Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[CH3:13][O:14][C:15](=[O:27])[CH:16]([NH2:26])[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([NH:26][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([O:24][CH3:25])[CH2:22][CH2:23]1
Reactant: COC(=O)C(N)CC1CCN(OC)CC1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCN(OC)CC1)NC(=O)Cc1cc(C)ccc1C
Reaction time: 0.5 h

Procedure:
2,5-Dimethylphenylacetyl chloride (2.1 g, 11.5 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester (1.7 g, 7.8 mmol) and K2CO3 (2.1 g, 15.2 mmol) in 50 mL of THF at room temperature. After the addition, the mixture was stirred for 0.5 h and diluted with 50 ml of water. The mixture was extracted with EtOAc five times and the combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel. Yield: 1.2 g of 2-[2-(2,5-dimethyl-phenyl)-acetylamino]-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester as a solid.
Reaction SMILES: COC([C:5]1[S:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[C:6]=1[NH2:15])=O.CN1CCNCC1.CN1CCCC1=O>O>[NH2:15][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:8]=2[S:9][CH:5]=1
Reactant: COC(=O)c1sc2cc(F)ccc2c1N
Agent: CN1CCNCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1csc2cc(F)ccc12
Temperature: 176 °C
Yield: 62.5 %

Procedure:
A mixture of methyl-6-fluoro-3-aminobenzo[b]thiophene-2-carboxylate (20.1 g), 1-methylpiperazine (13.1 g), and 1-methyl-2-pyrrolidinone (100 ml) was heated at 176° C. for 2 hrs, under nitrogen. The solution was diluted with water (400 ml) and extracted with ether. The combined extracts were washed with water, brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 9.32 g of 3-amino-6-fluorobenzo[b]thiophene.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[F:7][C:8]1[C:21]([NH2:22])=[CH:20][C:11]2[N:12]([CH2:17][C:18]#[CH:19])[C:13](=[O:16])[CH2:14][O:15][C:10]=2[CH:9]=1>O1CCOCC1>[CH2:1]([NH:4][C:5]([NH:22][C:21]1[C:8]([F:7])=[CH:9][C:10]2[O:15][CH2:14][C:13](=[O:16])[N:12]([CH2:17][C:18]#[CH:19])[C:11]=2[CH:20]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN=C=O
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Solvent: C1COCCO1
Product: C#CCN1C(=O)COc2cc(F)c(NC(=O)NCCC)cc21
Temperature: 80 °C

Procedure:
n-Propyl isocyanate (1.0 g, 11.7 mmol) was added to a solution of 7-fluoro-6-amino-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.20 g, 0.9 mmol) in dioxane (20 mL) with stirring. The reaction mixture was heated to 80° C. for 4 hours. More n-propyl isocyanate (0.43 g, 5 mmol) was added and the reaction mixture was maintained at 80° C. overnight. Then the solution was concentrated to dryness to afford N-n-propyl-N′-[7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one-6-yl]urea as a crude intermediate (1.1 g). This was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[O:6][C:5]([C:7]2[C:12]([C:13]#[N:14])=[C:11]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[F:23])[N:10]=[C:9]3[NH:24][N:25]=[C:26]([CH3:27])[C:8]=23)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH3:27][C:26]1[C:8]2[C:9](=[N:10][C:11]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([F:22])[C:16]=3[F:23])=[C:12]([C:13]#[N:14])[C:7]=2[C:5]2[O:6][C:2]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:3][CH:4]=2)[NH:24][N:25]=1
Reactant: Cc1n[nH]c2nc(-c3c(F)ccc(F)c3F)c(C#N)c(-c3ccc(Cl)o3)c12
Reactant: C1COCCN1
Product: Cc1n[nH]c2nc(-c3c(F)ccc(F)c3F)c(C#N)c(-c3ccc(N4CCOCC4)o3)c12
Yield: 35 %

