Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[CH:12][CH:11]=2)=[C:4]([OH:20])[CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH:16]([F:17])[F:18])=[CH:14][CH:15]=3)[O:20][C:4]=2[CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)F)cc1
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)c1ccc(-c2nc3ccc(Br)cc3o2)cc1
Yield: 26.7 %

Procedure:
N-(4-Bromo-2-hydroxyphenyl)-4-(difluoromethyl)benzamide (0.5 g, 1.5 mmol) was dissolved in 1,4-Dioxane (10 ml) and added Phosphorus oxychloride (0.4 ml, 4.4 mmol). This mixture was refluxed for 2 h. 1,4-Dioxane removed on rotavapour to obtain the residue. Residue was washed with water to obtain solid. Solid was purified by column on 60-120 mesh silica gel using DCM as eluent to obtain the titled compound (130 mg) as an off-white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.28 (d, J 8.4, 2H), 7.74 (d, J 1.7, 1H), 7.65-7.58 (m, 3H), 7.46 (dd, J 1.8, 8.4, 1H), 6.68 (t, J 56.2, 1H).
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]C1)#[N:2].C(C1(C2C=CC(OC)=C(C=2)[CH:27]=[O:28])CC1)#N>>[C:1]([C:3]1([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[C:13]([CH:14]=2)[CH:27]=[O:28])[CH2:8][CH2:7][CH2:6][CH2:5]1)#[N:2]
Reactant: COc1ccc(C2(C#N)CCCCC2)cc1
Reactant: COc1ccc(C2(C#N)CC2)cc1C=O
Product: COc1ccc(C2(C#N)CCCC2)cc1C=O

Procedure:
This compound was prepared from 4-(1-Cyanocyclohexyl)anisole in the same manner of Compound 2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:17]#[N:18].[C:19]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)#[N:20].C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:25][C:24]1[CH:26]=[CH:27][C:21]([C:19]#[N:20])=[CH:22][CH:23]=1)#[N:18]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)C[C@@H](Nc1cnc(C#N)c(Nc2ccc(C#N)cc2)n1)C(N)=O
Reaction time: 2 h
Yield: 58.3 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-4-methylpentanamide (75 mg, 0.280 mmol), 4-cyanoaniline (40 mg, 0.339 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 2 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(4-cyanophenylamino)pyrazin-2-ylamino)-4-methylpentanamide (57 mg).
Reaction SMILES: ClC1C=CC(CN)=CC=1.I.CSC1NCCN=1.[O-]CC.[Na+].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[NH:32][CH2:33][CH2:34][N:35]=2)=[CH:25][CH:24]=1.[N:36](=[C:38]([C:44]#[N:45])[C:39](OCC)=[O:40])[OH:37]>CCO>[NH2:45][C:44]1[N:30]([CH2:29][C:26]2[CH:25]=[CH:24][C:23]([Cl:22])=[CH:28][CH:27]=2)[C:31]2[N:35]([CH2:34][CH2:33][N:32]=2)[C:39](=[O:40])[C:38]=1[N:36]=[O:37]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: Clc1ccc(CNC2=NCCN2)cc1
Agent: CC[O-]
Agent: CSC1=NCCN1
Agent: I
Solvent: CCO
Product: NC1=C(N=O)C(=O)N2CCN=C2N1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 62.30 g. 0.44 mol) of 4-chlorobenzylamine in 500 ml absolute EtOH (dried over 4A molecular sieve aluminosilicate desiccant) is added 107.40 g (0.44 mol) 2-(methylthio)-2-imidazoline hydroiodide. The mixture is heated to boiling on a steam bath in an open flask and about 150 ml of the ethanol is allowed to slowly boil off over 2 hr. This solution is added while still hot to 1.76 mole of sodium ethoxide in 1650 ml absolute EtOH. To the resulting stirred, basic solution of 2-[(4-chlorophenyl)methyl]amino-2-imidazoline is then added 61.85 g (0.44 mol) crystalline (mp 129°-131°) ethyl oximinocyanoacetate in portions. The bright yellow solution is refluxed for 3 hr and then cooled to room temperature. The yellow precipitate is collected, washed with i-PrOH, and partially air-dried. The damp sodium salt is dissolved in 2000 ml H2O and acidified with glacial HOAc. The bright pink precipitate is filtered and aid-dried overnight, then oven-dried in vacuo at 100° to yield 103.05 g (77%) of pink powder, mp 238°-241° d. Recrystallization of this material from DMF-EtOH gives red crystals, mp 241° d.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6](Cl)[N:5]=1)[CH3:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:5]=1)[CH3:2]
Reactant: C1CCNC1
Reactant: CCN(CC)c1nc(Cl)cc(N2CCNCC2)n1
Product: CCN(CC)c1nc(N2CCCC2)cc(N2CCNCC2)n1

