Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1.[C:23]1([O:29][CH3:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:30][O:29][C:23]1[CH:28]=[CH:27][C:26]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:14][CH:15]=2)=[CH:25][CH:24]=1
Reactant: O=C(Cl)Cc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: COc1ccccc1
Product: COc1ccc(C(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 96.5 %

Procedure:
To a stirred solution of PPA (2.0 g, 20 mmol) were added 2-(4-(quinolin-2-ylmethoxy)phenyl)acetyl chloride (2.0 g, 5.0 mmol) and anisole (1.0 g, 10 mmol) at RT under an inert atmosphere. The reaction mixture was then heated at 80° C. for 3 h, quenched with ice cold water and stirred for another 10 minutes. The precipitated solid was filtered, and then the solid was stirred in 10% NaOH solution for 1 h, extracted with DCM (2×50 mL). The combined organic layers were washed with water (2×10 mL) and brine, concentrated, and dried under vacuum to afford 1-(4-methoxyphenyl)-2-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (1.85 g, 90%) as a solid.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:20][CH2:19]4)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C@H:21]([CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]4)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
To a solution of ethyl ((1S)-5-{2-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (18 mg, 0.04 mmol) (Example 35) in THF (1.2 mL), was added a solution of LiOH.H2O (5 mg, 0.11 mmol) in H2O (0.4 mL). The mixture was stirred for 12 h at rt. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in a small volume of water. Then, HCl (1 N aqueous solution) was added until the solution was below pH 3. The aqueous layer was extracted with excess EtOAc, and the organic layer was dried, filtered and then concentrated to give the crude product. The residue was purified by HPLC (C18 reverse phase column, using 0-80% CH3CN in water) to give 2.2 mg (13%) of the title compound as a white solid. LC-MS: RT3.78 min; (M+H)+:466.4.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[CH2:7]([OH:9])[CH3:8].Cl[C:11]1[CH:16]=[C:15]([C:17]2[N:21]3[CH:22]=[C:23]([NH:26][CH:27]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:14]=[CH:13][N:12]=1>CS(C)=O.O>[CH2:7]([O:9][C:13]1[CH:14]=[C:15]([C:17]2[N:21]3[CH:22]=[C:23]([NH:26][CH:27]4[CH2:28][CH2:29][CH:30]([OH:33])[CH2:31][CH2:32]4)[CH:24]=[CH:25][C:20]3=[N:19][CH:18]=2)[CH:16]=[CH:11][N:12]=1)[CH3:8]
Reactant: CCO
Reactant: OC1CCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc(-c2cnc3ccc(NC4CCC(O)CC4)cn23)ccn1
Temperature: 120 °C

Procedure:
Cs2CO3 (5 eq, 1.45 mmol, 480 mg) and 4A molecular sieves (400 mg) are stirred in a mixture of DMSO (5 ml) and ethanol (5 eq 0.8 ml). To this suspension is added [4-[3-(2-chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino]-cyclohexanol (Example 2.1) (1 eq, 100 mg, 0.29 mmol). The reaction is heated at 120° C. for 16 hours. The mixture is diluted with H2O (20 ml) and extracted with EtOAc. The combined organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo to give a blue oil. The residue is purified by flash chromatography on silica eluting with 0-10% methanol in EtOAc The resulting residue is loaded onto a SCX-2 cartridge (resin loading 0.67 mmol/g) eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+=353
