Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH2:14])=O)[CH:10]=2)[N:5]=[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][N:3]12.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][N:3]1[C:2]2=[O:1])#[N:14]
Reactant: NC(=O)c1ccc2nc3ccccn3c(=O)c2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc2nc3ccccn3c(=O)c2c1
Reaction time: 10 h

Procedure:
4.8 gm of 11-oxo-11-H-pyrido[2,1-b]quinazoline-2-carboxamide (see Example 14) were suspended in 150 ml of dimethylformamide, the suspension was heated to 50°-60° C, and 3.3 ml of thionyl chloride were added dropwise to the hot suspension. After all of the thionyl chloride had been added, the mixture was stirred for 10 hours at 90°-100° C. Thereafter, the reaction mixture was neutralized with a dilute aqueous sodium carbonate solution, and the precipitate was collected by suction filtration and recrystallized from dimethylformamide, yielding the compound of the formula ##STR23## which had a decomposition point of 268°-271° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]([CH3:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([O:17][C:18]([NH:20][NH2:21])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10](=[N:21][NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)C(=NOC)C(C)=O
Solvent: CCO
Product: CCOC(=O)C(=NOC)C(C)=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and anti isomers) (34.6 g.) and t-butoxycarbonylhydrazine (26.4 g.) in ethanol (200 ml.) was stirred for 7.5 hours at ambient temperature and allowed to stand overnight to precipitate crystals. The crystals were collected by filtration, washed with ethanol and dried to give ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn and anti isomers) (41.7 g.), mp 144° to 145° C.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([C:13]#[C:14][C:15]#[C:16][C:17]#[C:18][C@@H:19]2[O:21][C@H:20]2[CH2:22][OH:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:7]1([C:13]#[C:14][C:15]#[C:16][C:17]#[C:18][C@@H:19]2[O:21][C@H:20]2[CH:22]=[O:23])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OC[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
Chromium trioxide (951 mg, 9.51 mmole; dried in vacuo over phosphorous pentoxide) was added to a stirred solution of 1.49 g (18.88 mmole) of dry pyridine in 25 ml of dry methylene chloride. The deep red solution was stirred for 15 minutes at room temperature. A solution of (trans)-3-(6-phenyl-1,3,5-hexatriynyl)oxiranemethanol (300 mg, 1.35 mmole; see example 3) in 5 ml of dry methylene chloride was then added in one portion. A tarry, black deposit separated immediately. After stirring for 20 minutes at room temperature, the solution was decanted and filtered through a pad of silica gel. Several portions of ether were then passed through the silica gel. Solvent was removed from the combined filtrates and the residue was chromatographed on silica gel (ether-hexane) to afford 130 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[N:10]=2)[CH:7]=1.O1CCOCC1.[NH:26]1[CH:30]=[CH:29][C:28](B(O)O)=[N:27]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:14]1([NH:13][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([C:30]4[CH:29]=[CH:28][NH:27][N:26]=4)=[CH:7][N:6]3[CH:8]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1ccccc1)c1cn2cc(I)ccc2n1
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1cn2cc(-c3cc[nH]n3)ccc2n1
Yield: 16 %

Procedure:
300 mg of 6-iodo-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 2), 4 mL of dioxane, 4 mL of water, 185 mg of 1H-pyrazole-3-boronic acid, 45 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and 1.077 g of caesium carbonate are placed in a microwave tube. The mixture is heated for 20 minutes in a microwave machine set at 160° C., and then cooled, diluted with 20 mL of water and extracted twice with 20 mL of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a gradient of dichloromethane and methanol (from 0 to 10%). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 40 mg of N-phenyl-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[OH-].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.OS([O-])(=O)=O.C1COCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[CH:7][N:8]2[S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3ccc(Cl)cc32)cc1
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-1H-indole (2.0 g, 13.2 mmol) and NIS (4.45 g, 19.8 mmol) in THF (60 mL) is stirred at 0° C. After completion the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords 6-chloro-3-iodo-1H-indole as a colorless powder. A mixture of 6-chloro-3-iodo-1H-indole (4.14 g, 13.2 mmol), TsCl (3.77 g, 19.8 mmol), TBAHS (672 mg, 1.98 mmol) and NaOH (16.0 g, 400 mmol) in THF (60 mL) and H2O (25 mL) is stirred at RT. After completion the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Re-crystallization from EtOAc of the residue affords the title compound as a colorless powder; ES-MS: M−H=430.0: AtRet=8.66 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][Cl:24])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCCCCl
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCCCCl)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
4-Amino-piperidine-1-carboxylic acid benzyl ester (12.0 g) in dichloromethane (100 mL) was added to pyridine (7.2 mL). The solution was cooled to 0° C. then 5-chlorovaleryl chloride (7.3 g) was added drop wise to the reaction. The reaction was warmed to room temperature. After 5 hours the reaction was diluted with dichloromethane and washed with water (1×), saturated aqueous copper sulfate (2×), and water (1×). The organic extracts were dried and evaporated. The resulting solids were suspended in ether, filtered, and then placed under high vacuum to give the title compound as a white solid (15.6 g). Rf=0.60 in ethyl acetate.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH:7]([S+:14]([O-:19])[CH2:15][C:16]([NH2:18])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.C1(C(C2C=CC=CC=2)S(CC(O)=O)=O)C=CC=CC=1.CC(N)C1C=CC=CC=1>C(O)C>[CH:11]1[CH:10]=[CH:9][C:8]([CH:7]([S@@:14]([CH2:15][C:16]([NH2:18])=[O:17])=[O:19])[C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[CH:13][CH:12]=1
Reactant: NC(=O)C[S+]([O-])C(c1ccccc1)c1ccccc1
Agent: CC(N)c1ccccc1
Agent: O=C(O)CS(=O)C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: NC(=O)C[S@@](=O)C(c1ccccc1)c1ccccc1

