Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:4][N:3]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1.O>CN(C=O)C>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][S:1][C:2]2[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: NC(=O)c1c(S)nsc1Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(SCc2ccc(Cl)cc2)nsc1Nc1cccnc1
Reaction time: 1 h
Yield: 48.7 %

Procedure:
Compound 14 (50 mg, 0.14 mmol) is dissolved in DMF (0.15 mL) and Hunig's base is added (0.048 mL, 0.27 mmol) followed by 4-chlorobenzyl chloride (22 mg, 0.14 mmol) at room temperature. The reaction is stirred for 1 hour and then water (0.2 mL) is added and the resulting solids are filtered and washed with water and then methylene chloride to provide 3-(4-Chloro-benzylsuIfanyl)-5-(pyridin-3-ylamino)-isothiazole-4-carboxylic acid amide (25.7 mg, 49%). 1H NMR (d6 DMSO): δ 10.37 (1H, br. s), 8.51 (1H, d, J=2.8 Hz), 8.26 (1H, d, J=4.4 Hz), 7.61–7.64 (1H, m), 7.42 (2H, d, J=8 Hz), 7.38–7.41 (1H, m), 7.33 (2H, J=8 Hz), 4.40 (2H, s). LRMS (M+): 376.9, (M−): 374.9.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14](O)=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[Cl-].C[NH3+].[CH3:31][N:32](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:18]=[CH:17][C:11]([O:12][CH2:13][C:14]([NH:32][CH3:31])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1
Reactant: Nc1ncc(-c2ccc(OCC(=O)O)cc2)cc1-c1nc2ccccc2s1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COc1ccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-[6-amino-5-(1,3-benzothiazol-2-yl)pyridin-3-yl]phenoxyacetic acid (20 mg, 0.050 mmol) in DMF (1.0 mL) were added methylammonium chloride (4 mg, 0.06 mmol), TBTU (19 mg, 0.060 mmol) and DIEA (0.05 mL, 0.3 mmol). The mixture was left to stir at rt for 30 min. Purification via MDP afforded the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.67 (d, J=4.8 Hz, 3H), 4.51 (s, 2H), 7.04-7.10 (m, 2H), 7.45-7.52 (m, 1H), 7.54-7.59 (m, 1H), 7.63-7.68 (m, 2H), 7.97 (s, 2H), 8.10 (d, J=7.8 Hz, 1H), 8.13-8.17 (m, 2H), 8.48 (d, J=2.3 Hz, 1H). MS (ES+): m/z=391.10 (100) [MH+]. HPLC: tR=3.20 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([NH:13][CH3:14])=[S:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl>>[CH3:14][N:13]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][NH:10][C:11]1=[S:12]
Reactant: CNC(=S)NNC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1c(-c2ccccc2)n[nH]c1=S

Procedure:
A stirred mixture of 1-benzoyl-4-methylthiosemicarbazide (20.9 g, 1.00×10-1 mole) and 1 molar aqueous NaHCO3 (1000 ml, 1 mole) was heated to reflux. After refluxing overnight the reaction was cooled in an ice bath. With stirring the solution was carefully acidified by the dropwise addition of conc. HCl (92 ml, 1.1 mole). A colorless precipitate formed and this was subsequently collected by filtration. Crystallization from ethanol afforded colorless, chunky crystals, Mp 164°-166° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C.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]>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:31]3[CH:30]=[N:29][C:28]([O:27][CH3:26])=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(C(F)(F)F)ccc2/C=C/C(=O)Nc2ccc3[nH]ccc3c2)cn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol), 2-methoxy-5-pyridineboronic acid (60 mg , 0.39 mmol, Digital Specialty Chemicals), tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol, Aldrich) and triphenylphosphine (26 mg, 0.098 mmol, Aldrich) in toluene (1.2 mL), 2.0M aqueous Na2CO3 (0.4 mL) and ethanol (0.4 mL) was stirred at 120° C. overnight. The reaction mixture was filtered through a pad of Celite and diluted with water (50 mL). The aqueous phase was extracted with EtOAc (3×60 mL). The combined extracts were washed with satd NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (gradient: 0-20% EtOAc in hexane) provided the title product as a yellow solid. MP 219-221° C. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[I:15]Cl.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:15][C:6]1[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(I)c(CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
3,4-Dimethoxyphenylacetic acid (4.0 g, 20.4 mmol) was dissolved in 100 ml of glacial acetic acid. Iodine monochloride (1.35 eq, 1.38 ml) was added slowly and the mixture was allowed to stir at room temperature overnight. To the mixture was added 300 ml of a 10% aqueous solution of sodium bisulfite. The mixture was concentrated in vacuo to remove most of the acetic acid. The aqueous residue was extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with diethyl ether and the solid was then filtered and dried to give (2-iodo-4,5-dimethoxy-phenyl)-acetic acid (2.94 g, 44.8%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].C=O.[C:20](=O)([O-])[O-].[K+].[K+]>CO>[CH2:13]([CH:12]1[CH2:20][C:3]2[C:4](=[CH:5][C:6]([F:10])=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])[C:11]1=[O:17])[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])[O-]
Reactant: CCCCCC(=O)c1cc(F)c(OC)c(Cl)c1
Agent: C=O
Agent: [K+]
Solvent: CO
Product: CCCCC1Cc2c(cc(F)c(OC)c2Cl)C1=O
Temperature: 50 °C

