Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][NH:18]C=O)[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>CO>[N:1]1([CH2:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CNCCCOc1cccc(CN2CCCCC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cccc(CN2CCCCC2)n1
Yield: 63 %

Procedure:
N-[3-(6-Piperidinomethyl-2-pyridyloxy)propyl]formamide (19.6 g, 70.7 mmoles) [prepared in Step B] was added to a solution of 85% potassium hydroxide pellets (18.63 g, 0.332 mole) dissolved in 180 mL of methanol and the solution was heated at gentle reflux for 20 hours. The solvent was stripped in vacuum and the residue partially purified by redissolving in about 180 mL of 20% methanol-methylene chloride and passing through a pad of 38 g of silica gel. The silica was washed with an additional 120 mL of eluant and the combined filtrates were evaporated to an amber oil. Final purification was effected by flash chromatography on 120 g of silica gel (230-400 mesh) using a gradient elution of methanol-methylene chloride containing 0.5% NH4OH. The title compound was obtained as a yellow oil in 63% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].C(N(C(C)C)CC)(C)C.[F:34][C:35]([F:46])([F:45])[CH2:36]OS(C(F)(F)F)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH2:36][C:35]([F:46])([F:45])[F:34])[CH2:21][CH2:20]3)[CH:18]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2cnn(C3CCNCC3)c2)nc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2cnn(C3CCN(CC(F)(F)F)CC3)c2)nc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 5-chloro-6-ethyl-3-{[1-(piperidin-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide (350 mg) and diisopropylethylamine (685 μL) in N,N-dimethylformamide (3.5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (433 μL), followed by reacting at room temperature for 2 hours. The mixture was subjected to liquid separation by the addition of ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1-90:10) to obtain 5-chloro-6-ethyl-3-({1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide (424 mg) as a yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[K+].O>C(O)C>[CH3:11][C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(C(=O)CSC#N)c1
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of 2-bromo-1-(3-methylphenyl)ethanone (3.03 g, 14.2 mmol) and potassium thiocyanate (1.45 g, 14.2 mmol) in ethanol (30 ml) was stirred at 80° C. for 2 hours. After cooling to room temperature, water (30 ml) was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 2.29 mg (84.2%) of the desired product as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Cl:14])=[O:4].[I-].[K+].[N-:17]=[N+:18]=[N-:19].[Na+].CN(C)C=O>O>[N:17]([CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=1[Cl:14])=[O:4])=[N+:18]=[N-:19]
Reactant: Cc1cc(C)c(NC(=O)CCl)c(Cl)c1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(NC(=O)CN=[N+]=[N-])c(Cl)c1
Temperature: 50 °C

Procedure:
A mixture of 2-Chloro-N-(2-chloro-4,6-dimethyl-phenyl)-acetamide (0.100 g, 0.00043 mol), potassium iodide (0.0072 g, 0.00043 mol), sodium azide (0.056 g, 0.00086 mol), and anhydrous dimethylformamide (7 mL) was heated in a 50° C. oil bath for 4 h. Upon cooling to room temperature, the reaction mixture was cooled to 0° C., water (10 mL) was added, and the solid product was collected by suction filtration, washed several times with water, and placed in a vacuum oven set at low heat for 4 h. The dried product amounted to 0.0934 g (0.391 mmol, 91%). 1H NMR (CDCl3, 300 MHz) δ 7.70 (br s 1H), 7.12 (s, 1H), 6.98 (s, 1H), 4.2 (s, 2H), 2.3 (s, 3H), 2.23 (s, 3H). LC/MS: tR=1.23 min., (MH+)=239.06.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8].[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12](=[O:29])[N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[C:14]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:13]2[C:12](=[O:29])[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[O:9][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH3:8])[C:14]2=[O:19])=[CH:22][CH:23]=1
Reactant: COCCOCCBr
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOCCOc1cccc2c1C(=O)N(Cc1ccc(OC)cc1)C2=O
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 72.9 %