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:3]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C(NC(C)C)(C)C.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:13]([O:12][C:10]([NH:9][C:4]1[CH:3]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:7]=[CH:6][C:5]=1[F:8])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)Nc1cc(C#C[Si](C)(C)C)ccc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-2-(tert-butoxycarbonylamino)-1-fluorobenzene (0.57 g), trimethylsilylacetylene (0.55 mL), tetrakis(triphenylphosphine)palladium(0) (23 mg)and copper (I) iodide (7 mg) in N,N-diisopropylamine (5.7 mL) was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, and the mixture was diluted with diethyl ether. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=15/1) to give 1-(tert-butoxy -carbonylamino)-2-fluoro-5-trimethylsilylethynylbenzene (0.6 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution was added tetra(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 2.4 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=20/1 -10/1) to give the title compound (0.34 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.S(=O)(=O)(O)[OH:18].OO.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1)=[O:18]
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Reactant: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Reaction time: 7 h

Procedure:
To 0.230 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 3 ml of acetic acid was added 0.2 ml of concentrated sulfuric acid and, under ice-cooling, 0.3 ml of a 30% aqueous solution of hydrogen peroxide was added dropwise. The mixture was allowed to stand at 3°-5° C. for 7 hours, at the end of which time an aqueous solution of sodium sulfite was added to the mixture to decompose the excess hydrogen peroxide. The solvent was evaporated off and the residue was diluted with water. The crystals were collected by filtration. By the above procedure was obtained 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from methanol yielded colorless needles, m.p. 176°-177° C. Based on infrared absorption spectrum and other data, this compound was identified with the compound obtained in Example 17.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([O:22][P:23](=[O:40])([O:32]CC5C=CC=CC=5)[O:24]CC5C=CC=CC=5)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:41])[N:3]1[CH2:42][CH2:43][CH3:44]>CO.C1COCC1.[Pd]>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:19][CH2:18][C:17]([O:22][P:23](=[O:24])([OH:32])[OH:40])([CH2:16][CH2:15]3)[CH2:20][CH2:21]4)[NH:6][C:5]=2[C:4](=[O:41])[N:3]1[CH2:42][CH2:43][CH3:44]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(OP(=O)(OCc5ccccc5)OCc5ccccc5)(CC3)CC4)nc2n(CCC)c1=O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(OP(=O)(O)O)(CC3)CC4)nc2n(CCC)c1=O
Yield: 86 %

Procedure:
Phosphoric acid dibenzyl ester 4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl ester was dissolved in a mixture of 15 ml methanol and 10 ml of THF, Pd/C (10%, 50 mg) was added to the mixture. Hydrogenation was taken place at 50 psi for 8 h. Pd/C was filtered off and solvent was evaporated off. The residue was recrystallized in a mixture of methanol and ethyl acetate to get 190 mg title product (yield 86%). MS (M+1, 441)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:10](OC(=O)C)(=[O:12])[CH3:11].S(=O)(=O)(O)O>O>[C:10]([O:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
At room temperature, 3,4-dichlorophenol (298.5 g, 1.83 mol) was dissolved in 191 ml (207 g, 2.02 mol) of acetic anhydride in a 1 liter flask equipped with mechanical stirrer and condenser. Sulfuric acid (3 ml) was added, resulting in a strong exotherm. After 2 hours the mixture was poured into 2 liters of ice and water and extracted 3×1 liter diethyl ether. The organic layers were combined, washed 1×1 liter water, 2×1 liter saturated sodium bicarbonate and 1×1 liter saturated brine, dried over magnesium sulfate and stripped to yield title product as an orange oil, 375 g, tlc Rf 0.5 (1:1 diethyl ether:hexane).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:10])[CH2:8][OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>O>[O:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]1[O:9][CH2:8][CH2:7][OH:10]