Procedure:
A mixture of the crude 1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone from step 1, methanol (8.7 mL), 37% aqueous formaldehyde (0.786 mL, 10.5 mmol), and potassium carbonate (1.2 g, 8.72 mmol) was stirred and heated in an oil bath at 50° C. for 7 hours. The mixture was evaporated under vacuum and the residue partitioned between EtOAc (100 mL) and water (100 mL) containing 2N HCl (10 mL). The organic phase was washed with brine (50 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (1.86 g) consisting of predominantly 1-(3-chloro-5-fluoro-4-methoxyphenyl)-2-(methoxymethyl)-1-hexanone.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[C:13]1[NH:14][N:15]=[C:16]([CH2:18][O:19][CH3:20])[N:17]=1)=[O:4].ClCC(NC1C=CC(Cl)=CC=1C1NN=C(COC)N=1)=O>>[Br:12][C:9]1[CH:10]=[CH:11][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:14]3[C:13](=[N:17][C:16]([CH2:18][O:19][CH3:20])=[N:15]3)[C:7]=2[CH:8]=1
Reactant: COCc1n[nH]c(-c2cc(Br)ccc2NC(=O)CCl)n1
Agent: COCc1n[nH]c(-c2cc(Cl)ccc2NC(=O)CCl)n1
Product: COCc1nc2n(n1)CC(=O)Nc1ccc(Br)cc1-2
Yield: 68 %

Procedure:
As described for example 4d) 2-chloro-N-[4-bromo-2-(5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-phenyl]-acetamide (20.6 g, 57.3 mmol), instead of 2-chloro-N-[4-chloro-2-(5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-phenyl]-acetamide, was converted to the title compound (12.6 g, 68%) which was obtained as an off-white solid. MS: m/e=322.0/324.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)([CH3:9])[CH2:3][C:4](OCC)=[O:5].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.ClCCl>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:12]=[CH:11][C:10]([C:2]([OH:1])([CH3:9])[CH2:3][CH2:4][OH:5])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)(CCO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.00 g (25.34 mmol) of the compound from Example 88A, dissolved in 150 ml of tetrahydrofuran, were added dropwise to 76.0 ml (76.0 mmol) of a 1N solution of diisobutylaluminum hydride in dichloromethane in 250 ml of tetrahydrofuran, and the reaction mixture was stirred at room temperature for 3 h. After addition of 1N hydrochloric acid, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were washed with saturated aqueous sodium chloride solution. Drying over sodium sulfate and filtration was followed by removal of the solvents in a rotary evaporator. The crude product was purified by flash chromatography on silica gel (mobile phase: dichloromethane/methanol gradient) to result in 5.55 g (91% purity, 85% of theory) of the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH2:5]([S:7](Cl)(=[O:9])=[O:8])[CH3:6].CCOCC>C(N(CC)CC)C>[CH2:5]([S:7]([O:4][CH2:3][CH2:2][Br:1])(=[O:9])=[O:8])[CH3:6]
Reactant: CCS(=O)(=O)Cl
Reactant: OCCBr
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)OCCBr
Reaction time: 1 h

Procedure:
A mixture containing 12.5 ml. of 2-bromoethanol, 12.9 ml. of ethane sulfonyl chloride and 100 ml. of ether was formed. Then, 14 ml. of triethylamine was added dropwise over a 55 minute period at 5°-10° C. and stirred for 1 hour. The mixture was allowed to come to room temperature and stirred for an additional 15 minutes. To the mixture was added 100 ml. of water, the ether layer was separated, dried over magnesium sulfate and evaporated to yield 17.6 grams of a yellow oil. nD30 1.4760.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N[CH:9]=[N:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:13][CH:12]=1)#N>O>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:9]=[N:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: COCCN
Reactant: N#CNC=Nc1ccc(-c2c[nH]cn2)cc1
Solvent: O
Product: COCCNC=Nc1ccc(-c2c[nH]cn2)cc1

