Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N:8]=1)([OH:3])=[O:2].ClC1C=C(C=CC=1)C(OO)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([CH2:4]/[CH:5]=[CH:6]/[C:7]1[C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=[C:9]([CH3:26])[N+:8]=1[O-:32])([OH:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCCCCCCOc1ccc(C)nc1/C=C/CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C)[n+]([O-])c1/C=C/CC(=O)O
Reaction time: 0.5 h

Procedure:
2-(E-2-Carboxymethylethenyl)-3-dodecyloxy-6-methylpyridine (2.15 g, 5.95 mmol) was dissolved in dry CH2Cl2 (20 mL) and cooled to 0∞C.; 85% m-chloroperoxybenzoic acid (1.45 g, 7.14 mmol) was added and the reaction was stirred at 0∞C. for 30 minutes and at room temperature for 16 hours. The reaction solution was poured into saturated aqueous NaHCO3 (20 mL). The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined CH2Cl2 extracts were washed with H2O (20 mL) and brine and dried (MgSO4). The crude pale yellow solid was used directly in the next step without further purification: 1H NMR (250 MHz, CDCl3): δ8.23 (d, J=16.2 Hz, 1H, olefin), 7.58 (d, J=16.2 Hz, 1H, olefin), 7.13 (d, J=8.8 Hz, 1H, 5-pyridyl), 6.79 (d, J=8.8 Hz, 1H, 4-pyridyl), 4.06 (t, J=6.6 Hz, 2H, OCH2), 3.81 (s, 3H, CO2CH3), 2.45 (s, 3H, CH3), 1.92-0.85 (m, 23H, aliphatic); MS (CI): 378.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].[OH-].[Na+].[CH2:14](I)[CH3:15]>CS(C)=O.O>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH2:14][CH3:15]
Reactant: CCI
Reactant: COc1cccc(OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1c(OC)cccc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 56.8 %

Procedure:
To a stirred solution of 2,6-dimethoxyphenol (10 g) in dimethylsulfoxide (100 ml) under nitrogen was added a solution of sodium hydroxide (3.2 g) in water (20 ml). The mixture was warmed to 50° C., ethyl iodide (12.4 g) added, and stirring continued at 50° C. for 4 hours. The product was poured into 1 liter of water and the mixture extracted with diethyl ether. The extract was washed sequentially with 20% potassium hydroxide, water, and brine, and then dried over magnesium sulfate. Removal of the solvent under reduced pressure gave 1,3-dimethoxy-2-ethoxybenzene as a colorless oil (6.71 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:16]=1[NH2:17])([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:16]=1[NH:17][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Product: CCOc1ccc(Nc2ccccc2CC(=O)O)c([N+](=O)[O-])c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-nitro-4-ethoxyaniline to yield 2-[(2-nitro-4-ethoxyphenyl)amino]phenylacetic acid.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:13]([N:15]1[CH2:18][CH:17]([C:19]#[N:20])[CH2:16]1)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:7][C@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:16][CH:17]([C:19]#[N:20])[CH2:18]1)=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CC(C#N)C1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@@H](N)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution [(R)-1-(3-cyano-azetidine-1-carbonyl)-2,2-dimethyl-propyl]-carbamic acid tert-butyl ester (180 mg, 0.49 mmol) in dichloromethane (3 ml) at 0° C. was added trifluoroacetic acid (1.2 ml, 15.6 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated to afford 1-((R)-2-amino-3,3-dimethyl-butyryl)-azetidine-3-carbonitrile trifluoroacetate as a light yellow oil which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(C(=O)C2CCCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C1CCCCC1
Reaction time: 18 h