Reactant: C1=COCCC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: OCCOC1C=CC=CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,4-Dihydro-2H-pyran (30.0 g, 0.36 mol), ethylene glycol (310.0 cm3, 5.36 mol) and p-toluene sulphonic acid (ca. 1 mol %, catalyst) were added to dichloromethane (100 cm3) and the mixture stirred at ambient temperature for 18 hours under an inert gas atmosphere. Water (ca. 150 cm3) was then added, resulting in a biphasic mixture. The organic phase (containing the desired product) was collected and the aqueous phase (containing excess ethylene glycol) extracted with further portions of dichloromethane (3×50 cm3). The combined organic phase and washings were dried over anhydrous magnesium sulphate, filtered and solvent removed in vacuo to yield the crude product containing, almost exclusively, the mono-protected alcohol. The desired product was isolated via flash column chromatography (using silica gel 60 and a 3:1 ratio of hexane:ethyl acetate as eluant). Yield=9.10 g (17.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH2:21][OH:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1.CCOC(C)=O>[CH3:26][S:27]([O:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:12](=[C:11]([C:23](=[O:24])[NH2:25])[CH:10]=[CH:9][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:13][C:14]=2[CH:15]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(CO)ccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-fluorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-1, 223 mg, 0.667 mmol) and TEA (0.279 mL, 2.001 mmol) in THF (8 mL) was treated with methanesulfonyl chloride (0.104 mL, 1.334 mmol). The resulting suspension was stirred at rt for 15 min. The mixture was diluted with EtOAc, washed with water and brine, and dried and concentrated to provide crude (8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl)methyl methanesulfonate as a yellow glassy foam (300 mg, ca. 50% purity). A portion of this material (80 mg, 0.097 mmol) was dissolved in DMF (1 mL), treated with morpholine (84 mg, 0.970 mmol) and heated at 45° C. for 3 days. The mixture was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(morpholinomethyl)-9H-carbazole-1-carboxamide (9.6 mg, 23%). 1H NMR (400 MHz, methanol-d4) δ 7.94 (1 H, d, J=7.8 Hz), 7.59 (1 H, s), 7.52-7.58 (1 H, m), 7.48-7.52 (1 H, m), 7.33-7.39 (1 H, m), 7.30 (1 H, t, J=9.0 Hz), 7.21 (1 H, d, J=8.3 Hz), 7.14 (1 H, d, J=7.8 Hz), 6.99 (1 H, dd, J=8.3, 1.5 Hz), 3.81 (2H, s), 3.71-3.77 (4 H, m), 2.66 (4 H, br. s.). Mass spectrum m/z 404.2 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:11][C:10]2[C:12]([C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:13][C:14]([F:16])=[CH:15][C:9]=2[CH2:8][CH2:7]C1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[Cl:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:24])[C:17]=1[C:12]1[CH:13]=[C:14]([F:16])[CH:15]=[C:9]2[C:10]=1[O:11][C@@H:5]([CH2:4][NH2:1])[CH2:7][CH2:8]2
Reactant: [N-]=[N+]=NC[C@H]1CCCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@H]1CCc2cc(F)cc(-c3c(Cl)cccc3Cl)c2O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-2-(azidomethyl)-9-(2,6-dichlorophenyl)-7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxepine (0.17 g, 0.46 mmol) in tetrahydrofuran (10 mL) and water (1 mL) was added polymer-bound triphenylphosphine (˜3 mmol/g, 0.46 g, 1.4 mmol) and the reaction mixture stirred at room temperature for 2 days. The brown suspension was then filtered through celite, the filter cake washed with ethyl acetate (50 mL) and the combined filtrates concentrated under vacuum. The solvent was removed under vacuum. Chromatography with 0–10% methanol in methylene chloride plus 1% NH4OH afforded {[(R)-8-(2,6-dichlorophenyl)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]methyl}amine as a colorless oil. The colorless oil was dissolved in ethyl acetate and made into its hydrochloride salt (0.13 g, 71%) as a white foam using excess ethereal hydrochloric acid, [α]D25=+38.22° (c 1% solution in MeOH); MS (ES) m/z 340.0 ([M+H]+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[F:20][C:21]1[C:22]([O:31][CH3:32])=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[F:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=3)[N:3]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: COc1c(B(O)O)ccc(F)c1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COc1c(-c2ncnc(Nc3cccc(CS(C)(=O)=O)c3)n2)ccc(F)c1F

