Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.C(=O)(O)[O-].[Na+].C(N1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])(OCC)=O.O1CCCC1>O>[C:21]1(=[O:30])[N:2]([CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]12
Reactant: NC1CCC(O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A solution of 4-aminocyclohexanol hydrochloride (6.08 g, 0.04 mole) in water (60 ml) was brought to pH 8 with aqueous sodium bicarbonate solution. N-carbethoxy-phthalimide (8.76 g, 0.04 mole) was added followed by tetrahydrofuran (until homogenous solution was obtained). The clear solution was stirred at room temperature overnight. During this time a white solid was precipitated. The tetrahydrofuran was removed in vacuo and the remaining aqueous solution was extracted with ethyl acetate until the solution was clear. The ethyl acetate extracts were combined, washed with water, dried (MgSO4) and concentrated to give 4-phthalimido cyclohexanol as a white solid (7.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>CCOC(C)=O.O>[CH3:9][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:18]
Reactant: CSc1cccc(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69393.7 %

Procedure:
A mixture of 3-bromothioanisole (4.9687 g, 0.0245 mmol) and MCPBA (5.066 g, %) was stirred at room temperature. After 4 h, extractive EtOAc/H2O workup followed by flash chromatography (EtOAc/Hexanes, 50:50) provided the title compound (3.725 g, 69%) as an oil. 1H NMR (DMSO, 400 MHz): 7.80 (br s, 1H), 7.61 (d, J=8.01 Hz, 1H), 7.53 (d, J=8.01 Hz, 1H), 7.39 (t, J=8.01 Hz, 1H), 2.72 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14]>CC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: CC(C)=O
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-26A: To a solution of 4-acetyl-benzenesulfonyl chloride (Hoffman, R. V. Org. Syn. VII, 508; 4.18 g, 19.1 mmol) in acetone (30 mL) was added ammonia (28% in water, 8.2 mL, 57.3 mmol) dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 30 min. The precipitate was filtered and the residue was washed with water and dried in vacuo to afford 4-acetyl-benzenesulfonamide as a white solid (3.54 g, 93%). 1H NMR (DMSO-d6) δ 8.10 (d, J=9 Hz, 2H), 8.03 (d, J=9 Hz, 2H), 4.86 (bs, 2H), 2.65 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[NH2:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([Br:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc(N)c(C=O)cc1Br
Yield: 54.7 %

Procedure:
To a stirred solution of 2-amino-4-methoxybenzaldehyde (6 g, 39.7 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (7 g, 39.7 mmol). The reaction mixture was diluted with dichloromethane and water. The separated organic layer was dried sodium sulfate, filtered and concentrated to give the title compound (5 g, 56%) as a yellow solid. MS (ES+) C8H8BrNO2 requires: 229, 231, found: 230, 232 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.[CH3:44][O:45][NH2:46]>O1CCCC1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:46][O:45][CH3:44])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of the carboxylic acid (6b, 965 mg, 3.49 mmol) of Example 9 or 16 in tetrahydrofuran (20 mL) were added triethylamine (1.95 mL), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (802 mg), 1-hydroxybenzotriazole.monohydrate (658 mg), and O-methylhydroxylamine hydrochloride (363 mg), followed by agitating to room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/10) to afford 773 mg of the title compound (yield 72%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:11]([C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)=[O:12])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A 5 L, 3-necked round bottomed flask equipped with an overhead stirrer, dropping funnel, N2(g) inlet was charged with AlCl3 (432.5 g, 3.24 mol). The solids were cooled to 0° C. with an ice-H2O bath. DMF (71 ml) was added dropwise over a period of 35 min and the temperature was kept under 32° C. during the addition. The reaction mixture was heated to 50° C. and treated with 3-Nitrobenzoyl chloride (63.2 g, 0.34 mol). The reaction that ensued was exothermic and caused the internal reaction temperature to rise to 65° C. The reaction was stirred for 50 min then bromobenzene (33.5 ml, 0.32 mol) was added. The reaction was heated at 90° C. for 3 h. Thin layer chromatographic analysis (Hexanes/ethylacetate 1:1) indicated completion of reaction. The reaction was cooled and ice-H2O (3 L) was added dropwise over a period of 1.5 h. The reaction was allowed to stir overnight. The solids were filtered, washed with H2O (1 L), saturated NaHCO3(aq) (1 L), another portion of H2O (500 mL) and Hexanes (500 mL). The product was dried in the vacuum oven at 40° C., 28 in Hg for 30 hours to yield (4-Bromo-phenyl)-(3-nitro-phenyl)-methanone in 88% (85.34 g, 0.28 mol).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:3]1(/[CH:2]=[CH:1]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: Ic1ccccc1
Product: C(=C/c1ccccc1)\c1ccccc1
Yield: 100 %