Procedure:
A solution of 2.0 g (5.0 mmol) of 4-(5-chlorofuran-2-yl)-3-methyl-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in 11 ml of morpholine is refluxed for 20 h. The mixture is then concentrated, dissolved in dichloromethane and washed three times with 1N hydrochloric acid solution. The organic phase is dried over magnesium sulfate, filtered, and concentrated. The residue obtained is purified by chromatography on silica (ethyl acetate gradient in dichloromethane: 10 to 20%) to give 0.76 g (35%) of 3-methyl-4-(5-morpholinofuran-2-yl)-6-(2,3,6-trifluorophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of yellow crystals.
Reaction SMILES: Br[CH:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH2:9]([O:11][P:12]([O:16]CC)[O:13][CH2:14][CH3:15])[CH3:10]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([P:12]([O:13][CH2:14][CH3:15])([O:11][CH2:9][CH3:10])=[O:16])[CH2:7][CH3:8]
Reactant: CCOP(OCC)OCC
Reactant: CCC(Br)C(=O)OC
Product: CCOP(=O)(OCC)C(CC)C(=O)OC
Temperature: 110 °C
Reaction time: 72 h

Procedure:
Methyl 2-bromobutanoate (92 g, 0.508 mol) and triethylphosphite (95 g, 0.57 mol) were mixed, and the mixture was stirred at 110° C. for 3 days. The reaction mixture was dried under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1]S(OCC1CCOCC1)(=O)=O.[H-].[Na+].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([OH:33])=[O:32])=[CH:28][CH:29]=3)[C:24]([C:34]([CH:36]3[C:38]([CH3:40])([CH3:39])[C:37]3([CH3:42])[CH3:41])=[O:35])=[CH:23]2)[CH2:17][CH2:16]1.N>CN(C=O)C>[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([C:31]([O:33][CH3:1])=[O:32])=[CH:28][CH:29]=3)[C:24]([C:34]([CH:36]3[C:38]([CH3:40])([CH3:39])[C:37]3([CH3:42])[CH3:41])=[O:35])=[CH:23]2)[CH2:17][CH2:16]1
Reactant: CC1(C)C(C(=O)c2cn(CC3CCOCC3)c3ccc(C(=O)O)cc23)C1(C)C
Reactant: CS(=O)(=O)OCC1CCOCC1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(C(=O)C1C(C)(C)C1(C)C)cn2CC1CCOCC1
Yield: 44 %

Procedure:
The product of Example 114A (1.5 g, 5.1 mmol), the product of Example 18A (10 mmol), and NaH (60% dispersion in mineral oil, 0.61 g, 15 mmol) in 40 mL of DMF were processed as described in Example 1D to provide the title compound (0.89 g, 2.2 mmol, 44% yield) and 1-(tetrahydro-2H-pyran-4-ylmethyl)-3-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-1H-indole-5-carboxylic acid as a minor product (0.21 g, 0.55 mmol, 11% yield, MS (DCI/NH3) m/z 384 (M+H)+ for the carboxylic acid). Data for Example 114B (major product): 1H NMR (CDCl3, 300 MHz) δ ppm 1.33 (s, 6H), 1.36 (s, 6H), 1.40-1.58 (m, 4H), 1.95 (s, 1H), 2.06-2.24 (m, 1H), 3.34 (dt, J=11.6, 2.5 Hz, 2H), 3.92 (s, 3H), 3.94-4.01 (m, 2H), 4.06 (d, J=7.1 Hz, 2H), 7.36 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 8.00 (dd, J=8.5, 1.7 Hz, 1H), 9.12 (dd, J=1.7, 0.7 Hz, 1H); MS (DCI/NH3) m/z 398 (M+H)+; Anal. Calculated for C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C, 72.53; H, 7.90; N, 3.48.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])[CH2:52][OH:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.1 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl) methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 23l (3.30 g, 4.31 mmol) in methanol (60 mL) was added sodium borohydride (326 mg, 8.62 mmol) at 0° C. The mixture was warmed up to room temperature and stirred for 30 min. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL), and then water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23m as yellow oil (3.41 g, 100%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.57 (m, 1H), 7.45 (m, 2H), 7.28 (m, 13H), 7.03 (m, 2H), 6.78 (t, 1H), 6.60 (t, 1H), 4.87 (s, 1H), 4.79 (m, 3H), 4.68 (d, 1H), 4.51 (d, 1H), 4.39 (s, 1H), 4.06 (m, 5H), 3.93 (t, 3H), 3.77 (m, 2H), 3.52 (d, 1H), 3.18 (d, 1H), 3.09 (s, 3H), 1.32 (t, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([N+:25]([O-])=O)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[NH2:25][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:14]([N:11]1[CH2:12][CH2:13][CH:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]1)=[O:15])=[CH:24]2
Reactant: O=C(c1cc2cc([N+](=O)[O-])ccc2[nH]1)N1CCC(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]c(C(=O)N3CCC(Cc4ccccc4)CC3)cc2c1
Reaction time: 5 h
Yield: 58.7 %