Procedure:
Example 2 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (3,4-difluoro-2-methoxyphenyl)boronic acid (AOBChem USA). The batch was purified by preparative HPLC:
Reaction SMILES: [Li]C(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[C:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[CH2:19][CH2:18]2)([OH:16])[CH3:15])=[N:8][CH:9]=1
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Reactant: Clc1ccc(Br)nc1
Agent: [Li]C(C)(C)C
Solvent: ClCCl
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)(O)c2ccc(Cl)cn2)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
t-BuLi (0.950 mL, 1.52 mmol) was added dropwise to a cooled solution of 2-bromo-5-chloropyridine (225 mg, 1.17 mmol) in DCM (11 mL) at −78° C. over 2 minutes. The reaction mixture was stirred for 2 hours at −78° C. and a solution of butyl trans-4-acetylcyclohexanecarboxylate (291 mg, 1.286 mmol) in DCM (1 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to room temperature over a period of 16 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford trans-butyl 4-(1-(5-chloropyridin-2-yl)-1-hydroxyethyl)cyclohexanecarboxylate as a brown oil. MS ESI calc'd for C18H27ClNO3 [M+H]+ 340. found 340.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[CH2:15][OH:16].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>C1COCC1.O>[O:23]=[C:22]1[NH:1][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=2[CH2:15][O:16]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(=O)COc1ccc(N)c(CO)c1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc2c(c1)COC(=O)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.4 %

Procedure:
To a solution of ethyl 2-(4-amino-3-(hydroxymethyl)phenoxy)acetate (0.2 g, 0.888 mmol) in THF (5 mL) was added CDI (0.216 g, 1.332 mmol) at 0° C. and stirred at RT for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer washed with brine, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate as eluent to yield ethyl 2-((2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-6-yl)oxy)acetate (0.03 g, 13%). 1H NMR: 400 MHZ, DMSO-d6: δ 1.22 (t, J=7.20 Hz, 3H), 4.17 (q, J=6.80 Hz, 2H), 4.72 (s, 2H), 5.23 (s, 2H), 6.79-6.86 (m, 3H), 10.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:4][CH:3]1[CH2:5][CH2:6][OH:7].[Cl:9][C:10]1[CH:11]=[C:12]([N:17]=[C:18]=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16]>O1CCCC1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18](=[O:19])[O:7][CH2:6][CH2:5][CH:3]2[CH2:4][C:2]2([F:8])[F:1])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: OCCC1CC1(F)F
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)OCCC1CC1(F)F

Procedure:
2 g (16 mmol) 2-(2,2-Difluorocyclopropyl)ethanol, dissolved in 5 ml tetrahydrofuran (THF) was treated with 3 g (16 mmol) of 3,4-dichlorophenyl isocyanate. After 6 hours reaction time at room temperature, the mixture was concentrated in vacuo and the residue recrystallised from cyclohexane. A sample was analysed by thin layer chromatography (hexane:ethyl acetate=1:1) (Rf=0.54).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[N:3]=1.[NH2:24][C@@H:25]1[CH2:30][C@@H:29]([OH:31])[C@H:28]([CH3:32])[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:32][C@@H:28]1[CH2:27][CH2:26][C@H:25]([NH:24][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:3]=2)[CH2:30][C@H:29]1[OH:31]