Procedure:
In addition to hydrogenation of a series of alkenes, the nanospheres are proved to catalyze the Heck coupling reaction between styrene and iodobenzene forming trans-stilbene with ˜100% yield in 12 hours (FIG. 21). Furthermore, the catalyst showed good recyclability in the Heck coupling reaction as well.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[O:11]=[C:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=2)[NH:7]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)CC(=O)N2
Temperature: -30 °C
Yield: 90 %

Procedure:
A stirred solution of 5-amino-1,3-dihydro-indol-2-one (2 g, 13.5 mmol, prepared according to U.S. Pat. No. 6,114,371) in 30 ml of dichloromethane was added with triethylamine (1.9 ml). The solution was cooled down to −30° C. in an acetone-dry ice bath and added with methanesulfonyl chloride (1 ml, 13.5 mmol) dropwise. Upon the completion of the addition, the resulting mixture was heated at 45° C. for 1 hour until precipitate was formed. The solid was filtered, washed with water (50 ml×3) and dried in vacuo to give N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-methanesulfonamide (2.7 g, 90%) as a white solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.C(Cl)(Cl)Cl.P(Br)(Br)[Br:19].CCCCCC>C(Cl)Cl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:19])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: -5 °C
Yield: 42.5 %

Procedure:
A 500-mL three-necked round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and reflux condenser was purged with nitrogen and charged with (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol 103h (37.0 g, 148 mmol) and chloroform (160 mL). The reaction was cooled to −5° C. using an ice/acetone bath and phosphorous tribromide (40.0 g, 148 mmol) was added portionwise. The cooling bath was removed and the reaction stirred at reflux for 2 h. After this time, the reaction was cooled to −5° C. and saturated aqueous sodium bicarbonate (250 mL) was added until a pH of 8.5 was reached. The mixture was extracted with ethyl acetate (3×150 mL) and the combined organic layers were washed with saturated aqueous sodium carbonate (2×50 mL), brine (75 mL), dried over sodium sulfate and the drying agent was removed by filtration. The filtrate was concentrated under reduced pressure to afford a yellow residue that was dissolved with gentle heating in methylene chloride (60 mL). Hexane (approximately 20 mL) was added and the solution became cloudy. The mixture was heated until a solid precipitate formed, methylene chloride (9 mL) was added and the solution became clear. The solution was left to cool to room temperature and after 4 h the resulting crystals were collected by vacuum filtration. The filter cake was washed with a ice cold 1:2 mixture of methylene chloride:hexanes (2×20 mL) to afford 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 103i (19.7 g). The combined filtrates were evaporated and the procedure was performed again to afford an additional 9.70 g of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 103i. The solids were combined and dried under high vacuum for 18 h to afford a 57% yield (26.0 g) of 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 103i as white crystals: mp 95-97° C.; 1H NMR (300 MHz, CDCl3) δ 6.93 (s, 1H), 4.63 (t, 2H, J=6.0 Hz), 4.54 (s, 2H), 3.86 (t, 2H, J=6.0 Hz).
Reaction SMILES: [BH4-].[Na+].[CH3:3][S:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11])(=[O:6])=[O:5].O>C(O)C>[CH3:3][S:4]([C:7]1[CH:8]=[C:9]([CH2:10][OH:11])[CH:12]=[CH:13][CH:14]=1)(=[O:5])=[O:6]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
NaBH4 is added to a solution of 750 mg (4.08 mmol) 3-methanesulphonyl-benzaldehyde in 20 ml ethanol (see P. L. Ornstein, T. J. Bleisch, M. B. Arnold, R. A. Wright, B. G. Johnson, J. P. Tizzano, D. R. Helton, M. J. Kallman, D. D. Schoepp, M. Herin, J. Med. Chem. 1998, 41(3), 358-378 or B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97(5), 1470-81). The reaction mixture is stirred at room temperature for 1 h. The reaction mixture is poured into water and extracted three times with ethyl acetate. The combined organic layers are washed with water and brine, dried, filtered and concentrated in vacuo to afford the title compound, used in the next step without further purification.
Reaction SMILES: C(#N)C.[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1.[C:10]([O:18]OC(C)(C)C)(=[O:17])[C:11]1C=CC=CC=1>[Cu].C(O)(=O)C>[C:10]([O:18][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1)(=[O:17])[CH3:11]
Reactant: C1=CCCCC1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Agent: [Cu]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(=O)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of 1.100 g of the copper complex of N-salicylidene-3-amino-3-deoxy-1,2-O-isopropylidene-5-O-triphenylmethyl-α-D-ribofuranose, 0.70 g of copper powder, 15 ml of acetonitrile, 5 ml of acetic acid, 15 ml of cyclohexene and 5 of t-butyl peroxybenzoate was stirred at room temperature for 9 hours in a nitrogen atmosphere. After filtering the reaction solution, the filtrate was treated in the same manner as in Example 1 to obtain 1.80 g of 2-cyclohexenyl acetate.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:2]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1[I:17])[C:10]([O:12][CH3:13])=[O:11])[CH2:3][CH2:4][CH3:5]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCOc1cc(C(=O)OC)ccc1I
Temperature: 60 °C
Yield: 49.5 %

