Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][S:7][C:8]1[N:13]=[CH:12][N:11]=[C:10]([C:14]2[C:15](O)=[N:16][CH:17]=[N:18][CH:19]=2)[CH:9]=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[Cl:3][C:15]1[C:14]([C:10]2[CH:9]=[C:8]([S:7][CH3:6])[N:13]=[CH:12][N:11]=2)=[CH:19][N:18]=[CH:17][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1cc(-c2cncnc2O)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CSc1cc(-c2cncnc2Cl)ncn1
Temperature: 85 °C

Procedure:
POCl3 (1.51 mL, 16.2 mmol, 3.0 eq.) is added slowly to a suspension of 6-methylsulfanyl-[4,5′]bipyrimidinyl-4′-ol 6 (1.20 g, 5.44 mmol) and triethyl amine (0.76 mL, 5.44 mmol, 1.0 eq.) in acetonitrile (30 ml). After heating at 85° C. for 2 hours, the reaction mixture is cooled to room temperature, poured into ice-water, neutralized by saturated NaHCO3 solution, and then extracted with ethyl acetate. The organic layer is washed with brine and dried over Na2SO4, filtered and concentrated. The crude product is purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 0% to 40% to give 4′-chloro-6-methylsulfanyl-[4,5′]bipyrimidinyl as a white solid. 1H NMR 400 MHz (DMSO-d6) δ 9.19 (s, 1H), 9.12 (d, 1H, J=1.2 Hz), 9.07 (s, 1H), 7.91 (d, 1H, J=1.6 Hz), 2.62 (s, 3H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]

Procedure:
A mixture of 3-fluoro-6-nitrotoluene (50.0 g), 1,2,4-triazole (22.2 g) and sodium carbonate (34.0 g) was heated with stirring in dimethylformamide (300 cm3) at 130° for 16 hours. The cooled mixture was then concentrated in vacuo, the residue was acidified to pH1 with 4M hydrochloric acid, and the resulting solution was extracted with chloroform (2×25 cm3) to remove any neutral material. The combined aqueous phases were basified to pH10 with 2.5M sodium hydroxide solution and the mixture was extracted with chloroform (3×250 cm3). The combined and dried (MgSO4) organic extracts were concentrated in vacuo to give a solid which was recrystallised from toluene to give 1-(3-methyl-4-nitrophenyl)-1,2,4-triazole, m.p. 116°-7°.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[CH3:19][S-:20].[Na+]>CO>[CH3:19][S:20][CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CO
Product: CSC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 58.8 %

Procedure:
A solution of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.0 g, 7.2 mmol) and sodium thiomethoxide (1.0 g, 14.4 mmol) in methanol (30 mL) was refluxed for 15 h and then concentrated. The residue was partitioned between water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography on silica (3% ethyl acetate in hexanes) afforded tert-butyl 4-(methylthio)piperidine-1-carboxylate (0.98 g, 58% yield) as a colorless oil. MS (EI) for C11H21NO2S: 231 (M+).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH3:22][CH:21]([C:24]1[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=1[NH:26][C:1](=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[CH:21]([CH3:23])[CH3:22])=[O:13])[CH3:23]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CC(C)c1ccccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)c1ccccc1NC(=O)c1ccccc1SSc1ccccc1C(=O)Nc1ccccc1C(C)C
Yield: 14.3 %

Procedure:
This compound was prepared according to the general method of Example 90 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-isopropylaniline (1.60 g, 11.6 mmol) in 13 mL of pyridine. The crude product was recrystallized twice from acetonitrile-DMF to yield 0.45 g of the title compound, mp 235-237° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:6][N:5]=1.N12CCCN=C1CCCCC2.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][C:41]=1[Cl:42])N.CN(C)C=O>C(OCC)(=O)C>[Cl:42][C:41]1[CH:40]=[CH:39][C:37]([NH:20][C:18](=[O:19])[NH:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:21])[CH:9]=3)=[CH:12][CH:13]=2)=[CH:36][C:35]=1[C:34]([F:33])([F:43])[F:44]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(N)=O)cc2)ccn1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
N-methyl-4-(4-ureidophenoxy)picolinamide (50 g, 0.1746 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (33.95 ml, 0.2270 mol) and 3-trifluoromethyl-4-chloroaniline (34.2 g, 0.1746 mol) were mixed with N,N-dimethyl formamide (200 ml) (DMF) and the reaction mass was heated to reflux for 24 hours. It was then cooled to room temperature and quenched in water (600 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water to remove DMF traces. It was then dried over sodium sulfate and evaporated under vacuum to obtain solid. The solid thus obtained was then slurried in ethyl acetate (400 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base) (64 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH2:5].[NH2:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1>C(O)CCC>[C:6]1([CH:4]2[CH2:5][N:18]3[CH:17]=[N:16][N:15]=[C:14]3[NH:13][C:3]2=[O:2])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(C(=O)OC)c1ccccc1
Reactant: Nc1nc[nH]n1
Solvent: CCCCO
Product: O=C1Nc2nncn2CC1c1ccccc1
Yield: 18.9 %

