Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[CH2:4][N:5]=[C:6]([NH2:22])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH2:21])=[NH:20])[N:9]=1.[C:25](OCC)(=[O:30])[CH2:26][C:27]([CH3:29])=O.[H-].[Na+]>CO>[OH:30][C:25]1[CH:26]=[C:27]([CH3:29])[N:21]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:10]2[N:9]=[C:8]([NH:7][C:6]([NH2:22])=[N:5][CH2:4][C:3]([F:2])([F:23])[F:24])[CH:13]=[CH:12][N:11]=2)[N:20]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)CCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(O)nc(CCCCOc2nccc(NC(N)=NCC(F)(F)F)n2)n1

Procedure:
5-(4-[2-(2,2,2-Trifluoroethyl)guanidino]pyrimid-2-yloxy)valeramidine hydrochloride (0.5 g.) was added to a solution of ethyl acetoacetate (0.352 g.) and sodium hydride (0.07 g.) in MeOH (6 ml.). The resulting solution was heated under reflux for 18 hours. The solvent was evaporated and the residue taken up in aqueous HOAc and extracted with EtOAc. The aqueous layer was basified with potassium carbonate and extracted with EtOAc. Work up gave a sticky solid which was crystallised from acetonitrile to give 4-hydroxy-6-methyl-2-[4-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yloxy)butyl]pyrimidine as white crystals (0.22 g.), m.p. 191°-193°.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.Cl[Sn](Cl)(Cl)Cl.[CH:16]([O:19]C)(Cl)Cl>C(Cl)Cl>[OH:10][C:7]1[C:8]([CH:16]=[O:19])=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: COC(Cl)Cl
Reactant: Oc1ccc2c(c1)OCO2
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc2c(cc1O)OCO2
Temperature: 0 °C
Reaction time: 3 h

Procedure:
This Example was repeated on a larger scale. Sesamol (50.98 g, 369 mmol) was dissolved in 600 mL of CH2Cl2 followed by 52 mL (448 mmol) of SnCl4 and the solution was cooled to 0° C. Cl2CHOCH3 (35 mL, 387.5 mmol) was added dropwise as the reaction mixture warmed to room temperature, and was then stirred for 3 h. The mixture was poured over ice, the water layer was separated and extracted once with CH2Cl2 (30 mL). The organic extracts were combined, washed with 2M HCl (5×100 mL), and brine (50 mL), and then passed through a small column packed with MgSO4, which removed color. The solvent was evaporated to yield 28 g (46% yield): mp 119° C.; 1H-NMR (CDCl3) δ 9.63 (s, 1, CHO); 6.87 (s, 1, ArH); 6.47 (s, 1, ArH); 6.02 (s, 2, ArOCH2O); 1.54 (s, 1, ArOH); low resolution CIMS: m/z (rel. intensity) 167 (MH+, 100). Anal. Calcd. for C8H6O4: C, 57.84; H, 3.64. Found: C, 57.65; H, 3.76.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[O:18])=[CH:19][CH:20]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4]
Reactant: NCCc1ccccn1
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)O)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)=CCC/C(C)=C/COc1ccc(C(=O)NCCc2ccccn2)cc1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
4-geranyloxybenzoic acid(1.37 g) was dissolved in chloroform(30 ml) and triethylamine(1.53 ml), and then diphenylphosphinic chloride(1.05 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 2-(2-aminoethyl)pyridine(0.67 g) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.39 g of the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5](=[N:12][OH:13])[NH2:6]
Reactant: NO
Reactant: N#Cc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1ccc(F)c(Cl)c1
Yield: 33 %

Procedure:
To a solution of 3-chloro-4-fluoro benzonitrile (1.0 g, 6.42 mmol) in ethanol (20 mL), was added hydroxylamine hydrochloride (0.665 g, 9.64 mmol), followed by addition of potassium carbonate (2.66 g, 19.28 mmol). The reaction mass was refluxed for 10-12 h. Excess of solvent was removed under vacuum and the reaction mass was diluted with water, acidified with dilute HCl and filtered to afford 0.400 g the desired product. 1HNMR (DMSO-d6): δ 5.95 (s, 2H), 7.42 (t, J=8.7 Hz, 1H), 7.69 (m, 1H), 7.83 (dd, 1H), 9.80 (s, 1H); MS [M+H]+: 189.12.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[Br:22])(=[O:3])[CH3:2].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:23]([O:21][C@@H:8]1[C@H:7]([Br:22])[C@@H:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:10][C@H:9]1[N:11]1[C:20]2[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=2[N:13]=[CH:12]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1Br
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(=O)c2ccccc2)[C@@H]1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
After 1 g (2.7 mmols) of 5'-O-acetyl-3'-deoxy-3'-bromoadenosine was added to 10 ml of pyridine, 418 mg (1.1 eq.) of benzoyl chloride was added to the mixture. The mixture was stirred at room temperature for 2 hours and pyridine was distilled off under reduced pressure. The residue was added to 30 ml of water followed by extraction twice with 30 ml of chloroform. After the organic solvent was washed with water and then dried over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography to give 1.18 g (yield, 92%) of 2'-O-benzoyl-5'-O-acetyl-3'-deoxy-3'-bromoadenosine.
Reaction SMILES: [Ag:1]=O.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+].[F:10][C:11]([F:18])([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=[O:13]>O>[F:10][C:11]([F:18])([CH2:15][CH:16]=[CH2:17])[C:12]([O-:14])=[O:13].[Ag+:1]
Reactant: C=CCC(F)(F)C(=O)O
Reactant: O=[Ag]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCC(F)(F)C(=O)[O-]
Yield: 87 %