Procedure:
A solution of 2-diethylamino-4-piperazino-6-chloro-pyrimidine (4.10 g) in pyrrolidine (4.10 g) is heated for 12 hr at 100°, then concentrated. The concentrate is partitioned between aqueous sodium bicarbonate and methylene chloride. The phases are separated, the organic phase is dried and concentrated to give 2-diethylamino-4-piperazino-6-pyrrolidino-pyrimidine. A solution of this amine (4.01 g), 21-bromo-17α-hydroxypregna-4,9(11)-diene-3,20-dione (5.41 g), and potassium carbonate (1.75 g) are stirred in acetonitrile (200 ml) for 19 hr. The reaction mixture is partitioned between methylene chloride and aqueous sodium bicarbonate. The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (methylene chloride to 4% methanol/methylene chloride) to give the free base corresponding to the title compound. An ethyl acetate solution of this compound is converted to the hydrochloride salt with ether/hydrochloric acid to give the title compound.
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([N+:33]([O-:35])=[O:34])=[C:30](O)[CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([N+:33]([O-:35])=[O:34])=[C:28]([CH:27]=1)[O:5][CH2:4][C@@H:2]1[CH2:1][O:3]1
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(F)cc1OC[C@@H]1CO1
Yield: 70.7 %

Procedure:
In a flask was added (R)-glycidol (0.994 g, 13.4 mmole) and triphenylphosphine (3.52 g, 13.4 mmole) and THF (20 ml, dried over molecular sieves), and 5-fluoro-2-nitrophenol (2.10 g, 13.4 mmole). The mixture was stirred until a homogeneous solution was obtained. The solution was cooled in an ice bath and diethylazodicarboxylate (DEAD, 2.11 ml, 13.4 mmole) was added dropwise over a few minutes. After completed addition, the flask was allowed to reach room temperature and stirred for an additional 2 hours. The solvent was removed in vaccuo and to the residue was added chloroform (5-10 ml). The precipitate (PPh3O) was removed by filtration and the solid was washed with an additional amount of chloroform (5-10 ml). The filtrate was added to a flash column (SiO2, Heptane:Ethyl acetate 4:1), and purified to give 2.02 g (71%) of the sub-title compound as a crystalline material after concentration of pure fractions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][N:22]=[CH:21][C:20]=2[CH2:24][CH2:25][C:26](O)=[O:27])=[CH:15][CH:14]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([NH:11][C:26](=[O:27])[CH2:25][CH2:24][C:20]2[CH:21]=[N:22][O:23][C:19]=2[C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Reactant: COc1cccc(C(C)N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(C(C)NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 1-(3-methoxyphenyl)ethylamine (0.32 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.45 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.33 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.40 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[1-(3-methoxyphenyl)ethyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.61 g, yield 88%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 89–90° C.
Reaction SMILES: N1C=CC=C(OC#CC2C=CC=CC=2)[CH:2]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([O:31][CH3:32])[CH:24]=2)[CH:17]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([O:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)=[CH:24][C:25]=1[O:31][CH3:32])#[CH:2]
Reactant: C(#Cc1ccccc1)Oc1cccnc1
Reactant: COc1cc(Oc2cccnc2)ccc1C=O
Product: C#Cc1ccc(Oc2cccnc2)cc1OC

Procedure:
3-(4-ethynyl-3-methoxyphenoxy)pyridine was prepared as for 4-(pyridine-3-yloxy)ethynylbenzene, using 4-(pyridine-3-yloxy)-2-methoxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH3:29][C:30]1[O:34][C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][C:31]=1[CH2:41][CH2:42]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:42][CH2:41][C:31]2[N:32]=[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[O:34][C:30]=2[CH3:29])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
A 2 L 3-neck flask was charged with 3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (67.9 g, 0.178 mol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (76.6 g, 0.214 mol) and DMF (680 mL). Cesium carbonate (75.4 g, 0.231 mol) was added, and the reaction mixture was heated at 55° C. for 18 h. After cooling, ethyl acetate (890 mL) and DI water (1200 mL) were added, the mixture was agitated, and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (740 mL). The organic layers were combined and washed with 1N NaOH (375 mL) then saturated NaCl solution (2×375 mL). The organic solution was dried (Na2SO4), filtered, and concentrated to an oil (107 g). The crude oil was dissolved in toluene (50 mL), and heptane was added (˜100 mL) until cloudiness remained even with agitation. The mixture was warmed to 50° C. on a rotary evaporator to yield a solution. Seed crystals were added, and rotation was continued at ambient temperature overnight. The product slurry was placed in the freezer overnight and filtered. The title compound was dried in a vacuum oven at 35° C. (71.4 g, 70.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19][N:18]=1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:33]>N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]([CH3:24])[C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[CH:19][N:18]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:33]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)c1cc(C)ncn1
Agent: N
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN(C)c1cc(C)ncn1
Yield: 91.5 %