Procedure:
5 ml of 2-methoxy-ethylamine were added all at once to a suspension of N-cyano-N'-[4-(imidazol-4-yl)-phenyl]-formamidine (1.8 g) in water (2 ml). When the exothermic reaction subsided, a solution was obtained from which the title compound quickly crystallized out. The product was filtered off and purified via its maleate in acetone.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:13])[C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.C1COCC1.C([Li])CCC.C(O)(=O)C>CCCCCC.C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:12][C:8]1[C:7]([F:13])=[C:6]2[C:11]([CH:2]=[CH:3][C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Fc1c(Cl)ccc2c(Br)cc(-c3ccccc3)nc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Fc1c(Cl)ccc2ccc(-c3ccccc3)nc12
Temperature: -100 °C

Procedure:
To a stirred solution of 3-chloro-2-fluoroaniline (2.9 g, 20 mmol) and trans-cinnamaldehyde (2.64 g, 20 mmol) in toluene (25 ml) was added 6N HCl (100 ml). The resulting suspension was heated at reflux for 40 hours. After cooling, the reaction mixture was poured into 5N NaOH solution (200 ml) and extracted with EtOAc (3×100 ml). The combined organics were washed with brine (2×100 ml), dried (MgSO4), filtered and concentrated. The crude product was dissolved in MeOH and loaded onto an SCX-2 cartridge (50 g/150 ml), and the product eluted with MeOH, giving the title compound as a yellow solid. Additionally, the title compound could be prepared as follows: 4-Bromo-7-chloro-8-fluoro-2-phenyl-quinoline (6.0 g, 0.018 mole) and THF (240 mL) were combined in a 3 neck 1 L round bottom flask with a magnetic stir bar under an atmosphere of nitrogen. The reaction was stirred and cooled with a THF/liquid nitrogen bath to −100° C. 2.5 M of n-butyllithium in Hexane (7.34 mL) was then added dropwise over 3 minutes so as not to exceed −90° C. The solution turned light green, and darkened over a few minutes. Acetic acid (1.22 mL, 0.0214 mole) was added 3 minutes after the n-butyllithium addition was done. The cooling bath was removed, and the reaction was allowed to stir for 20 minutes. To work up, saturated sodium bicarbonate solution (100 mL) was added, and the mixture was transferred to a 1 L separatory funnel with 250 mL of ethyl acetate. The layers were separated, and the organic layer was washed with 2×60 mL of brine. The organic solution was suction filtered through a short pad of silica gel, rinsing with ethyl acetate. The filtrate was concentrated in vacuo, and the residue was placed under high vacuum overnight to afford the crude product. The crude product was pre-adsorbed on 55 mL of Silica gel from methylene chloride. 100 mL of Toluene was added, and the slurry was concentrated on the rotovap to afford a finely divided powder. This was applied to a silica column and chromatographed (4:3 hexanes/methylene chloride) affording the title compound as a white solid. The solid was re-chromatographed with, and then placed in the vacuum oven at 45° C. overnight to afford the very pure product as a white solid; 1H NMR (CDCl3, 400 MHz) δ 8.24-8.21 (3H, m), 7.96 (1H, d, J=8.6 Hz), 7.58-7.48 (5H, m); MS (ES+): m/z 258.13 [MH+]; HPLC: tR=3.64 min (MicromassZQ, non-polar—5 min).
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[N:29]([CH3:30])[C:28]3[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:21]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:20](=[O:39])[C:19]=3[C:18]=2[O:40][CH3:41])=[O:16])[CH2:10][CH2:9]1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO.O>C1COCC1.C(=O)([O-])O.[Na+]>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]3[N:29]([CH3:30])[C:17]([C:15]([NH:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:5][OH:4])[CH2:13][CH2:12]4)=[O:16])=[C:18]([O:40][CH3:41])[C:19]=3[C:20]2=[O:39])=[CH:37][CH:36]=1
Reactant: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)n(Cc1ccc(Cl)cc1)c1ccccc21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCN(C(=O)CO)CC2)n(C)c2c1c(=O)n(Cc1ccc(Cl)cc1)c1ccccc21
Yield: 12.6 %