Procedure:
A suspension of silver oxide in water was prepared by adding a solution of NaOH (1.76 g, 0.044 mol) in water (100 ml) to an aqueous solution of silver nitrate (7.14 g, 0.042 mol in 100 ml), decanting the supernatant liquid, washing the residue with water (3×100 ml) and adding 100 ml of water. To this vigorously stirred suspension was added a solution of 2,2-difluoro-4-pentenoic acid (5.44 g, 0.04 mol) in water (100 ml). After 10 minutes the mixture was filtered and the filtrate concentrated (20 Torr, 30° C.) to afford a solid residue; which was dried over phosphorus pentoxide (0.05 Torr, 50° C., 24 hours) to give 8.4 g (87%) of silver 2,2-difluoro-4-pentenoate; a white amorphous powder. A suspension of 7.3 g (0.03 mol) of the silver salt in 50 ml of dichloromethane was stirred under nitrogen, cooled to 0° C. and then 1.9 g (1.3 ml, 0.015 mol) of oxalyl chloride was added slowly. The cooling bath was removed and the reaction mixture allowed to warm up to room temperature. Heating to 40° C. for 30 minutes completed the reaction. Cooled again to room temperature, the supernatant liquid was decanted and the residue washed with dichloromethane (2×5 ml). The organic layers were combined and the solvents removed by distillation at atmospheric pressure. The so-obtained oily residue was then purified by distillation to yield 2.85 g of very hydroscopic 2,2-difluoro-4-pentenoic acid anhydride, bp 78°-80° C.,/20 Torr.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH2:15][C:16](O)=[O:17])[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]3)=[CH:4][CH:3]=1.[CH2:23]([NH2:26])[CH2:24][CH3:25]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[CH2:15][C:16]([NH:26][CH2:23][CH2:24][CH3:25])=[O:17])[C:12]2[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=2[S:10]3)=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: Cc1ccc(-c2nc3sc4ccccc4n3c2CC(=O)O)s1
Solvent: C1CCOC1
Product: CCCNC(=O)Cc1c(-c2ccc(C)s2)nc2sc3ccccc3n12
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
1.6 g (0.005 mole) of 2-(5-methylthien-2-yl)imidazo[2,1-b]-benzothiazole-3-acetic acid are treated, at room temperature, with 0.85 g (0.005 mole) of N,N'-carbonyldiimidazole in 30 ml of anhydrous tetrahydrofuran for 3 h 30 min. A solution composed of 3 g (0.05 mole) of propylamine in 10 ml of anhydrous tetrahydrofuran is added and the mixture is stirred for 4 h at room temperature. The solvent is evaporated under reduced pressure, the compound is collected by filtration, it is washed with water up to neutral pH, then with ethanol and finally with ethyl ether and it is purified by recrystallization from methanol. 1.1 g of a light yellow solid are obtained. Melting point: 204°-206° C.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28]I)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][CH:7]([S:4]([CH3:3])(=[O:6])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:25][CH:26]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ICCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
Sodium hydride (1.80 g, 45 mmol, 60% in mineral oil) was added in three portions to a solution of ethyl (methylsulfonyl)acetate (6.70 g, 40.3 mmol) in DMF (200 mL) at 0° C. The reaction was allowed to warm to room temperature and stirred for 1 hour. 1-(Benzyloxy)-4-(2-iodoethyl)benzene was added to the solution and the reaction was stirred overnight at rt. The reaction was quenched with 1N aqueous HCl (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on a Biotage 40 L column using 1:4 ethyl acetate in heptane afforded the title compound as a white solid (13.13 g, 86.5%). LC-MS m/z 375.2 (M−1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (t, J=7.03 Hz, 3H) 2.31-2.47 (m, 2H) 2.55-2.68 (m, 1H) 2.70-2.80 (m, 1H) 3.00 (s, 3H) 3.66-3.80 (m, 1H) 4.18-4.38 (m, 2H) 5.06 (s, 2H) 6.92 (d, J=8.59 Hz, 2H) 7.09 (d, J=8.59 Hz, 2H) 7.31-7.47 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:26]([Cu])#[N:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:25])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:26]#[N:27])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2Cc1ccccc1