Procedure:
A solution of 11 g (50.4 mmol) of 4-methoxyphenyl cyclohexyl ketone in 730 ml of dichloromethane p.a. is treated at -70° C. under argon with 101 ml of a 1M solution of boron tribromide (101 mmol) in dichloromethane and then left at room temperature for 18 h. It is concentrated in vacuo, the residue is taken up with 500 ml of ethanol and 80 ml of water and the mixture is heated under reflux for 3 h. After concentration in vacuo, the residue is taken up in dichloromethane, and the organic phase is washed with water, dried over sodium sulphate and concentrated to dryness in vacuo. The crude product is chromatographed on silica gel using dichloromethane/methanol (20:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]1[C@@H:11]([CH3:12])[C@@H:10]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:9]1=[O:23].[OH-:24].[Na+]>O1CCOCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][C@H:10]([C@@H:11]([NH:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH3:12])[C:9]([OH:23])=[O:24])=[CH:17][CH:18]=1
Reactant: C[C@H]1[C@@H](CCCc2ccc(Cl)cc2)C(=O)N1OC1CCCCO1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H](NOC1CCCCO1)[C@@H](CCCc1ccc(Cl)cc1)C(=O)O
Temperature: 23 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of (3R,4S)-1-(2-tetrahydropyranyloxy)-3-(3-(4-chlorophenyl)-1-propyl)-4-methylazetidin-2-one (360 mg, 1.07 mmol) in dioxane (3.2 mL) is added 1 M aqueous sodium hydroxide (1.6 mL). The solution is stirred at 23° C. for 72 h, then extracted with hexanes (20 mL). The aqueous layer is acidified to pH=3 with saturated aqueous sodium bisulfate solution, and is extracted with two 30 mL portions of ethyl acetate. The combined organics are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide (2R,3S)-2-(3-(4-chlorophenyl)-1-propyl)-3-(2-tetrahydropyranyloxyamino)butanoic acid as an oil (380 mg, 99% yield).
Reaction SMILES: [CH:1]1([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[S:16]([NH2:19])(=[O:18])=[O:17])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>>[CH:1]1([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[S:16]([NH:19][C:23]([NH:22][CH2:20][CH3:21])=[S:24])(=[O:18])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCN=C=S
Reactant: NS(=O)(=O)c1cnccc1NC1CCCCCCC1
Product: CCNC(=S)NS(=O)(=O)c1cnccc1NC1CCCCCCC1

Procedure:
The procedure is identical to that of Example 5, using (4-(cyclooctylamino)pyrid-3-yl)sulfonamide and ethylisothiocyanate as the starting materials. Yield is similar. Melting point: 196°-198° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH3:12])[CH2:7]2.[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][CH:8]1[CH2:7][C:6]2[C:10](=[C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH:14]=[CH2:13])=[CH:16][CH:17]=3)[CH:3]=[CH:4][CH:5]=2)[C:9]1=[O:11]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: CC1Cc2cccc(Cl)c2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: OCCO
Solvent: O
Product: C=Cc1ccc(-c2cccc3c2C(=O)C(C)C3)cc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
Using a method similar to Example 16d), 2.0 g (0.011 mol) of (1), 1.92 g (0.013 mol) of 4-styreneboronic acid and 2.6 g (24.6 mmol) of sodium carbonate were placed in 55 ml of ethylene glycol/5 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 18 mg (0.09 mmol) of palladium acetate and 0.15 g (0.27 mmol) of TMSPP, the reaction mixture was stirred for 2 hours at 125° C. After addition of 60 ml of water, the aqueous phase was extracted 4 times with 60 ml each time of ether, the combined ether phases were washed with 60 ml of water and 60 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 2.2 g of 2-methyl-7-(4-vinylphenyl)-1-indanone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([OH:9])[N:3]=1.C([O-])(=O)C.[Na+].O.Br[CH:17]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=1)[CH:18]=O>CO>[CH3:31][O:30][C:28](=[O:29])[C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:17]2[C:5]3[C:4](=[O:9])[NH:3][C:2]([NH2:1])=[N:7][C:6]=3[NH:8][CH:18]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(CCC(Br)C=O)cc1
Reactant: Nc1cc(O)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CCc2c[nH]c3nc(N)[nH]c(=O)c23)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To 1.69 g (13.4 mmol) of 2,4-diamino-6-hydroxypyrimidine, 2.20 g (26.8 mmol) of sodium acetate and 20 ml of water at 80° C. were added 3.82 g (13.4 mmol) of 2-bromo-4-(4-carbomethoxyphenyl)butanal, prepared in Preparation 2, in 7 ml of methanol over 5 minutes. The mixture was maintained at 80° C. for 5 minutes, cooled to room temperature and stirred for 30 minutes. The mixture was filtered, washed with water, and dried for 18 hours at 50° C. @10 torr to provide 3.32 g of 4-(2-[2-amino-4-oxo-3,7-dihydropyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoic acid methyl ester (m.p. >220° C.) in a yield of 79.4 percent. The remaining filtrate was cooled to 5° C. and filtered to provide an additional 0.069 g of the above product, for a combined yield of 81 percent. 1H NMR (DMSO-d6) δ2.80 (m, 2H), 2.93 (m, 2H), 3.78 (s, 3H), 5.97 (s, 2H), 6.26 (d, J=2.0 Hz, 1H), 7.28 (d, J=8.2 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 10.12 (s, 1H), 10.58 (s, 1H); FDMS 312 (M+), Anal. for C16H16N4O3, Calcd: C, 61.53; H, 5.16; N, 17.94; Found: C, 61.79; H, 5.33; N, 17.66.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)=[CH:4][C:3]=1[N+:16]([O-])=O.[Sn](Cl)(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: Cc1nnc(-c2ccc(Cl)c([N+](=O)[O-])c2)nc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Product: Cc1nnc(-c2ccc(Cl)c(N)c2)nc1C