Procedure:
14.7 ml (130 mmol) of iodobutane is added to a solution of 30 g (110 mmol) of methyl 3-hydroxy-4-iodobenzoate and 17.9 g (130 mmol) of potassium carbonate in 300 ml of 2-butanone. The reaction mixture is heated at 60° C. for 16 hours. After adding 100 ml of water and then extraction with ethyl acetate, the organic phases are combined, dried over sodium sulfate, and filtered. The solvents are evaporated and then the residue is taken up in heptane and filtered. 18.2 g of methyl 3-butoxy-4-iodobenzoate is obtained in the form of white crystals. The filtrate is concentrated and the residue is purified by silica column chromatography, eluted with a heptane/ethyl acetate mixture 8/2, obtaining 11.6 g of methyl 3-butoxy-4-iodobenzoate. 29.8 g (82%) of methyl 3-butoxy-4-iodobenzoate is thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Yield: 97.9 %

Procedure:
To a solution of 4-bromophenol (17.3 g, 100 mmole) in dry DMF (100 mL) at RT was added imidazole (13.62 g, 200 mmole), followed by triisopropylsilyl chloride (22.5 mL, 105 mmole). After 4 hr the mixture was diluted with H2O (50 mL) and extracted with hexanes (3×75 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound (32.23 g, 100%) as a clear oil which was used without purification: 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J=6 Hz, 2 H), 6.71 (d, J=6 Hz, 2 H), 1.22 (m, 3 H), 1.09 (m, 18 H).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28][CH3:29])=[O:27].Cl>CN(C=O)C>[CH3:29][O:28][C:26]([C:25]1[CH:24]=[C:23]([CH2:22][N:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]2=[O:18])[CH:32]=[CH:31][CH:30]=1)=[O:27]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 25 %

Procedure:
To 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (4.76 g, 20 mmol) in 50 mL DMF was added to a suspension of NaH (0.8 g, 20 mmol) in 25 mL DMF. The suspension was stirred at ambient temperatures for 30 minutes, then heated to 50° C. for 30 minutes. A solution of methyl 3-bromomethylbenzoate (2.86 g, 12.5 mmol) in 20 mL DMF was then added and the reaction stirred for 10 min at 50° C. The mixture was poured into 1N HCl, filtered, washed with water and dried. Chromatography on silica gel (2% EtOH in 7:3 methylene chloride/ethyl acetate) afforded 1.2 g of 3-(3-methoxycarbonylphenyl)methyl-4,5-diphenyl-1H-imidazol-2-one as a whim solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C@@H:8]([NH:10][C:11]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17])[CH3:9])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Methanesulfonyl chloride (13.2 mL, 170 mmol) was added to a 0° C. solution of tert-butyl [(2S)-1-hydroxypropan-2-yl]carbamate (28.4 g, 162 mmol) and triethylamine (27 mL, 190 mmol) in dichloromethane (350 mL), and the reaction mixture was allowed to stir for 30 minutes. After aqueous ammonium chloride solution was added to the reaction mixture, the aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting sticky white solid was slurried with diethyl ether (100 mL), stirred for 10 minutes, and filtered to afford the product as a white solid. Yield: 28.8 g, 114 mmol, 70%. The filtrate was concentrated under reduced pressure and recrystallized from diethyl ether (the hot mixture was filtered through Celite before crystallization) to provide additional product as a white solid. Yield: 11.66 g, 45.63 mmol, combined yield 98%. 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=7.0 Hz, 3H), 1.45 (s, 9H), 3.04 (s, 3H), 3.91-4.04 (br m, 1H), 4.16 (dd, half of ABX pattern, J=10.1, 4.2 Hz, 1H), 4.19-4.28 (br m, 1H), 4.62 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[N:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CC(O)C>[O:16]1[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]3[C:5]([CH3:19])=[CH:4][N:3]=[C:2]([NH:33][C:30]4[CH:29]=[CH:28][C:27]([N:24]5[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]5)=[N:32][CH:31]=4)[N:7]=3)=[CH:18][C:13]=2[NH:14][C:15]1=[O:17]
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(N3CCN(C)CC3)nc2)nc1Nc1ccc2oc(=O)[nH]c2c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53 %