Procedure:
Prepared in analogy to that of Example 105(a) from 1-benzyl-2,3,7-tribromo-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 478 (M+H)+.
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[C:7]([CH2:13][CH2:14][OH:15])[C:8](O)=[CH:9][CH:10]=2)[CH:5]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:4]1)=[O:2].CS(Cl)(=O)=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[CH:1]([N:3]1[C:11]2[C:6](=[C:7]3[CH2:13][CH2:14][O:15][C:8]3=[CH:9][CH:10]=2)[CH:5]([CH2:16][CH2:17][NH:18][C:19](=[O:22])[CH2:20][CH3:21])[CH2:4]1)=[O:2]
Reactant: CCC(=O)NCCC1CN(C=O)c2ccc(O)c(CCO)c21
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)NCCC1CN(C=O)c2ccc3c(c21)CCO3
Reaction time: 0.33 h
Yield: 33.2 %

Procedure:
To a solution of N-[2-[1-formyl-2,3-dihydro-5-hydroxy-4-(2-hydroxyethyl)indol-3-yl]ethyl]propionamide (0.8 g, 2.61 mmol) in pyridine (10 mL) was added methansulfonyl chloride (0.2 mL, 2.61 mmol.) around −10° C. The mixture was stirred for 20 minutes while keeping the temperature −10 to 5° C. To this was added additional methansulfonyl chloride (0.1 mL, 1.3 mmol.) and the mixture was stirred for further 15 minutes at the same temperature. The mixture was diluted with ethyl acetate(10 mL). Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added slowly and the mixture was stirred for 30 minutes at room temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with 2N-hydrochloric acid and water, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to afford the title compound (yield 0.25 g, 33%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:26])([F:25])[F:24])=[N:15][C:16]([C:17](=[O:22])N(OC)C)=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][Mg]Br.[Cl-].[NH4+]>O1CCCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([C:23]([F:25])([F:26])[F:24])=[N:15][C:16]([C:17](=[O:22])[CH3:27])=[C:10]2[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)OC(C)(C)C)CC2
Yield: 91.1 %

Procedure:
1-(Methoxy-methyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27e (0.3 g, 0.79 mmol) was dissolved in 20 mL of tetrahydrofuran under stirring, and methylmagnesium bromide (1.13 mL, 1.58 mmol) was then added dropwise to the solution at 0° C. The reaction mixture was reacted at 0° C. for 1.5 hours and monitored by thin layer chromatography until the disappearance of the starting materials. 50 mL of saturated ammonium chloride and 10 mL of saturated brine were added to the reaction mixture. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic phase was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 1-acetyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester 27f (0.24 g, yield 90%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH3:22][NH:23][C:24](=[O:34])[O:25][CH2:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(O)(CC)(C)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]>[CH3:22][NH:23][C:24](=[O:34])[O:25][CH2:26][C:27]1[N:28]=[C:29]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:30]=[CH:31][N:32]=1
Reactant: CNC(=O)OCc1nccc(Cl)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CNC(=O)OCc1nccc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-Amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (85 mg, 0.272 mmol), (4-chloropyrimidin-2-yl)methyl methylcarbamate (54.9 mg, 0.272 mmol), Pd2 dba3 (24.92 mg, 0.027 mmol), K2CO3 (41.4 mg, 0.299 mmol) and X-Phos (64.9 mg, 0.136 mmol) were added to a 5 mL microwave vial. Degassed tert-amyl alcohol (0.6 mL) was added and the vial evacuated and back-filled with N2 (3×). The resulting mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, MeOH and silica gel were added, and the solvent was removed in vacuo. Purification of the residue twice by silica gel chromatography (0-10% MeOH-DCM) gave [4-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyrimidin-2-yl]methyl methylcarbamate as a beige solid after triturating in DCM.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][C@H:5]1[O:7][C@@H:6]1[CH2:8][OH:9].O(O)O.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[S:21]([CH:5]([CH2:4][CH:3]([O:10][CH3:11])[O:2][CH3:1])[CH:6]([OH:7])[CH2:8][OH:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(C[C@H]1O[C@@H]1CO)OC
Reactant: Sc1ccccc1
Agent: OOO
Product: COC(CC(Sc1ccccc1)C(O)CO)OC

Procedure:
The epoxy alcohol (2R,3R) 3-(2,2-dimethoxyethyl)oxiranemethanol is reacted with thiophenol in the presence of a metal catalyst to obtain 3-thiophenoxy-5,5-dimethoxy pentane-1,2-diol: ##STR15##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([NH2:28])=[N:10][CH:11]=[N:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH2:28][C:9]1[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])[CH:7]=[CH:6][CH:5]=2)=[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[N:12]=[CH:11][N:10]=1
Reactant: Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)Nc1cccc(-c2c(N)ncnc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 26 %

