, 2H), 2.48-2.29 (m, 1H), 2.00-1.85 (m, 1H); Anal Calcd for C18H14O4 +0.5 H2O: C, 71.27; H, 4.98. Found: C, 71.33; H, 4.87.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](C#N)[CH:15]=3)[N:10]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:25]([CH:32]([CH3:36])[C:33]([OH:35])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[CH3:38][N:39](C)CCCN=C=NCC>ClC(Cl)C>[C:38]([CH:22]1[CH2:21][O:20][CH:19]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:33](=[O:35])[CH:32]([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH3:36])[CH:7]=[CH:6][CH:5]=3)=[N:9]2)[CH2:24][CH2:23]1)#[N:39]
Reactant: CC(Oc1ccccc1)C(=O)O
Reactant: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: CC(Oc1ccccc1)C(=O)Nc1cccc(-c2nn(C3CCC(C#N)CO3)c3ccccc23)c1

Procedure:
To a solution of 3-(3-aminophenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.300 g, 0.94 mmol) in dichloroethane (10 mL) was added 2-phenoxy propionic acid (0.172 g, 1.034 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.216 g, 1.13 mmol). After overnight reaction at room temperature, the reaction mixture was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate and evaporated to dryness. The title compound was purified by column chromatography (SiO2, 25% ethyl acetate in hexanes) (0.370 g, 84%): ES-MS (m/z) 489 [M+Na], 467 [M+H]+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[CH2:10]([C:12]1[C:20]2[C:19]([C:21](O)=[O:22])=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:16][C:15]=2[NH:14][N:13]=1)[CH3:11].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>CN(C=O)C.CN1CCOCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:21]([C:19]1[C:20]3[C:12]([CH2:10][CH3:11])=[N:13][NH:14][C:15]=3[N:16]=[C:17]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[CH:18]=1)=[O:22])[CH2:2]2.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: NC1CN2CCC1CC2
Reactant: CCc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)NC3CN4CCC3CC4)c12
Temperature: 25 °C

Procedure:
To a solution of 1-aza-bicyclo[2.2.2]oct-3-ylamine (17 mg, 0.135 mmol) in 1 mL of DMF, N-methyl morpholine was added (42 mg, 0.42 mmol) followed by 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (34 mg, 0.12 mmol) dissolved in 0.5 mL of DMF. Then a solution of TOTU (43 mg, 0.13 mmol) in 0.5 mL DMF was added and the mixture stirred at r.t. over the weekend. The mixture was treated with 0.1 mL TFA, filtered off and purified by prep. HPLC to obtain the desired product 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide as TFA salt. In order to change from TFA salt to HCl salt and deprotection (for compounds bearing BOC-protecting groups) the compound was dissolved in 2 mL of 5-6M HCl iPrOH and the reaction was stirred at r.t. overnight. Then 10 mL of water were added and the mixture was freezed dried to give the desired product 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide as hydrochloride salt (12.7 mg, 23%).