Procedure:
This compound was obtained by reducing 3-(4-chloro-3-nitrophenyl)-5,6-dimethyl-[1,2,4]triazine with tin chloride.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([N+:18]([O-])=O)[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:13][C:8]=2[O:7][N:6]=1)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:4][C:5]1[C:9]2[CH:10]=[C:11]([NH2:18])[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:13][C:8]=2[O:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc2onc(OCC=C)c2cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOc1cc2onc(OCC=C)c2cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,6-bis-allyloxy-5-nitrobenzo[d]isoxazole (0.60 g, 2.17 mmol) in EtOAc (12 mL) is added portionwise tin(II) chloride dihydrate (2.2 g, 9.75 mmol). The mixture is stirred at room temperature for 2 h and then at 60° C. for 1.5 h. The mixture is diluted with EtOAc and saturated NaHCO3 is added dropwise, resulting in the formation of a precipitate. Sodium carbonate (2N) is added and the insoluble precipitate is filtered off. The phases are separated and the aqueous phase is extracted with EtOAc (3×). The organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel, eluting with a gradient of hexanes/EtOAc to afford 3,6-bis-allyloxybenzo[d]isoxazol-5-ylamine as a waxy solid: (M+H)+=247.2.
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]1=[O:30]>N1C=CC=CC=1>[C:1]1([Si:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[CH:35]=[CH:34][C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn(CCCCCCO)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1ccn(CCCCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Reaction time: 0.75 h

Procedure:
A solution of triphenylsilyl chloride (0.337 g, 1.14 mmol) in dry pyridine (3 mL) was added drop-wise to a solution of 1-(6′-hydroxyhexyl)uracil (0.200 g, 0.94 mmol) in dry pyridine (4 mL) cooled in an ice-salt bath. The reaction mixture was kept at 0° C. under nitrogen for 3 h30. As TLC monitoring evidenced the presence of unreacted starting material, triphenylsilyl chloride (0.325 g, 1.10 mmol) in dry pyridine (1 mL) was added. After a further 45 min at 0° C., the reaction had reached completion and was quenched with CH3OH (0.1 mL). Removal of the solvent in vacuo afforded a crude yellow oil which was purified by silica gel chromatography using a Jones Chromatography Isolute SI column with a gradient elution of 0→5% CH3OH in CHCl3. The title compound was obtained as a white solid (0.140 g, 32%) from the fractions with Rf=0.52 (10% CH3OH/CHCl3). Some starting material (0.130 g, 65%) was also recovered, possibly resulting from hydrolysis during the work up.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#N)[CH:10]=[N:9]2)=[C:5]([CH3:23])[O:4][N:3]=1.Cl.C[OH:26]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:14][C:15]4[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH:10]=[N:9]2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NCc2ccccc2C#N)cn1
Reactant: CO
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(N2Cc3ccccc3C2=O)cn1
Yield: 50 %