Procedure:
(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride using Method E (26% yield). HPLC: 97%, RT=3.608 min. MS: m/z=482 [M+H]+, RT=3.57 min. 1H-NMR (DMSO-d6), δ 10.33 (s, 1H), 9.66 (s, 1H), 8.01 (s, 1H), 7.66-7.64 (m, 2H), 7.38 (t, 1H), 7.32 (t, 2H), 7.11-6.92 (m, 8H), 6.68 (m, 1H), 6.41 (m, 3H), 3.88 (m, 2H), 2.73 (s, 6H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[I-].C([NH3+])(C)(C)C.[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>O1CCCC1>[CH2:18]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH:20]1[O:22][CH2:21]1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: CC(C)(C)[NH3+]
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: O=Cc1ccc(OCC2CO2)cc1
Yield: 40 %

Procedure:
A 250 ml. three neck flask was equipped with magnetic stir bar, reflux condenser, addition funnel and nitrogen inlet. Dry nitrogen was swept through the apparatus while it was heated with a heat gun. After the apparatus was cooled, 5.95 g. of a 60% oil dispersion of sodium hydride (0.149 mole) was added and triturated three times with 25 ml. of petroleum ether to remove the oil. A solution of 36.6 g. (0.3 mole) 4-hydroxybenzaldehyde in 100 ml. of tetrahydrofuran was added dropwise to the sodium hydride over 30 mins. When the addition was complete, 1.1 g. (0.0003 mole) tert-butyl ammonium iodide was added along with 30.7 g. (0.33 mole) epichlorohydrin. The reaction mixture was refluxed overnight, cooled, filtered, and the solvent removed under vacuum. Excess epichlorohydrin was removed by azeotropic distillation using a ten fold excess of toluene. Yield was 40% of 4-glycidoxy benzaldehyde.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][OH:35])=[CH:32][CH:31]=1>>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:35][CH2:2][C:3]2[N:4]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)[CH:5]=[C:6]([C:8]3[C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:10][O:11][C:12]=3[CH3:13])[N:7]=2)=[CH:32][CH:31]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: OCc1ccc(Br)cc1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccc(Br)cc2)n1
Yield: 15 %

Procedure:
As described for Example 153, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 4-bromobenzyl alcohol instead of 4-methylbenzyl alcohol, was converted to the title compound (21 mg, 15%) which was obtained as a light yellow solid. MS: m/e=545.3/547.3 [M+H]+.
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][C@H:32]([CH2:39][CH3:40])[CH:33]([OH:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)([CH3:13])[CH3:12]
Reactant: CC[C@@H](N)C(O)C(C)(C)C
Reactant: CC(C)n1cnc2c(NCc3ccccn3)nc(F)nc21
Solvent: CCCCO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](Nc1nc(NCc2ccccn2)c2ncn(C(C)C)c2n1)C(O)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of-(2-fluoro-9-isopropyl-9H-purin-6-yl)-pyridin-2-ylmethyl-amine (30 mg, 1 eq, 0.10 mmol) in n-BuOH/DMSO (5 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.10 mL, 5.5 eq, 0.57 mmol) followed by (3RS,4R)-4-amino-2,2-dimethyl-hexan-3-ol (52 mg, 3.41 eq, 0.36 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with CHCl3:MeOH (100:0→98:2), to afford the title compound as a white solid. Yield: 6.3 mg (15%). (55% de 4R,3S: 45% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 1.00-1.03 (m, 12H, —NHCH(CH2CH3) CH(C(CH3)3OH), 1.56 & 0.58 (2×d, 6H, J=6.63 & 6.63 Hz, —CH(CH3)2), 1.69-1.89 (m, 2H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.56 (d, 1H, J=1.89 Hz, —NHCH(CH2CH3)CH(C(CH3)3)OH), 3.72-3.84 (m, 1H, —NHCH(CH2CH3) CH(C(CH3)3) OH), 4.58-4.70 (m, 1H, —CH(CH3)2), 4.88-4.98 (m, 2H, —HNCH2-Pyr), 5.22-5.39 (m, 1H, —NHCH(CH2CH3)CH(C(CH3)3)OH), 6.70-6.80 (m, 1H —HNCH2-Pyr), 7.18-7.24 (m, 1H, Pyr-H), 7.38 (d, 1H, J=7.90, Pyr-H), 7.57 (s, 1H, —N═CH—N—), 7.63-7.70 (m, 1H, Pyr-H), 8.61 (d, 1H, J=4.90 Hz, Pyr-H). FABMS m/z (relative intensity): 412 ([M+H]+, 100), 324 (70). Accurate Mass (M+H): Actual: 412.2825, Measured: 412.2835.