Procedure:
A solution of 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (365 mg, 0.8 mmol) in methanolic ammonia (30 ml of a 3M solution) was stirred at ambient temperature for 16 hours. The volatiles were removed by evaporation, the residue was triturated with ether, the solid was collected by filtration, washed with ether and dried under vacuum to give 6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)-3,4-dihydroquinazolin-4-one (250 mg, 92%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[F:23][C:24]1[C:29]([CH:30]=[O:31])=[C:28]([F:32])[CH:27]=[CH:26][C:25]=1B(O)O.B(O)O>>[F:23][C:24]1[C:25]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:26][CH:27]=[C:28]([F:32])[C:29]=1[CH:30]=[O:31]
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: O=Cc1c(F)ccc(B(O)O)c1F
Agent: OBO
Product: O=Cc1c(F)ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)c1F

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 2,4-difluoro-3-formylphenylboronic acid as a boronic acid, 2,6-difluoro-3-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-benzaldehyde was obtained. Methanol and sodium borohydride were added, which was stirred at room temperature for 1 hour, followed by elution with 2M ammonia methanol solution through SCX resin and then concentration. Purification by preparative TLC afforded the desired compound as a colorless solid.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[N:10]=[C:9]([Cl:20])[N:8]=1)(=O)=O.[I-:21].[Li+]>O1CCOCC1>[Cl:20][C:9]1[N:10]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][C@H:14]2[CH3:19])[CH:12]=[C:7]([CH2:6][I:21])[N:8]=1
Reactant: [I-]
Reactant: C[C@@H]1COCCN1c1cc(COS(C)(=O)=O)nc(Cl)n1
Agent: [Li+]
Solvent: C1COCCO1
Product: C[C@@H]1COCCN1c1cc(CI)nc(Cl)n1
Temperature: 107 °C
Yield: 85.3 %