Procedure:
2-((1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylamino)methyl)benzonitrile (example 9-2) (30 mg, 0.14 mmol) was stirred in a mixture of MeOH/2N aqueous NaOH (5 mL) at 100° C. for 30 minutes in the microwave reactor. The reaction was acidified with 1N aqueous HCl (100 mL) and extracted with ethyl acetate (3×, 70 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was dissolved in MeOH (3 mL) and purified by reversed phase HPLC in 2-1.5 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (21 mg, 50%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ 2.15 (s, 3H), 2.41 (s, 3H), 4.81 (s, 2H), 5.17 (s, 2H), 7.48-7.50 (m, 1H), 7.51-7.52 (m, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.75 (s, 1H), 8.20 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 11 μM.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([OH:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]1([S:35]([O-:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(O)c1ccccc1
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Solvent: CCO
Product: O=S(=O)([O-])c1ccccc1

Procedure:
3.790 g of Donepezil is dissolved in 20 ml of ethanol. A solution (35 ml) of benzenesulfonic acid (1.852 g) in acetone is added slowly and drop-wisely. The solid precipitated is filtered with suction to give the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:21]1([OH:28])[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)#[CH:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[CH3:27][N:24]1[CH2:25][CH2:26][C:21]([C:19]#[C:20][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][N:6]=[C:5]3[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([OH:28])[CH2:22][CH2:23]1
Reactant: Ic1ccc2ncnc(Oc3ccccc3)c2c1
Reactant: C#CC1(O)CCN(C)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CN1CCC(O)(C#Cc2ccc3ncnc(Oc4ccccc4)c3c2)CC1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To a 100 mL round bottom flask under nitrogen were added, quinazoline 13 (1.32 g, 3.80 mmol), 4-ethynyl-1-methyl-piperidin-4-ol (1.06 g, 7.6 mmol), Pd(OAc)2 (51 mg, 0.23 mmol), PPh3 (120 mg, 0.46 mmol) and triethylamine (18 mL). The flask was equipped with a reflux condenser and the mixture heated to 100° C. for 16 hours. The dark solution was then cooled and the triethylamine removed under reduced pressure. The resulting residue was diluted with EtOAc (75 mL) and H2O (25 mL) and transferred to a separatory funnel. The organic layer was washed successively with H2O (2×25 mL) and the combined aqueous washes back extracted with EtOAc (25 mL). The combined organic layers were dried (MgSO4) and the solvent removed under reduced pressure. The resulting black foam was purified on silica gel (50 g) eluting with 250 mL 30:1 CH2Cl2:MeOH, then 400 mL 30:1:1 CH2Cl2:MeOH:NEt3 to provide the desired product as a yellow foam (930 mg, 68%). 1H NMR: (CDCl3; 400 MHz) δ: 8.71 (s, 1H), 8.36 (d, 1H, J=1.9 Hz), 7.89 (d, 1H, J=8.7 Hz), 7.80 (dd, 1H, J=8.7 Hz, 1.9 Hz), 7.45 (t, 2H, J=8.3 Hz), 7.31 (m, 1H), 7.21 (m, 2H), 2.72 (br, 2H), 2.47 (br, 2H), 2.31 (s, 3H), 2.09 (m, 2H), 2.00 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>O>[NH2:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([CH3:18])=[C:11]([NH2:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(N)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: O
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)c(N)c3)n2)cc1N
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MEOH (1 ml) and H2O (0.1 ml). 3-amino-4-methylaniline (146 mg, 1.2 mmol) was added and the mixture was refluxed for 20 hours (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3-Acetone, 2:1) to give N2,N4-bis(3-amino-4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 8.11 (d, 1H, J=5.1 Hz), 7.98 (bs, 1H) (7.68 (dd, 1H, J=2.4, 8.1 Hz), 7.40–7.55 (m, 4H), 2.43 (s, 3H), 2.42 (s, 3H); LCMS: purity: 95.0%; MS (m/e): 338.66 (M+, 70).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[OH-].[Li+:26].O1CCCC1.CO>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[Li+:26]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)[O-])cc3)oc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 106.9 %