Procedure:
A solution of 9.01 g (55.6 mmol) 2-phenyl acrylic acid methyl ester and 4.24 g (50.4 mmol) 3-amino-1,2,4-triazole in 41 ml n-butanol was refluxed for 24 hours. The solvent was removed under reduced pressure. The residue was treated with a small amount of ethanol and diethyl ether and cyclohexane were added. The diethyl ether is slowly removed under reduced pressure. The crude 6-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-on precipitated during evaporation, was isolated by filtration and washed with diethyl ether. 6-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-on was recrystallized from a small amount of ethanol. 2.04 g (19%) 6-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-7-on was isolated (m.p. 184-186° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][O:2][C:3]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][CH2:24][NH2:25]
Reactant: COc1c(C=O)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(CCN)cccc1Oc1cc(C)ccc1[N+](=O)[O-]
Yield: 38.8 %

Procedure:
2-Methoxy-3-(5-methyl-2-nitrophenoxy)benzaldehyde (0.36 g, 1.3 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (100 mg, 1.6 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.14 g, 1.2 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with hot methanol and allowed to cool overnight. The filtrate was collected, the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give [2-methoxy-3-(5-methyl-2-nitrophenoxy)benzyl]methylamine fumarate (195 mg, 38%) as a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])=[O:7].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:31][CH2:32]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCCl)c1ccccc1F
Product: O=C(CCCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccccc1F

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-(2-fluorophenyl)-1-pentanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 423.1 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][C:15]1[C:14]2[C:9](=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][C:6]=1[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1cccc2c(=O)c(C(=O)C(C)C)c[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1cccc2c(Cl)c(C(=O)C(C)C)cnc12
Yield: 71 %

Procedure:
3-Isobutyryl-8-methoxy-4(1H)-quinolone (8.31 g, 0.034 mol) was heated under reflux in a mixture of phosphorus oxychloride (20 ml) and chloroform (30 ml) for 30 minutes. The mixture was evaporated and the residue was partitioned between dichloromethane and sodium hydrogen carbonate solution. The organic solution was washed with sodium hydrogen carbonate solution, water and brine, dried, filtered and evaporated to give 4-chloro-3-isobutyryl-8-methoxyquinoline as a brown oil (6.4 g, 71%).
Reaction SMILES: [O:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C(CCO)=CC=CC=1>C(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:1]1[C:5]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[CH:16]=[O:17])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: OB(O)c1cc2ccccc2o1
Reactant: O=Cc1ccccc1Br
Agent: [Pd]
Agent: Cc1ccccc1CCO
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=Cc1ccccc1-c1cc2ccccc2o1
Temperature: 100 °C

Procedure:
A mixture of 3 g of benzo[b]furan-2-boronic acid, 3.14 g 2-bromobenzaldehyde, 0.56 g tetrakis(triphenylphosphine)-palladium (0), and 17 ml of 2N aqueous sodium carbonate in 50 ml of a 9:1 mixture of toluene-ethanol, under a nitrogen atmosphere, was heated to 100° C. for 10 h. The mixture was cooled to room temperature, diluted with 100 ml of methylene chloride and washed with 50 ml of 5% sodium bicarbonate containing 5 ml of 0.880 ammonia. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 2-(benzo[b]furan-2-yl)benzaldehyde as a brown gum, GC-M.S. (E.I.) (M/Z): 222 [M+ ].
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23].[K].C1(C)C=CC=CC=1>O>[CH2:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:7]([S:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:27][CH:26]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)c2cccnc2Cl)cc1
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(-c2ncccc2S(=O)(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 55.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium(b) (0.076 g) was added to a deoxygenated mixture of 4-nitrophenyl 2-chloropyridine-3-sulphonate (0.69 g), 4-isobutylphenylboronic acid (0.47 g), potassium fluorsde (0.38 g), toluene (15 ml) and water (2.5 ml) and the mixture was stirred and heated under reflux for 24 hours. Water (50 ml) was added and the mixture was extracted with ethyl acetate (2×80 ml). The organic extracts were washed with saturated sodium chloride solution and then combined and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by gradient elution with dichoromethane/hexane (1:1-1:0 v/v) then dichloromethane/hexane/ethyl acetate (10:9:1 v/v) through a silica gel Mega Bond Elut column followed by recrystallisation from ethyl acetate/hexane to give 4-nitrophenyl 2-(4-isobutylphenyl)pyridine-3-sulphonate (0.50 g), m.p. 123-124° C.; 1H NMR (d6 -DMSO): 0.9 (d, 6H), 1.9 (m, 1H), 2.55 (d, 2H), 7.2-7.3 (m, 4H), 7.5 (d, 2H), 7.7 (dd, 1H), 8.2 (d, 2H), 8.4 (dd, 1H), 9.0 (dd, 1H); mass spectrum (+ve FAB, NBA/DMSO): 413 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:24])[F:23])[C:11]=2[C:26](OC)=[O:27])[CH2:9][CH2:8]1>O1CCCC1>[CH:7]1([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]([F:25])([F:23])[F:24])[C:11]=2[CH2:26][OH:27])[CH2:8][CH2:9]1
Reactant: COC(=O)c1c(-c2ccccc2OC(F)(F)F)noc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(-c2ccccc2OC(F)(F)F)noc1C1CC1