Procedure:
U.S. Pat. No. 4,927,855 describes the preparation of the levorotatory enantiomer of modafinil by chiral resolution of the 2-[(diphenylmethyl)sulfinyl]acetic acid with α-methylbenzyl amine. After recovery and amidation of the enantiomerically pure acid, (−) modafinil was obtained as white crystals by crystallization from ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C@H:10]([OH:14])[C:11]([O-:13])=[O:12].C[C@H]([NH3+])C1C=CC=CC=1.Cl>O>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@H:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[C@H:10]([OH:14])[C:11]([OH:13])=[O:12]
Reactant: COc1ccc([C@@H](Sc2ccccc2N)[C@H](O)C(=O)[O-])cc1
Agent: C[C@H]([NH3+])c1ccccc1
Agent: Cl
Solvent: O
Product: COc1ccc([C@@H](Sc2ccccc2N)[C@H](O)C(=O)O)cc1
Yield: 80 %

Procedure:
Dissolve the (-)-salt 4 (42.85 g, 97.26 mmol) in boiling water (430 mL). Add hot 1N HCl (98 mL). Reflux for 1 min. Cool the mixture in an ice-water bath and stir vigourously to precipitate. Check (and adjust if necessary) the pH of the solution to 5.0 (pH meter). Collect the solid by filtration. Wash with water and dry in vacuo at 40° C. to obtain the title compound 5 (24.85 g, 80%). m.p. 175°-176° C. [α]D23 -362.8° (1.2 DMF).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[F:19][C:20]1[CH:21]=[C:22]([CH2:28]C(O)=O)[CH:23]=[C:24]([F:27])[C:25]=1[F:26].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:19][C:20]1[CH:21]=[C:22]([CH2:28][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:23]=[C:24]([F:27])[C:25]=1[F:26]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cc1cc(F)c(F)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Triethylamine (0.808 mL) and benzyl chloroformate (0.752 mL) were sequentially added dropwise to a solution of 3,4,5-trifluorophenylacetic acid (1 g) in methylene chloride (15 mL) at 0° C., and the reaction solution was stirred at 0° C. for five minutes. DMAP (64.4 mg) was added to the reaction solution which was then stirred at 0° C. for 30 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.43 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=O)[C:14]2([CH3:18])[CH3:17])=[CH:9][CH:8]=1.Cl.[F:21][C:22]1[CH:23]=[C:24]([NH:28]N)[CH:25]=[CH:26][CH:27]=1.O>CCCCCC.C(OCC)(=O)C>[F:21][C:22]1[CH:23]=[C:24]2[C:25]([C:12]3[CH2:11][C:10]4[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:16][C:15]=4[C:14]([CH3:18])([CH3:17])[C:13]=3[NH:28]2)=[CH:26][CH:27]=1
Reactant: NNc1cccc(F)c1
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2
Temperature: 95 °C
Reaction time: 3.75 h
Yield: 49.7 %