Procedure:
1-(2-Bromo-ethoxy)-2-methoxy-ethane (107 mg, 0.58 mmol) was added to a suspension of 4-hydroxy-2-(4-methoxy-benzyl)-isoindole-1,3-dione (150 mg, 0.53 mmol) and potassium carbonate (200 mg, 1.4 mmol) in DMF (2 mL). After 3.5 hours, a catalytic amount of potassium iodide was added. After a further 17 hours, the mixture was warmed to 60° C. After 3 hours, an additional amount of 1-(2-bromo-ethoxy)-2-methoxy-ethane (20 mg, 0.11 mmol) was added and the mixture maintained at 60° C. for a further 20 hours. The mixture was concentrated in vacuo then the residue was taken up in ethyl acetate and washed with potassium carbonate solution and brine. The organic phase was dried (MgSO4) and concentrated to give the title compound as a yellow oil (149 mg, 73%). 1H NMR (methanol-d4) 7.71 (1H, t), 7.43-7.40 (2H, m), 7.31-7.27 (2H, m), 6.87-6.83 (2H, m), 4.71 (2H, s), 4.37-4.34 (2H, m), 3.92-3.89 (2H, m), 3.77-3.74 (5H, m), 3.55-3.53 (2H, m), 3.33 (3H, s). MS:
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[C:13](=[O:15])[CH3:14]>CO.O>[CH3:3][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:13]([CH3:14])[OH:15]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C(C)O)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.2 %

Procedure:
Sodium borohydride (0.02 g, 0.6 mmol) is added to a solution of 1-(2-methyl-3-nitrophenyl)ethanone (0.2 g, 1.1 mmol) in methanol (50 mL) at 0° C. The reaction mixture is stirred at room temperature for 1.5 hours, and then is diluted with water (100 mL). The aqueous mixture is stirred at room temperature an additional 5 hours followed by extraction with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, and evaporated. Flash chromatography of the residue (silica, methylene chloride) gives 2,α-dimethyl-3-nitrobenzenemethanol (0.14 g, 77%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[N:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: Cc1ccc(-c2cccc3c(N)c(C(=O)NC4CC4)nnc23)cn1
Yield: 79.3 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 6-methylpyridine-3-boronic acid (128 mg, 0.94 mmol) were reacted. After purification the title compound (119 mg, 80% yield) was obtained as a white solid. MS APCI, m/z=320.
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[N:10]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C[OH:24]>>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[N:10]=[C:9]([NH:8][C@@H:2]1[CH2:1][C@@H:6]3[CH2:7][C@H:3]1[CH2:4][C@H:5]3[OH:24])[CH:18]=[N:17]2
Reactant: CO
Reactant: CCCCCC(C)Nc1cnc2cc(OC)c(OC)cc2n1
Product: COc1cc2ncc(N[C@@H]3C[C@@H]4C[C@H]3C[C@H]4O)nc2cc1OC
Temperature: 22 °C
Reaction time: 24 h

Procedure:
The fungi is stored at −25° C. 250 mL conical flasks each containing 50 mL seed culture medium (medium 216) are inoculated with 2 mL of fungi suspension and incubated on a rotary shaker (200 rpm at 23° C. for 3 days. 250 mL conical flasks each containing 50 mL of the same medium were inoculated with mL of the seed culture and incubated on a rotary shaker (200 rpm ) at 23° C. After 24 hours, (1R,2R,4)- (+)-Bicyclo[2.2.]hept-2-yl-(6,7-dimethoxyquinoxalin-2-yl)-amine of Example 25 is dissolved in MeOH added to the flasks to a final concentration of 300 mg/L. The cultures are harvested after 24 hours of incubation. (Medium 216: Glucose 0.4%, Yeast extract 0.05%, Soya flour 0.05%, NaCI 0.05%, KH2PO4 0.05.) The extraction is performed using 2 volumes of acetonitrile, 1 volume de tert-butylmethyl ether and volume of n-heptane were added to 1 volume of broth. After magnetic stirring at 22° C, the extract separates to 3 layers. The intermediate layer is collected and evaporated to dryness, and redissolved in ethyl acetate. The ethyl acetate extract is separated on silica gel (0.04-0.063 mm) using ethyl acetate as eluent. Fractions containing the biotransformation product are separated on C1 8 silica using a H2O/MeOH gradient as eluent. This chromatography yields the pure titled compound as an amorphous yellow powder, m.p. 190-192° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[F:36]>>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:33]5[CH:32]=[CH:31][C:30]([F:29])=[C:35]([F:36])[CH:34]=5)=[CH:3][C:4]([C:25]([F:27])([F:28])[F:26])=[CH:5][C:6]=4[N:7]=3)[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncc(Cl)cc4Cl)CC3)[nH]c2c1
Product: Fc1ccc(-c2cc(C(F)(F)F)cc3nc(N4CCN(c5ncc(Cl)cc5Cl)CC4)[nH]c23)cc1F