Procedure:
A solution of 2-[4-({[5-(4-chlorobenzyl)-3-methoxy-1-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]quinolin-2-yl]carbonyl}amino)piperidin-1-yl]-2-oxoethyl acetate (60 mg) and potassium carbonate (72 mg, 0.52 mmol) in THF (2 mL)-methanol (1 mL)-water (1 mL) was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (7 mg, 2%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:3]=1[C:4]([NH:6][NH:7][C:8](=[O:24])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)=O>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:3]=1[C:4]1[O:24][C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)=[N:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(C(=O)NNC(=O)c2cc(Br)ccc2Br)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCOc1ccc(-c2nnc(-c3cc(Br)ccc3Br)o2)cc1
Yield: 89 %

Procedure:
A mixture of 2,5-dibromo-N′-[4-(octyloxy)benzoyl]benzohydrazide (39.1 g, 0.0743 mol) and phosphorus oxychloride (203 mL) was refluxed for 8 hrs. Unreacted phosphorus oxychloride was distilled off and the residue poured onto crushed ice. The precipitated solid was collected by filtration and re-crystallized from EtOH/water to give 33.6 g (89% yield) 2-(2,5-dibromophenyl)-5-[4-(octyloxy)phenyl]1,3,4-oxadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4].[CH3:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([NH2:37])(=[O:36])=[O:35].CC(C)=O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:37][S:34]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH3:27])(=[O:35])=[O:36])=[O:21])=[CH:18][C:17]=1[O:25][CH3:26])=[O:4]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)Cl)cc1OC)cn2C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Temperature: 15 °C
Yield: 96.4 %

Procedure:
A solution of 4-(dimethylamino)pyridine (8.17 g, 66.9 mmole) in dichloromethane (20 ml) was added over 15 minutes to a stirred suspension of the product of step c) (9.94 g, 26.8 mmole) and 2-methylbenzenesulfonamide (6.87 g, 40.1 mmole) in dichloromethane (30 ml). After 45 minutes the solution was heated to reflux and 20 ml distillate collected. Acetone (150 ml) was added and a further 80 ml distillate collected. The mixture was allowed to cool overnight and finally stirred at 15° C. before collection of the solid by filtration. This was then slurry-washed with methanol (3×30 ml) to afford 16.22 g (96.4%) of 4-(5-methoxycarbonyl-1-methylindol-3-ylmethyl)-3-methoxy-N-(2-methylphenylsulfonyl)benzamide, as its 4-(dimethylamino)pyridine salt; m.p. 185°-187° C. (with partial melting and resolidification at 138°-140° C.); NMR (250 MHz, DMSO-d6): 2.53 (s, 3H, ArCH3), 3.13 (s, 6H, N(CH3)2), 3.76, 3.83, 3.86 (each s, 3H, OCH3 plus NCH3 plus CO2CH3), 4.02 (s, 2H, ArCH2Ar'), 6.92 (d, 2H), 7.02 (d, 1H), 7.11-7.32 (m, 4H), 7.39-7.53 (m, 3H), 7.75 (dd, 1H), 7.88 (d, 1H), 8.20 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:4]=1[OH:11].FC(F)(F)S(O)(=O)=O>CCCCCCC>[CH3:1][O:2][C:3]1[C:4]2[O:11][C:6]([CH3:10])([CH3:7])[CH2:5][C:5]=2[C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9]
Reactant: COc1c(C)cc(C)cc1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCCCCCC
Product: COc1c(C)cc(C)c2c1OC(C)(C)C2
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 202.3 %