Procedure:
Under nitrogen atmosphere, the acetic acid (1 mL) suspension of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 101.0 mg, 0.495 mmol) and (3-fluoro-phenyl)-hydrazine hydrochloric acid salt (Compound V1, 96.5 mg, 0.593 mmol) was stirred at ambient temperature of 95° C. for 3.75 hr. After cooling to room temperature, the reaction mixture was added with water (1 mL) and hexane/ethyl acetate (15:1) (0.5 mL), and stirred at room temperature for 15 min. The solid was filtered, washed with hexane/ethyl acetate (15:1), and then dried under reduced pressure to obtain the title compound (beige powder, 72.7 mg, 50%).
Reaction SMILES: [C:1]([N:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:10]1=[CH:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[O:29][Si](C(C)(C)C)(C)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([N:9]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:10]1=[CH:11][CH2:12][C@@H:13]1[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]1[CH2:15][CH2:16][C@@H:17]2[OH:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H]2[C@@H]3CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: *CC*
Agent: F
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4N(C(=O)c5ccccc5)C(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
To the product of Step A, above, (2.0 g) in THF (80 ml) in a polyethylene bottle was added hydrofluoric acid (2.0 ml) dropwise. The mixture was sitrred at room temperature until the reaction was complete. The mixture was neutralized with saturated sodium bicarbonate solution until slightly alkaline. The mixture was concentrated, and extracted with methylene chloride. The organic layer was dried (Na2SO4), and concentrated to a residue which was purified via flash silica gel column chromatography eluted with 40-50% EtOAc in hexane to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])=[C:4]2[N:3]=1.[OH-].[NH4+:26]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:26])[N:5]2[N:9]=[C:10]([CH3:24])[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[C:14]=3[CH3:23])=[C:4]2[N:3]=1
Reactant: [NH4+]
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn2c(N)cc(Cl)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 20 °C
Reaction time: 30 h

Procedure:
To a suspension of 5,7-dichloro-2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidine (374 mg, 1.0 mmol), prepared as described in Example 1 step c, and 30% ammonium hydroxide solution (584 mg, 5.0 mmol) in 1,4-dioxane (5 mL) stirred at 20° C. for 30 hours. Reaction mixture was concentrated in vacuo. The residue was dissolved with ethyl acetate (50 mL) and 5 NaHCO3 solution (10 mL). Organic layer was separated, washed with brine (5 mL) and dried. Crude product was purified on silica gel column chromatography (methanol and DCM, 0-10%). Fractions were collected and concentrated to afford the titled product, which was in next step. (331 mg, 93%); LC/MS: MS (ES+) m/e 355 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[NH2:25].N#N.C(O[K])(C)(C)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C(Cl)(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:5]3=[N:6][CH:7]=2)[CH:26]=[CH:27][C:28]=1[N:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]1
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2nc(C)c3cc(Nc4ccc(N5CCN(C)CC5)c(F)c4)cnc32)cc1
Temperature: 90 °C

Procedure:
A stirred solution of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (100 mg, 0.301 mmol) and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline (168) (77 mg, 0.33 mmol, 1.1 eq) in 1,4-dioxane (10 mL) was degassed and purged with N2 for 10 min. tert-BuOK (101 mg, 0.903 mmol, 3.0 eq) was added and the reaction mixture purged and degassed again. To this reaction mixture was added ±BINAP (8 mg, 0.00301 mmol, 0.01 eq) and Pd2(dba)3 (11 mg, 0.0012 mmol, 0.04 eq) and the resulting reaction was heated at 90° C. for 12 hrs in sealed tube condition. After completion of the reaction the contents were cooled and diluted with CHCl3 and filtered through Celite bed. The CHCl3 layer was completely distilled off to get the crude product. The crude was passed through 100-200 mesh silica gel, eluting the pure compound N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-amine 169 obtained with 6% MeOH in CH2Cl2 as an off-white colored solid in 40 mg quantity.
Reaction SMILES: CS([CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[C:19]#[N:20])=[CH:8][CH:7]=1)(=O)=O.[Li+].[Br-:24]>C1COCC1>[Br:24][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[C:19]#[N:20])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cc1ccc(Oc2cccc(C#N)c2C#N)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(Oc2ccc(CBr)cc2)c1C#N
Temperature: 25 °C