Procedure:
The reaction of 4-bromo-2-[4-(3,5-dichloropyridin-2-yl)piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (99 mg, 0.2 mmol, Example 9) and 3,4-difluorophenylboronic acid (40 mg, 0.25 mmol, Aldrich) under the conditions of Example 10 gave the title compound as a light-yellow amorphous solid. MS (ESI, pos. ion) m/z: 528 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[CH:7]=1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Br)cc1-n1ccnc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
A mixture of 1-bromo-5-fluoro-4-nitro-2-(trifluoromethyl)benzene (16.0 g, 0.0556 mol), imidazole (4.0 g, 0.0588 mol) and N,N-diisopropylethylamine (10.1 mL, 0.0582 mol) in acetonitrile (160 mL) is stirred under nitrogen for 1.5 hour at 80° C. After concentration of the reaction mixture, the residue is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate, the combined organic phases are washed in turn with a saturated solution of ammonium chloride, brine and dried over sodium sulfate. Concentration and purification by cake filtration over silica gel, eluting with a mixture of ethyl acetate and cyclohexane from 2/8 to 1/1 affords the title compound as a yellow solid (16.1 g, 86.2%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10](Cl)(=[O:12])=[O:11].CC(C)=O.[OH-].[NH4+:19]>O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([NH2:19])(=[O:12])=[O:11]
Reactant: [NH4+]
Reactant: Cc1cccc(C)c1CS(=O)(=O)Cl
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cccc(C)c1CS(N)(=O)=O
Temperature: 2.5 °C
Yield: 84.6 %

Procedure:
A solution of (2,6-dimethylphenyl)-methanesulfonyl chloride (452 g, 2.07 mol) and acetone (2.0 L) was added over 90 m to cooled (0-5° C.), stirred, concentrated ammonium hydroxide (28%, 900 mL, 227 g NH3, 13.3 mol). The reaction mixture was maintained <10° C. during the addition. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Water (2.0 L) was added to the reaction mixture and it was stirred for 1 h at 0-5° C. The white solid was collected by filtration, washed with cold water (2×1 L), and vacuum dried to give 349 g (85%) of (2,6-dimethylphenyl)-methanesulfonamide with 99% purity (as determined by HPLC).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6](O)/[CH:7]=[CH:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:27]>>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH:9]([OH:27])[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCCC(O)/C=C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: CCCCCC=CCC(O)C=CC=CCC=CCCCC(=O)O

Procedure:
Unlabeled 15-HETE and (3H)-12-HETE are added to the citric acid quenched samples as internal standards. After chromatography of the extracted products on silica gel, (14C)-12-HETE is located by the UV absorbence of the added 15-HETE (with which it cochromatographs) and is quantitated by scintillation spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH3:2].[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N+:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[O-:17])[CH3:2]
Reactant: CCOc1ccccc1C=O
Reactant: CC(C)(C)NO
Solvent: ClC(Cl)Cl
Product: CCOc1ccccc1C=[N+]([O-])C(C)(C)C
Temperature: 25 °C
Reaction time: 70 h
Yield: 78 %

Procedure:
2-Ethoxybenzaldehyde (12.0 g, 79.90 mmol) and N-tert-butylhydroxylamine (10.69 g, 119.86 mmol) were mixed in chloroform with molecular sieves (50 g, 4A) and silica gel (10 g). The mixture was sealed under argon gas and stirred for 70 h at room temperature. The mixture was then filtered and the solid washed with ethyl acetate and the combined solution was rotary evaporated. Pentane (50 mL) was added to the liquid residue and isolation of the resulting solid afforded 13.79 g (78.0% yield) of the title compound as white crystals, m.p. 58.3° C. (Rf=0.55 on a silica gel plate using ethyl acetate as the eluant).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][N:15]2[C:20]([C:22]2[N:23]=[C:24]([CH3:34])[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:21])[O:11][CH:12]=1.[CH3:35][N:36]1C(=O)CCC1>C(OCC)(=O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]2[S:25][C:24]([CH3:34])=[N:23][C:22]=2[C:20]([N:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]2[CH2:13][C:10]2[O:11][CH:12]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:35]#[N:36])[N:9]=2)=[O:21])=[CH:28][CH:29]=1
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3Br)co2)c(-c2ccc(F)cc2)s1
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc(-c3ccccc3C#N)co2)c(-c2ccc(F)cc2)s1
Temperature: 180 °C