Procedure:
Methyl 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoate (118 mg, INTERMEDIATE 2, Step A) and lithium hydroxide (18 mg) were combined in 10 ml of a 1:1:1 mixture of tetrahydrofuran, methanol, and water. The solution was stirred at 50° C. for 5 h. The solvents were removed in vacuo to provide the title compound as an off-white solid (123 mg). Mass spectrum (ESI) 307.0 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[O:9]=[C:10]1[N:15]([NH2:16])[CH2:14][C:13]([CH3:17])=[N:12][NH:11]1>Cl.C(O)C>[O:9]=[C:10]1[N:15]([N:16]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:14][C:13]([CH3:17])=[N:12][NH:11]1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCO
Product: CC1=NNC(=O)N(N=Cc2cccnc2)C1

Procedure:
26.8 g (0.25 mole) of pyridine-3-carbaldehyde and 1 drop of concentrated HCl are added at 60° C. to 32 g (0.25 mole) of 2,3,4,5-tetrahydro-3-oxo-4-amino-6-methyl-1,2,4-triazine dissolved in 250 ml of ethanol. After boiling for half an hour under reflux, the reaction mixture is cooled and the solid portion is isolated by filtration, washed with ether and dried to give the title compound of formula ##STR22## in the form of a colourless solid; m.p. 227°-228° C.; yield: 48 g (90%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[CH:9]1)=[O:21]
Reactant: CN1CCC(c2c[nH]c3ccncc23)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-4-piperidinyl)-5-azaindole (20 mg, 0.094 mmol), 2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2)C1
Reaction time: 24 h
Yield: 78.1 %

Procedure:
A mixture of 2-(4-nitro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (20 mg, 0.064 mmol) and Pd/C (5%, 2 mg) in methanol was stirred under hydrogen for 24 h. The catalyst was filtered off and washed with methanol. The filtrate was evaporated to give the title compound as an off-white solid (14 mg, 0.050 mmol, 78%). ESMS m/z 223 (M+H-tBu)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (d, J=8.3 Hz, 2H) 6.52 (d, J=8.3 Hz, 2H) 5.04 (s, 2H) 4.15 (dd, J=10.5, 2.5 Hz, 1H) 3.88 (dd, J=11.8, 2.5 Hz, 1H) 3.76 (d, J=12.8 Hz, 2H) 3.48 (td, J=11.7, 2.8 Hz, 1H) 2.92 (br. s., 1H) 2.77 (br. s., 1H) 1.41 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:9]1[C:10]([O:11][CH3:12])=[C:2]([Cl:1])[C:3]([OH:13])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(O)c1Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Br)cc(C(=O)O)c(O)c1Cl
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 3-chloro-2-hydroxy-4-methoxybenzoic acid (11.1 g) in acetic acid (275 mL) was added bromine (8.79 g) at room temperature, and the mixture was stirred for 16 hr. To the reaction mixture was added water, and the precipitate was collected by filtration. The precipitate was washed with water, and dissolved in ethyl acetate, and the solution was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (10.4 g).