Procedure:
To a solution of 3-[4-(methansulfonylmethyl)phenoxy]phthalonitrile (1.1 g, 3.1 mmol) prepared according to Example 2, in anhydrous THF (15 ml) kept in an inert atmosphere, LiBr (0.4 g, 4.6 mmol) was added. The solution was refluxed for 1 hour, during which a white precipitate formed, then it was allowed to cool at room temperature. The white precipitate was filtered off and the solvent was evaporated. From the crude mixture the desired product was isolated by filtration on silica gel (eluent: chloroform). (900 mg, 93%).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].I[CH3:13]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: CI
Reactant: O=C(O)c1cccc(Br)c1F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Br)c1F
Temperature: 50 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzoic acid (10 g, 0.045 mol) in N,N-dimethylformamide (50 mL) was added iodomethane (5 mL) dropwise. The reaction was heated to 50° C. for 24 hours. After the reaction was cooled and diluted with water (500 mL), ethyl acetate (200 mL) was added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.Cl.Cl.Cl.[NH2:9][N:10]1[O:22][C:21]2[C:20]3[CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[S:14][C:13]=2[N:12]=[C:11]1[S:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:29][CH2:28]1.C(Cl)(=O)C>C(N(CC)CC)C>[C:2]([N:17]1[CH2:16][C:15]2[S:14][C:13]3[N:12]=[C:11]([S:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:42]=[CH:41][C:40]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:34]=5)[CH2:29][CH2:28]4)[N:10]([NH2:9])[O:22][C:21]=3[C:20]=2[CH2:19][CH2:18]1)(=[O:1])[CH3:3]
Reactant: C1CCOC1
Reactant: NN1Oc2c(sc3c2CCNC3)N=C1SCCCN1CCN(c2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2c(sc3c2ON(N)C(SCCCN2CCN(c4ccc5ccccc5n4)CC2)=N3)C1
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 10 ml of tetrahydrofuran, 203 mg of 3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)-propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene trihydrochloride as synthesized in Example 1-59 was added and into which 133 mg of triethylamine was dropped. Acetyl chloride was added to the mixture under cooling with ice, followed by 30 minutes stirring and distillation under reduced pressure. The residue was purified on silica gel column chromatography (chloroform:methanol=25:1) to provide 150 mg (83%) of 7-acetyl-3-amino-2-[3-(4-quinolin-2-ylpiperazin-1-yl)propylthio]-3,4,5,6,7,8-hexahydro-4-oxa-9-thia-1,3,7-triaza-9H-fluorene.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1Cl.[CH3:12]O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:4]=[C:3]([CH3:12])[C:2]([NH2:1])=[C:9]([I:10])[CH:8]=1
Reactant: CO
Reactant: N#Cc1cc(Cl)c(N)c(I)c1
Solvent: C1CCOC1
Product: Cc1cc(CN)cc(I)c1N
Reaction time: 12 h

Procedure:
4-Amino-3-chloro-5-iodobenzonitrile (65.2 mg, 0.23 mmol) was dissolved in THF at 0° C. After Borane-THF complex (4 eq, 0.94 mmol, 0.94 ml) was slowly added into the reaction mixture, A reaction temperature was heated to reflux. The reaction mixture was stirred for 12 hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4 hr. The reaction solvent was removed in vacuo. A residue was extracted with Ethyl acetate, washed with H2O and brine, dried with Na2SO4 and concentrated in vacuo to yield 4-Aminomethyl-2-iodo-6-methyl-phenylamine (19.4 mg).
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([N+:32]([O-])=O)[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[CH:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CO.O.[Zn]>[F:1][C:2]1[CH:31]=[C:30]([CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)[CH:18]=3)[S:13][C:6]=12)[NH2:32]
Reactant: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cn2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CN1CCN(CCn2cc(-c3cc4nccc(Oc5ccc(N)cc5F)c4s3)cn2)CC1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
To a solution of 152 (150 mg, 0.311 mmol) in MeOH (20 mL) was added ammonium chloride (33.3 mg, 0.622 mmol) in water (5 mL) and zinc powder (81 mg, 3.01 mmol) and the reaction mixture was heated to reflux for 3 hours. The mixture was cooled to RT then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM and washed with water. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 153 (132 mg, 92% yield) that was used directly in the next step with no additional purification. MS (m/z)=453.2 (M+H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.[CH3:35][NH2:36]>O>[CH2:33]([O:32][C:30]([C:28]1[N:27]=[N:26][N:25]([C:13]2[N:12]=[C:11]3[C:16]([N:17]=[CH:18][N:10]3[CH:3]3[C@H:2]([OH:1])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4]3)=[C:15]([NH:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[N:14]=2)[CH:29]=1)=[O:31])[CH3:34].[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([NH:36][CH3:35])=[O:32])[N:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CN
Agent: CCOC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Solvent: O
Product: CNC(=O)c1cn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)nn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
70 mg of the ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylate prepared in Example 4A was dissolved in 5 mL of 40% methylamine in water in a sealed tube. The mixture was stirred at 50° C. for 2 hours. A white precipitate formed and was collected by filtration. The collected filtrate was washed with water and ethyl ether to provide the product, (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}(1,2,3-triazol-4-yl))-N-methylcarboxamide ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-1,2,3-triazole-4-carboxylate.