Procedure:
A 250-mL round-bottom flask was purged with nitrogen and a suspension of LiAlH4 (2.5 g, 65.8 mmol, 2.87 equiv) in tetrahydrofuran (50 mL) was added. This was followed by the addition of a solution of methyl 5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-carboxylate (7.5 g, 22.9 mmol, 1.00 equiv) in tetrahydrofuran (50 mL) dropwise at −10°C. The resulting reaction mixture was stirred fo(30 min at −10°C. When the reaction was complete, it was quenched by the addition of 3 mL of ethyl acetate, followed by 3 mL of water and O1 mL of 15% aqueous NaOH, all whilst maintaining a vigorous stirring. The resulting white precipitate was filtered through celite®, and the filter cake was washed with 200 mL of ethyl acetate. The filtrate was washed with brine (2×100 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 7 g of (5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methanol as yellow oil. (1H-NM(300 MHz, CDCl3) δ 7.56 (m, 2H), 7.41 (m, 2H), 4.50 (s, 2H), 2.20 (m, 1H), 1.72 (s, 1H, —OH) 1.11-1.28 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of 4-chloro-3-nitrophenol (5.21 g, 30 mmol) in acetone (60 ml) were added ethyl iodide (5.94 g, 38 mmol) and potassium carbonate (4.53 g, 33 mmol), followed by stirring at 50° C. for 5 hours. After allowing to stand overnight, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate-hexane (1:4)] to give the title compound (5.72 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[N-:21]=[N+:22]=[N-:23].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:21]=[N+:22]=[N-:23]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCCCCCCCCCCCCN=[N+]=[N-]

Procedure:
16-bromohexadecanoic acid methyl ester is reacted with sodium azide in acetonitrile for four days at reflux temperature to give the corresponding azide (Zinic et al., Positionally Isomeric Organic Gelators: Structure-Gelation Study, Racemic versus Enantiomeric Gelators, and Solvation Effects, Chem. Eur. J. 2010; 16:3066-82).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:11]3[N:16]=[CH:15][S:14][C:12]=3[N:13]=2)[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.ClCC[I:40]>C1COCC1>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[C:11]3[N:16]=[C:15]([I:40])[S:14][C:12]=3[N:13]=2)[C:6]2[CH:23]=[CH:24][CH:25]=[CH:26][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2ncsc2n1
Reactant: ClCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(I)sc2n1
Temperature: -5 °C