Procedure:
Lithium iodide (17.57 g, 131.27 mmol) was added to (R)-(2-chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (19.2 g, 59.67 mmol) in dioxane (300 ml) and heated to 100° C. for 2 hours under nitrogen. The reaction mixture was quenched with water (200 ml) and extracted with EtOAc (3×200 ml). The organic layers were combined and washed with 2M sodium bisulfite solution (400 ml), water (400 ml), brine (400 ml) dried over MgSO4 and then evaporated. The residue was triturated with Et2O to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (13.89 g, 66%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.29 (1H, br s), 6.41 (1H, s); m/z: (ESI+) MH+ 354.31. The mother liquors were concentrated down and triturated with Et2O to afford a further crop of (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (2.46 g, 12%); 1H NMR (400 MHz, CDCl3) 1.32 (3H, d), 3.28 (1H, td), 3.54 (1H, td), 3.69 (1H, dd), 3.78 (1H, d), 3.98-4.02 (2H, m), 4.21 (2H, s), 4.30 (1H, s), 6.41 (1H, s); m/z: (ESI+) MH+, 354.31. Alternatively, this step can be carried out as follows: (R)-(2-Chloro-6-(3-methylmorpholino)pyrimidin-4-yl)methyl methanesulfonate (80 g, 248.62 mmol) and lithium iodide (83 g, 621.54 mmol) were dissolved in dioxane (300 ml) and then heated at 107° C. for 1 hour. The reaction mixture was quenched with water (250 ml), extracted with EtOAc (3×250 ml), the organic layer was dried over MgSO4, filtered and evaporated. The residue was dissolved in DCM and Et2O was added, the mixture was passed through silica (4 inches) and eluted with Et2O. Fractions containing product were evaporated and the residue was then triturated with Et2O to give a solid which was collected by filtration and dried under vacuum to afford (R)-4-(2-chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (75 g, 86%); m/z: (ESI+) MH+, 354.27. e) (R)-4-(2-Chloro-6-(iodomethyl)pyrimidin-4-yl)-3-methylmorpholine (17.0 g, 48.08 mmol) was dissolved in DMF (150 ml), to this was added sodium methanethiolate (3.37 g, 48.08 mmol) and the reaction was stirred for 1 hour at 25° C. The reaction mixture was quenched with water (50 ml) and then extracted with Et2O (3×50 ml). The organic layer was dried over MgSO4, filtered and then evaporated. The residue was purified by flash chromatography on silica, eluting with a gradient of 50 to 100% EtOAc in iso-hexane. Pure fractions were evaporated to afford (R)-4-(2-chloro-6-(methylthiomethyl)pyrimidin-4-yl)-3-methylmorpholine (12.63 g, 96%); m/z: (ES+) MH+, 274.35.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:25])[NH:17][C@@H:18]([C:22](F)=[O:23])[CH:19]([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16](=[O:25])[NH:17][C@@H:18]([C:22](=[O:23])[NH:7][CH2:8][CH2:9][SH:10])[CH:19]([CH3:20])[CH3:21])([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Reactant: NCCS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (1 74.0 mg, 2.07 mmol) in 10.1 mL was added 2-aminoethanethiol hydrochloride (126.6 mg, 1.11 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25f (222.2 mg, 1.0 mmol) in 10.1 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo, to afford 195.2 mg (71% from 24f) of clean 26f as a white solid. FTIR (film) 3289, 1687, 1645 cm −1.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1F)[C:15]([OH:17])=[O:16].Cl>CN(C=O)C>[CH2:1]([O:8][C:20]1[C:19]([F:22])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzyl alcohol (22.0 mL) in DMF (100 mL) was added sodium hydride (60% oil, 8.52 g), and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added 3,4,5-trifluorobenzoic acid (15.0 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (100 mL) were added potassium carbonate (11.8 g) and methyl iodide (5.30 mL), and the mixture was stirred with heating at 60° C. for 15 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate). To a solution of the obtained oil in a mixed solvent of THF (100 mL) and methanol (50 mL) was added 2 M aqueous sodium hydroxide solution (85 mL), and the mixture was stirred with heating at 60° C. for 40 min. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with diethyl ether/hexane to give the title compound (18.2 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([O:15]C)[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].B(Br)(Br)Br.CO.O>C(Cl)Cl>[CH3:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[C:4]([OH:15])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ccc(NC(=O)C(F)(F)F)c(C)c1[N+](=O)[O-]
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: Cc1c(NC(=O)C(F)(F)F)ccc(O)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 3-methyl-2-nitro4-trifluoroacetamidoanisole (5.37 g, 19.3 mmol) in dry methylene chloride (250 mL) at -78° C. under nitrogen atmosphere is treated dropwise with a solution of boron tribromide (9.16 mL, 96.9 mmol) in dry methylene chloride (50 mL). After complete addition, the mixture is allowed to warm to room temperature and stirring is maintained for one hour. The mixture is cooled to -78° C. and methanol (100 mL) is added dropwise. After complete addition, the solution is allowed to warm to room temperature. The reaction mixture is distributed between water (100 mL) and methylene chloride (200 mL). The methylene chloride layer is dried over magnesium sulfate and concentrated under reduced pressure to yield 4.81 g of 3-methyl-2-nitro-4-trifluoroacetamidophenol.
Reaction SMILES: C[N:2]1[CH:7]2[CH2:8][C:9]([CH2:11][CH:3]1[CH2:4][CH2:5][CH2:6]2)=[O:10].[Cl:12][C:13]([Cl:20])([Cl:19])[CH2:14][O:15][C:16](Cl)=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>[Cl:12][C:13]([Cl:20])([Cl:19])[CH2:14][O:15][C:16]([N:2]1[CH:7]2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:11][C:9](=[O:10])[CH2:8]2)=[O:17]
Reactant: CN1C2CCCC1CC(=O)C2
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1CC2CCCC(C1)N2C(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.1 %

Procedure:
To a solution of pseudopelletierine (52 g, 0.34 mol) in toluene (220 mL) at 50° C. was added anhydrous potassium carbonate (1.0 g), followed by the slow addition of trichloroethylchloroformate (79 g, 0.37 mol). After addition was completed (30 minutes), triethylamine (10 mL) was added. The reaction was allowed to cool to room temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and 1N hydrochloric acid (200 mL). After the organic layer was washed with 1N hydrochloric acid (100 mL), it was washed with aqueous 10% sodium hydroxide (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to afford a beige solid which was triturated with hexane (300 mL) to afford 81.4 g of crystalline solid (76% yield); mp 95°-96° C. after recrystallization from ethyl acetate-hexane. Anal. (C11H14C13NO3).