Procedure:
A mixture of 0.5 g (1.38 mmol) of 1-(4-benzylpiperidine-1-yl)-1-(5-nitro-1H-indole-2-yl)methanone, 20 ml of methanol and 0.1 g of 10% Pd/C catalyst is hydrogenated for 5 h. The catalyst is filtered off, washed with methanol and the filtrate is concentrated. The residue is treated with diethylether and the precipitated crystals are filtered off to yield 0.27 g (59%) of the title compound. Mp.: 175-180° C. (diethylether).
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([F:7])([F:6])[CH2:4]I.[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[N:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:4][C:3]([F:7])([F:6])[CH:2]([F:8])[F:1])=[N:16][CH:17]=1)([O-:11])=[O:10]
Reactant: FC(F)C(F)(F)CI
Reactant: O=[N+]([O-])c1ccc(O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCC(F)(F)C(F)F)nc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
1,1,2,2-Tetrafluoro-3-iodo propane (0.5 g, 2 mmol) was added to a mixture of 5-nitro-2-hydroxy pyridine (860 mg, 6.1 mmol) and potassium carbonate (1.4 g, 10 mmol) in DMF (10 ml) and the reaction heated at reflux for 6 hr. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate (50 ml), washed successively with bicarbonate solution, water, brine, and dried. Concentration to dryness yielded 5-nitro-2-(2,2,3,3-tetrafluoro-propoxy)pyridine (394 mg, 75%) as an oil.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[C:9]([NH:20][C:21]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[O:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[C:9]([NH:20][C:21]([C:23]3[CH:24]=[N:25][C:26]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[O:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(N2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenyl-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 6.5 with a saturated sodium hydrogen carbonate aqueous solution. A solid substance was separated by filtration to obtain 56 mg of 4-phenyl-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoic acid as white solid.
Reaction SMILES: C(OCC)(=O)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCC(=O)CC1.C([O:26][C:27](=[O:36])[CH2:28][C:29]1([OH:35])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)C.[OH-].[Li+]>C1COCC1.O.O1CCOCC1>[OH:35][C:29]1([CH2:28][C:27]([OH:36])=[O:26])[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CCOC(=O)CC1(O)CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCOCC1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of ethyl acetate (2.3 mL, 24 mmol) in THF (60 mL), 1M solution of lithium hexamethyldisilazide in THF (24 mL, 24 mmol) is added at −78° C. After stirring 1 hour at the same temperature, tetrahydro-4H-pyran-4-one (1.9 mL, 20 mmol) is added dropwise, and the reaction mixture is allowed to warm to rt over 2 hours. The reaction mixture is diluted with H2O and extracted with EtOAc. The combined organic phases are washed with H2O and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give a crude product. To a solution of (4-hydroxy-tetrahydro-pyran-4-yl)-acetic acid ethyl ester (1.85 g) in 1,4-dioxane (5 mL) and H2O (5 mL), lithium hydroxide (235 mg, 9.8 mmol) is added at 0° C. After stirring for 7 hours at rt, the reaction mixture is diluted with H2O and extracted with Et2O. The aqueous layer is acidified with 1N HCl aq. and extracted with Et2O. The combined organic phases are washed with H2O and dried over Na2SO4. Concentration under reduced pressure and filtration through silica gel give a crude product. The material is used in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.C1C[O:13][CH2:12]C1>[Ni]>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][CH:12]=[O:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: N#Cc1ncccc1Cl
Agent: [Ni]
Product: O=CNCc1ncccc1Cl
Temperature: 90 °C