Procedure:
A solution of 5 -(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine (1.92 g, 5.23 mmol) in THF (60 mL) was cooled to −40° C. before the drop wise addition of LiHMDS (6.3 mL, 6.28 mmol, 1 M solution in THF). The resulting mixture was warmed to −5° C. over 30 min then mixture was cooled back to −30° C. before the addition of a solution of 1-chloro-2-iodoethane (2.0 g, 10.47 mmol) in THF (6 mL) The resulting mixture was allowed to warm to 0° C. then quenched with NH4Cl and extracted with EtOAc. The combined organics were washed with brine then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:DCM, 50-80%) followed by recrystallisation from iPrOAc affording the title compound as a yellow solid (1.58 g, 62%)._LCMS (method A): RT 3.50 min [M+H]+ 493.0
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13](CC4C=CC(OC)=CC=4)[C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[CH:30]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:26])[N:11]([CH3:27])[C:10]=3[N:9]=[C:8]2[C:28](=[O:40])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:37])([F:38])[F:39])[CH:30]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(Cn2c(=O)c3c(nc(C(=O)c4cccc(OC(F)(F)F)c4)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)[nH]c(=O)c2c1nc(C(=O)c1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.5 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (15 mg, 0.025 mmol) in DCM (1 ml) was added TFA (1 ml) dropwise followed by trifluoromethanesulfonic acid (0.25 ml), both at 0° C. The reaction was stirred at 0° C. for 10 min, then stirred at room temperature for 16 h. The reaction was quenched with aqueous saturated sodium bicarbonate and extracted with DCM. The organic phase was washed with water dried over sodium sulfate, filtered and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzoyl)-1H-purine-2,6(3H,7H)-dione (10 mg, 83.7%) as yellow oil. LCMS retention time 1.821 min; LCMS MH+ 479.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]COCCOC)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCOCCOC)cc3)ncc2F)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(O)cc3)ncc2F)c1
Yield: 6.9 %

Procedure:
In a 25 mL 3-neck RBF equipped with a rubber septum, N-(3-((5-fluoro-2-((4-((2-methoxyethoxy)methoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (0.180 g) was taken and TFA (1.0 mL) was added drop wise at room temperature under stirring. The reaction mixture was further stirred for 30 min. Completion of reaction was monitored by TLC using CHCl3:MeOH (9.5:0.5). After completion, the reaction mixture was quenched in water. The aqueous solution was basified with saturated sodium bicarbonate solution. The product was extracted into DCM, washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was treated with DBU and 75 mg of product was collected. This was further purified by preparative TLC using CHCl3:MeOH (9.5:0.5) as a mobile phase to give 10 mg of N-(3-((5-fluoro-2-((4-hydroxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide. M+1=365.9 1H NMR: DMSO-d6 (400 MHz) 5.73-5.76 (dd, 1H, J=2, 8), 6.23-6.28 (dd, 1H, J=2, 18.8), 6.48-6.55 (m, 1H), 6.59. 6.61 (d, 2H, J=8.8), 7.22-7.261 (t, 1H, J=8.16), 7.40-7.51 (m, 4H), 8.03-8.04 (d, 2H, J=3.6), 8.426 (s, 1H), 8.902 (s, 1H), 9.331 (s, 1H), 10.26 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](=O)[CH2:7]Br)([O-:3])=[O:2].[C:14]([NH:17][C:18]([NH2:20])=[S:19])(=[NH:16])[NH2:15].O.[OH-].[Na+]>CN(C)C=O>[NH:17]([C:18]1[S:19][CH:7]=[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:20]=1)[C:14]([NH2:16])=[NH:15]
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)Nc1nc(-c2ccccc2[N+](=O)[O-])cs1
Yield: 95 %

Procedure:
A solution of 16.5 gm of 2-nitro-phenacyl bromide and 7.98 gm of amidinothiourea in 70 ml of dimethylformamide was stirred at room temperature for 16 hours, and then poured into 350 ml of water. The solution was made alkaline with 10% sodium hydroxide, and the solid which separated out after cooling was filtered, washed with water and dried, yielding 16.9 gm of the title compound, m.p. 176°-178° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([C:8]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:9]=1[NH2:10])[CH3:7].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[Cl:1][CH2:2][C:3]([NH:10][C:9]1[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:6][CH3:7])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(C)c1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cccc(C)c1NC(=O)CCl
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
Chloroacetyl chloride (84.8 g) was added, over 20 minutes, to a solution of 2-ethyl-6-methylaniline (67.5 g), glacial acetic acid (230 ml), sodium acetate (anhydrous 110.5 g) in water (200 ml) at such a rate that the reaction temperature did not exceed 10° C. The resulting suspension was then stirred vigorously for 30 minutes at 10° C. (requiring the addition of further quantities of acetic acid and water to maintain fluidity). The suspension was filtered, the resulting solid was air-dried on the filter and was then recrystallised from ethanol/water to yield the N-chloroacetyl-2-ethyl-6-methylaniline as a colourless solid (58.7 g), m.p. 122°-123° C. This product (10.8 g) was dissolved in toluene and added dropwise to a stirred mixture of N-chloroacetyl-2-ethyl-6-methylaniline (21.2 g), polyethyleneglycol-400 (8.0 g), sodium hydroxide (16.0 g in 15 ml water) and toluene at such a rate to maintain the reaction temperature at 10°-15° C. for 2 hours.