Procedure:
Further, by using 2-methoxy-3,5-dimethylphenol (7.60 g, 41.7 mmol), synthesis was also performed according to the following method. That is, to a solution of n-heptane (76 mL) containing 2-methoxy-3,5-dimethylphenol (7.60 g, 41.7 mmol) and isobutyl aldehyde (5.71 mL, 62.6 mmol), trifluoromethanesulfonic acid (1.85 mL, 20.9 mmol) was added dropwise, and the mixture was stirred at 55° C. for 2.5 hours. After cooled to room temperature, the reaction solution was washed with water and dried using anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by basic silica gel chromatography (hexane-ethyl acetate 100:0) and silica gel chromatography (hexane-ethyl acetate 100:0-95:5) to give 8.70 g of the title compound (yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[OH:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[N:29][C:30]=2[Cl:32])[N:25]([CH3:33])[N:24]=1>>[Cl:32][C:30]1[N:29]=[CH:28][N:27]=[C:26]2[N:25]([CH3:33])[N:24]=[C:23]([CH2:22][O:14][C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])[C:31]=12
Reactant: Cn1nc(CBr)c2c(Cl)ncnc21
Reactant: Cc1nnc(-c2ccc(C)c(O)c2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nnc(-c2ccc(C)c(OCc3nn(C)c4ncnc(Cl)c34)c2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenol (73.3 mg, 0.385 mmol) and potassium carbonate (60.9 mg, 0.432 mmole) was stirred at room temperature for 30 minutes before 3-bromomethyl-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (89.6 mg, 0.343 mmole, Example 5) was added. The reaction was stirred at room temperature overnight and then concentrated under reduced pressure to remove dimethylformamide. The residue was dissolved in ethyl acetate, washed with water, dried and concentrated. The crude product was either used directly in the next step or purified by flash chromatography (silica gel, hexanes-ethyl acetate, 90/10 to 60/40) to give pure 4-chloro-1-methyl-3-[2-methyl-5-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenoxymethyl]-1H-pyrazolo[3,4-d]pyrimidine as a white solid. (Yield 34.9 mg).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[O:18][CH:19]([CH2:29][CH2:30][O:31][CH2:32][P:33]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:34])[CH2:20][O:21][Si](C(C)(C)C)(C)C)=[C:11]([O:41]C)[N:10]=1)=O)(C)(C)C.Cl>C(O)C>[CH2:36]([O:35][P:33]([CH2:32][O:31][CH2:30][CH2:29][CH:19]([O:18][N:15]1[CH:14]=[N:13][C:12]2[C:11](=[O:41])[NH:10][C:9]([NH2:8])=[N:17][C:16]1=2)[CH2:20][OH:21])([O:38][CH2:39][CH3:40])=[O:34])[CH3:37]
Reactant: CCOP(=O)(COCCC(CO[Si](C)(C)C(C)(C)C)On1cnc2c(OC)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc21)OCC
Agent: Cl
Solvent: CCO
Product: CCOP(=O)(COCCC(CO)On1cnc2c(=O)[nH]c(N)nc21)OCC
Yield: 47.6 %

Procedure:
A solution of 2-[bis(t-butoxycarbonyl)amino]-9-[1-(t-butyldimethylsilyloxy)-4-(diethoxyphosphorylmethoxy)but-2-oxy]-6-methoxypurine (415 mg, 0.57 mmol) was dissolved in ethanol (5 ml) and 5M hydrochloric acid (0.6 ml) and heated under reflux for 3.5 h. The reaction was evaporated in vacuo and the residue chromatographed on silica, eluting with chloroform-methanol 10:1, affording 9-[4-(diethoxyphosphorylmethoxy)-1-hydroxybut-2-oxy]guanine (110 mg, 48%) as a pale tan solid. νmax (KBr) 3400, 1680, 1640 and 1600 cm-1 ; δH [(CD3)2SO] 1.22 (6H, t, J7.1 Hz, 2×CH2CH3), 1.91 (2H, m, CHCH2CH2O), 3.54 (2H, m, CH2OH), 3.74 (2H, m, CH2OCH2P), 3.85 (2H, d, J8.2 Hz, CH2P), 4.03 (4H, m, 2×CH2CH3), 4.30 (1H, m, HOCH2CH), 5.01 (1H, m, D2O exchangeable OH), 6.65 (2H, br.s, D2O exchangeable, NH2); m/z (FAB+ve Ion), 428 (MNa+), 406 (MH+).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O>CO>[C:1]1([C:7]2[S:8][C:9]([Br:12])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccs2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: Brc1ccc(-c2ccccc2)s1

Procedure:
Next, 3.21 g (20 mmol) of the thus synthesized 2-phenylthiophene was dissolved into 20 mL of methanol, and then to this solution was added a solution wherein 3.92 g (22 mmol) of N-bromosuccinimide (Wako Pure Chemicals Industries, Ltd.) was dissolved into 40 mL of methanol, to produce a white precipitation of 2-phenyl-5-bromothiophene immediately. This reaction solution was put into a refrigerator to ensure the production of the precipitation. This precipitation was filtered and then was sufficiently washed with a great deal of a mixture solution of equivalent amounts of water and methanol. The resultant was dried one day and night to obtain a white crystal (2.4 g) of 2-phenyl-5-bromothiophene.