Procedure:
A mixture of the bromide (0.240 g) of example 176, Cu(I)CN (0.060 g) and N-Methyl pyrrolidinone (5 ml) was heated at 180° C. for 16 h. The cooled reaction mixture was diluted with ethyl acetate and passed through kiesselguhr, washing with ethyl acetate. The filtrate was washed with water, dried (sodium sulfate) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 20-50% ethyl acetate-pentane) to give the title compound as a pale yellow gum (0.101 g
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35]C(=O)OCC2C=CC=CC=2)[CH2:31][CH2:30]1.O>CS(C)=O>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Solvent: CS(C)=O
Solvent: O
Product: NC1CCN(c2cccc(-c3n[nH]c4cnc(-c5cccnc5)cc34)n2)CC1
Temperature: 100 °C

Procedure:
A mixture of 56.3 mg (0.150 mmol) of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and 211 mg, 0.90 mmol) of benzyl piperidin-4-ylcarbamate in 1.0 ml of dimethyl sulfoxide was heated at 100° C. for 24 hours. The mixture was mixed with water and extracted with ethyl acetate. The organic extracts were washed with water, 1% aqueous citric acid, water, brine, dried over MgSO4 and concentrated. The residue was heated in a mixture of 4 M of hydrogen chloride in 6 ml of dioxane and 2 ml of conc. hydrochloric acid at 60° C. for 18 hours. The mixture was concentrated in high vacuum and triturated with ethyl ether. The solid material was filtered out and washed with ethyl ether to give 144. Yield 13.7 mg (19%) over two steps. ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO): 14.17 (s, 1H), 9.41 (s, 1H), 9.29 (s, 1H), 8.99 (s, 1H), 8.93 (d, J=7.9 Hz, 1H), 8.87 (d, J=5.0 Hz, 1H), 8.14 (s, 3H), 8.07-7.99 (m, 1H), 7.76-7.69 (m, 1H), 7.51 (d, J=7.4 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 4.52 (d, J=13.3 Hz, 3H), 3.40 (s, 2H), 3.12 (t, J=11.9 Hz, 2H), 2.08 (d, J=10.1 Hz, 2H), 1.66 (dt, J=12.0, 8.5 Hz, 2H)
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([C@@H:9]3[CH2:13][C@H:12]([CH3:14])[CH2:11][N:10]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:8][C:4]=2[CH:3]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]([C@@H:37]3[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]3[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[NH:35][CH:36]=2)=[CH:28][CH:27]=1)#[CH:25].C(Cl)Cl>CN(C=O)C.[Cu]I>[C:18]([O:17][C:15]([N:10]1[CH2:11][C@@H:12]([CH3:14])[CH2:13][C@H:9]1[C:7]1[NH:6][C:5]2[CH:22]=[CH:23][C:2]([C:25]#[C:24][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[N:33]=[C:34]([C@@H:37]5[CH2:41][C@H:40]([CH3:42])[CH2:39][N:38]5[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[NH:35][CH:36]=4)=[CH:28][CH:27]=3)=[CH:3][C:4]=2[N:8]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@H]1C[C@@H](c2nc3cc(I)ccc3[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: C#Cc1ccc(-c2c[nH]c([C@@H]3C[C@H](C)CN3C(=O)OC(C)(C)C)n2)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]1C[C@@H](c2nc(-c3ccc(C#Cc4ccc5[nH]c([C@@H]6C[C@H](C)CN6C(=O)OC(C)(C)C)nc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of tert-butyl (2S,4S)-2-(5-iodo-1H-benzimidazol-2-yl)-4-methyl-pyrrolidine-1-carboxylate (68.5 mg, 0.16 mmol) in DMF (3 mL) are sequentially added tert-butyl (2S,4S)-2-[4-(4-ethynylphenyl)-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (47 