Procedure:
3-Chloro-pyridine-2-carbonitrile (0.4 g) was reduced by hydrogenation in the presence of RaNi (0.1 g) in THF/20% NH3 (5 mL) at 30 psi. The solvent was removed and the residue was treated with 88% formic acid (10 mL) and heated at 90° C. overnight. The solvent was removed under reduced pressure, and the residue was re-dissolved in EtOAc. The organic layer was washed with Na2CO3, brine, dried, and concentrated. The residue was purified by silica gel column chromatography eluting with 100% EtOAc to give 0.3 g of the title compound. MS (APCI) m/e 171 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.8.51-8.53 (m, 2H), 8.15 (s, 1H), 7.93 (d, J=7.98 Hz, 1H), 7.38 (dd, J=8.13, 4.16 Hz, 1H), 4.53 (d, J=5.52 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[N+:6]([C:9]1[C:14]([N+]([O-])=O)=[CH:13][C:12]([OH:18])=[C:11]([O:19][CH3:20])[CH:10]=1)([O-:8])=[O:7]>O>[CH2:1]([NH:5][C:14]1[C:9]([N+:6]([O-:8])=[O:7])=[CH:10][C:11]([O:19][CH3:20])=[C:12]([OH:18])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1O
Solvent: O
Product: CCCCNc1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A mixture consisting of 80 ml of n-butylamine, 10 ml of water and 0.1 ml (21.4 g) of 4,5-dinitro-2-methoxyphenol, prepared in Example 2, is heated under reflux. After 4 hours' heating, the reaction mixture is diluted with 800 g of ice-cold water; the expected product precipitates. After being drained and dried, it is taken up in 300 ml of dilute caustic soda and precipitated by adding acetic acid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14].[OH-].[Na+].Cl>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[C:11]([F:10])[CH:12]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Fc1cccc(Nc2nc(Cl)nc(Cl)n2)c1
Temperature: 2.5 °C

Procedure:
To cyanuric chloride (1.6614 g, 9 mmol) dissolved in acetone (20 mL) stirring at 0-5° C., was added a solution of 3-fluoroaniline (0.9 mL, 9 mmol) in acetone (5 mL) followed by the addition of 2.5 N NaOH (3.6 mL, 9 mmol). The reaction mixture was allowed to stir at 0-5° C. for 1 hour under nitrogen. The reaction mixture was poured over crushed ice and neutralized with 10% HCl and 10% NaOH. The solid that formed was collected by vacuum filtration and the resulting solid was dried overnight under vacuum. Flash column chromatography (SiO2, 70:30 hexanes:ethyl acetate) yielded a faint yellow solid (159a, 1.67 g, 72%), mp 143° C.; HPLC: Inertsil ODS-3V C18, 40:30:30 [KH2PO4 (0.01M, pH 3.2): CH3OH: CH3CN], 264 nm, Rt 23.5 min, 87.0% purity.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:2]=1.[C:16]([O-:20])(=[O:19])[CH2:17][CH3:18].[Na+].C(OC(=O)CC)(=O)CC.[OH-].[Na+]>>[CH3:18][C:17](=[CH:12][C:11]1[CH:14]=[CH:15][C:8]([O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)[C:16]([OH:20])=[O:19]
Reactant: CCC(=O)[O-]
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Agent: CCC(=O)OC(=O)CC
Agent: [Na+]
Agent: [OH-]
Product: CC(=Cc1ccc(Oc2cccnc2)cc1)C(=O)O
Yield: 55.7 %

Procedure:
A mixture of 7 g of 4-(3-pyridyloxy)benzaldehyde, 4 g of sodium propionate and 8 ml of propionic anhydride was heated at a temperature of 135° to 140° C. for 2 hours. After allowing the mixture to cool, the mixture was rendered alkaline with an aqueous solution of sodium hydroxide, washed with dichloromethane and rendered acidic with acetic acid. The precipitated crystals were separated by filtration, washed with water and recrystallized from methanol to obtain 5 g (56% yield) of 2-methyl-3-[4-(3-pyridyloxy)phenyl]propenoic acid as colorless prisms having a melting point of 191°-194° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]2=[O:20]>O1CCCC1.[OH-].[Na+]>[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16](=[O:19])[C:15]2([OH:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1
Reactant: O=C1Nc2c(Cl)cccc2C1=O
Agent: [Mg]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1Nc2c(Cl)cccc2C1(O)c1ccccc1