Procedure:
To a vial with 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (27.7 mg, 0.5 mmol) and 6-(4-methylpiperazin-1-yl)pyridin-3-amine (38.4 mg, 1.0 mmol), i-PrOH (2 mL) was added, followed by TFA (10 μL, 0.13 mmol). The vial was tightly closed, and the reaction mixture was stirred at 85° C. for 2 days. The solvents were removed in vacuo, and the crude product was purified by RP-HPLC. Purified compound (as a trifluoroacetate salt) was dissolved in MeOH—H2O (1:4, 2 mL) and was passed through a PL-HCO3-MP-SPE column, washing with same solvents (1 mL). The filtrate was collected and the solvent was removed by lyophilization. N4-(benzoxazolin-2-on-5-yl)-N2-[2-(4-methylpiperazin-1-yl)pyridin-5-yl]-5-methylpyrimidine-2,4-diamine was obtained as a purple solid, 23.1 mg (53% yield); 1H NMR (300 MHz, DMSO) δ 11.57 (s, 1H), 8.73 (s, 1H), 8.30-8.28 (m, 2H), 7.87-7.84 (m, 2H), 7.46-7.28 (m, 2H), 7.22 (d, J=8.5, 1H), 6.71 (d, J=9.1, 1H), 3.40-3.37 (m, 4H, overlapped with H2O), 2.44-2.41 (m, 4H), 2.25 (s, 3H), 2.11 (s, 3H); LCMS (M+) m/z 433.52.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16]Cl>CN(C)C=O>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a stirred soluton of 3-nitrophenol (5 g, 36 mmol) in dimethylformamide (100 ml) at 0° C. was added sodium hydride (1.029 g, 80% dispersion in mineral oil, 34.3 mmol). After the effervescence had subsided 2-dimethylaminoethyl chloride was added (5.746 g, 37.8 mmol). After 1 hour the reaction mixture was allowed to warm to room temperature. After a further 2 hours the reaction mixture was heated to 70° C. for 14 hours, then evaporated under reduced pressure. The residue was then partitioned between water and ethyl acetate and the organic phase washed twice with aqueous sodium hydroxide solution (SM) and then saturated aqueous sodium chloride solution. Drying and evaporation gave the product as a brown oil (4.64 g, 61%)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6](Cl)[N:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][C:5]=2[CH3:9])=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1nnc(Cl)nc1Cl
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COc1cc(-c2nc(Cl)nnc2C)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetralis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacuo and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]([Mg]Cl)#[CH:9].[NH4+].[Cl-]>C1COCC1>[C:8]([C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[CH:9]
Reactant: O=C1CCOCC1
Reactant: C#C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
A stirred solution of dihydro-2H-pyran-4(3H)-one (500 mg, 5.0 mmol) in dry THF (20 mL) was cooled to −70° C. and 0.5 M ethynylmagnesium chloride in THF (20 mL, 10 mmol) was added in a slow stream. The cooling bath was allowed to expire and the mixture was stirred as it warmed to rt. After 6 h, satd aq NH4Cl (20 mL) was added and the mixture was concentrated on the rotary evaporator. The aqueous residue was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and concentrated to leave crude 4-ethynyltetrahydro-2H-pyran-4-ol (491 mg, 78%) as a brown oil. 1H NMR (CDCl3) 1.80 (m, 2H), 1.92 (m, 2H), 2.57 (s, 1H), 3.68 (m, 2H), 3.90 (m, 2H).