mg, 0.13 mmol), Pd(DPPF)(Cl)2.CH2Cl2 (5.4 mg, 0.0067 mmol). The mixture is degassed well under vacuum and to it is added TEA (37 uL, 0.27 mmol), followed by CuI (1.2 mg, 0.0067 mmol). Then the reaction mixture is stirred under nitrogen at rt overnight. After removal of the solvent, the crude is purified by flash column chromatography on silica gel using methanol/CH2Cl2 0-5% to obtain tert-butyl (2S,4S)-2-[4-[4-[2-[2-[(2S,4S)-1-tert-butoxycarbonyl-4-methyl-pyrrolidin-2-yl]-1H-benzimidazol-5-yl]ethynyl]phenyl]-1H-imidazol-2-yl]-4-methyl-pyrrolidine-1-carboxylate (56 mg, 64%).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:11])=[N:6][CH:7]=[N:8][C:9]=1[Cl:10])[CH:2]=C.C[N+]1([O-])CC[O:16]CC1.CCCCCC>O1CCOCC1.[Os](=O)(=O)(=O)=O>[Cl:11][C:5]1[C:4]([CH2:1][CH:2]=[O:16])=[C:9]([Cl:10])[N:8]=[CH:7][N:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1c(Cl)ncnc1Cl
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=CCc1c(Cl)ncnc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a stirred solution of 5-allyl-4,6-dichloropyrimidine (2.5 g) in dry dioxane (25 mL), N-methyl morpholine N-oxide (2.3 g) and osmium tetroxide (0.85 mL, 25% solution in water) were added. The reaction mixture was stirred at room temperature for 2 hours before being quenched by solid sodium bisulphate. The reaction mixture was filtered through celite bed. The celite bed was washed with dioxane (10 mL). The combined filtrate was taken into a 100 mL three necked round bottom flask and sodium metaperiodate (6 g, in 5 mL water) was added. The reaction mixture was stirred at room temperature for about 3 hours, then diluted with water (30 mL). Aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. Evaporation of solvents under reduced pressure gave crude product, which was treated with hexane to offer a solid. The solid obtained was filtered, washed with cold hexane (50 mL) and dried under vacuum to get 2-(4,6-dichloropyrimidin-5-yl)acetaldehyde (1.7 g) as white solid. 1H NMR (DMSO-d6): δ 4.21 (s, 2H), 8.86 (s, 1H), 9.7 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8](Br)[C:9]([OH:11])=[O:10].[CH2:13]([N:15]1[C:19]([C:20]([C:22]2[CH:27]=[C:26]([OH:28])[C:25]([OH:29])=[C:24]([Cl:30])[C:23]=2[Cl:31])=[O:21])=[CH:18][CH:17]=[N:16]1)[CH3:14].Cl>CN(C)C=O.O>[Cl:30][C:24]1[C:25]2[O:29][CH:8]([C:9]([OH:11])=[O:10])[O:28][C:26]=2[CH:27]=[C:22]([C:20]([C:19]2[N:15]([CH2:13][CH3:14])[N:16]=[CH:17][CH:18]=2)=[O:21])[C:23]=1[Cl:31]
Reactant: O=C(O)C(Br)Br
Reactant: CCn1nccc1C(=O)c1cc(O)c(O)c(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nccc1C(=O)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)O2
Reaction time: 5 h
Yield: 38.1 %

Procedure:
6.9 g of potassium carbonate and 2.83 g of dibromoacetic acid are added to a solution of 3.01 g of (1-ethylpyrazol-5-yl)-(2,3-dichloro-4,5-dihydroxyphenyl)-methanone in 30 ml of dimethylformamide and the mixture is at 80° C. for 5 hours. After cooling the reaction mixture, water is added thereto and the mixture is adjusted to pH 1 by addition of 6N hydrochloric acid. The resultant crystals are collected by filtration, washed with water and recrystallized from dimethylformamide-water to give 1.36 g of 4,5-dichloro-6-(1-ethyl-5-pyrazolylcarbonyl)-1,3-benzodioxole-2-carboxylic acid.