Procedure:
A Grignard reagent prepared from 62 g. magnesium, 400 g. bromobenzene in two liters tetrahydrofuran (THF) is added to 181 g. (1.0 mole) 7-chloroisatin (1a) in two liters THF at a rate to keep a gentle reflux. After three hours of reflux, the reaction is cooled and decomposed with 350 ml. saturated ammonium chloride, filtered, and the THF stripped to give a dark oil. The oil is dissolved in aqueous sodium hydroxide and precipitated with hydrochloric acid. Recrystallization from aqueous ethanol gives 7-chloro-3-hydroxy-3-phenyl-2-indolinone, m.p. 154°-156°.
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([NH:9][CH:10]=[N:11]2)=[C:7]([Cl:14])[N:6]=1)(=O)C.C([O:18][C@@H:19]1[C@H:23]([O:24]C(=O)C)[C@@H:22]([CH2:28][O:29]C(=O)C)[O:21][C@H:20]1C1N=C2C(NC=N2)=CN=1)(=O)C.N>Cl[Hg]>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:20]2[O:21][C@H:22]([CH2:28][OH:29])[C@H:23]([OH:24])[C@H:19]2[OH:18])=[C:7]([Cl:14])[N:6]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ncc3[nH]cnc3n2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)Nc1nc(Cl)c2[nH]cnc2n1
Agent: Cl[Hg]
Agent: N
Product: Nc1nc(Cl)c2ncn([C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)c2n1

Procedure:
The chloromercury derivative of 2-acetamido-6-chloropurine is condensed with 2,3,5-tri-O-acetyl-β-D-ribofuranosylpurine utilizing the method of Lee et. al. (1971), J. Med. Chem., 14:819. The condensation product was treated with ammonia to yield 2-amino-6-chloro-9-(β-D-xylofuranosyl)purine. Further treatment with sodium hydroxyethylmercaptide gives the title compound.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[Cl:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[Cl:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(n2c(Cl)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O

Procedure:
(±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (850 mg, 1.92 mmol) in dry N,N-dimethylformamide (5 mL) was maintained at 95° C. while N-chlorosuccinimide (760 mg) was added in portions over 3 hours. Heating was continued for a total of 6 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Title compound was eluted with ethyl acetate:hexanes/3:7 as a yellow solid (160 mg, 17%), 1H-NMR consistent with structure and almost identical with that of title compound of Example 3.
Reaction SMILES: [Na+].[C:2]([O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O-:15])=[O:14])=[O:8])([CH3:5])([CH3:4])[CH3:3].CN(C=O)C.[I-].[K+].[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(OCC)(=O)C>[C:2]([O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:14])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)[O-])c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)OCOC(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.8 %

Procedure:
3-(t-Butyloxycarbonylamino)benzoic acid sodium salt (10 g), DMF (60 ml) and potassium iodide (6.3 g) are mixed, and thereto is added dropwise pivaloyloxymethyl chloride (6 g) under ice cooling. The mixture is stirred at room temperature for 15 hours, and thereto is added ethyl acetate (200 ml). The mixture is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is recrystallized from 70% aqueous acetonitrile to give pivaloyloxymethyl 3-(t-butyloxycarbonylamino)benzoate (11.9 g).
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(OCC)(=O)C>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][CH:6]([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:5][CH2:4]1
Reactant: CON1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CON1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 126.3 %

Procedure:
21 g 1-Methoxy-piperidin-4-ol (from Step 1) and 19.4 g triethylamine were dissolved in 200 ml ethyl acetate, and cooled to 0° C. 15.0 g Methanesulfonyl chloride was added slowly. The resulting white suspension was stirred at 0° C. for 1 hour, then at room temperature for an additional 1 hour. Then the mixture was filtered and the solvent evaporated, yielding 34.6 g of methanesulfonic acid 1-methoxy-piperidin-4-yl ester. This material was used for the next step without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[N:20][NH:21][CH:22]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:23]([F:25])([F:26])[F:24])=[N:20][N:21]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH:22]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: CCOC(=O)c1cn(-c2ccc3[nH]ccc3c2)nc1C(F)(F)F
Yield: 72.1 %

Procedure:
1H-indol-5-ylboronic acid (1,000 mg, 6.21 mmol) and 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (646 mg, 3.10 mmol) were reacted according to the same procedure as Preparation 1 to give the title compound (723 mg, 72% Yield).