Reactant: C[C@@H]1CC[C@H](N)C[C@H]1O
Reactant: FC(F)(F)c1ccncc1CNc1ncc(C(F)(F)F)c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@H](Nc2nc(NCc3cnccc3C(F)(F)F)ncc2C(F)(F)F)C[C@H]1O
Temperature: 60 °C
Yield: 47.3 %

Procedure:
4-Chloro-5-(trifluoromethyl)-N-((4-(trifluoromethyl)pyridin-3-yl)methyl)pyrimidin-2-amine (1.0 equiv.) was placed in a sealable flask with (1R,2R,5S)-5-amino-2-methylcyclohexanol (1.1 equiv.), DIEA (2.0 equiv.), and THF (0.1 M). The flask was purged with nitrogen and sealed. The reaction mixture was heated to 60° C. for 18 h. Standard work-up, afforded (1R,2R,5S)-2-methyl-5-(5-(trifluoromethyl)-2-((4-(trifluoromethyl)pyridin-3-yl)methylamino)pyrimidin-4-ylamino)cyclohexanol (47.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65-8.76 (m, 2H) 8.01-8.14 (m, 1H) 7.71 (d, J=5.08 Hz, 1H) 5.74 (br. s., 1H) 4.67-4.80 (m, 1H) 4.57-4.67 (m, 1H) 4.54 (br. s., 1H) 4.39 (d, J=4.30 Hz, 1H) 4.14 (br. s., 1H) 3.21-3.31 (m, 1H) 1.78 (br. s., 1H) 1.54 (br. s., 1H) 1.41 (br. s., 1H) 1.33 (br. s., 1H) 1.10-1.24 (m, 1H) 0.96 (br. s., 1H) 0.81-0.89 (m, 2H). MS (ESI) m/z 450.2 [M+1]+
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[F:17][C:18]([F:41])([F:40])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=O.O>C1COCC1>[F:17][C:18]([F:40])([F:41])[C:19]1[CH:20]=[C:21]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:22][O:23][CH2:24][C:25]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
Ethyl diethoxyphosphorylacetate (30 mL, 150 mmol) was dropped into a suspension of sodium hydride (60% oily) (6.00 g, 150 mmol) in THF (300 mL) at room temperature during 30 minutes. After the dropping, the mixture was stirred at room temperature for 1 hour more, a solution of 2-(3,5-bis(trifluoromethyl)-benzyloxy)-1-phenylethanone (48.90 g, 135 mmol) in THF (100 mL) was dropped thereinto at room temperature during 30 minutes and the mixture was stirred for 1 hour more. The reaction mixture was added to water (1000 mL) followed by extracting with ethyl acetate. The organic layers were combined, washed with water and a saturated saline solution and dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The residual oily product was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to give ethyl 4-(3,5-bis(trifluoromethyl)-benzyloxy)-3-phenyl-2-butenoate (40.00 g, 69%) as an oily product. 1H-NMR (DMSO-d6) δ: 1.23 (t, J=7.1 Hz, 3H), 4.15 (q, J=7.1 Hz, 2H), 4.63 (s, 2H), 5.08 (s, 2H), 6.24 (s, 1H), 7.39-7.43 (m, 3H), 7.57-7.61 (m, 2H), 7.79 (s, 2H), 7.96 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].C([N:26]1[CH2:31][CH2:30][CH2:29][C@H:28]([NH2:32])[CH2:27]1)(OC(C)(C)C)=O.[ClH:33]>O1CCOCC1>[ClH:33].[NH2:32][C@H:28]1[CH2:29][CH2:30][CH2:31][N:26]([C:16]([C:14]2[S:15][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=3)=[CH:12][CH:13]=2)=[O:18])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Reaction time: 12 h
Yield: 71 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and N-Boc-3-(S)-aminopiperidine by the method described in Example 2 Method B. The reaction mixture was evaporated to a solid, triturated and filtered with the aid of water, then washed with a 1 N aqueous hydrochloric acid solution followed by water. The solid was air dried then chromatographed on silica gel with EtOAc/hexanes (50 then 75%) as eluant to afford intermediate N-Boc protected product as a colorless solid (87 mg, 76%). The Boc-protected intermediate was dissolved in 1,4-dioxane (5 mL) and treated with a 4 N solution of hydrogen chloride in 1,4-dioxane and stirred for 12 hr, after which time the reaction mixture was evaporated to approximately ½ volume and diluted with ethyl ether (20 mL). The resulting solids were filtered and air dried to afford product as a colorless solid (70 mg, 71% overall). 1H NMR (D2O) 1.36 (m, 1H), 1.58 (m, 2H), 1.90 (s, 3H), 1.96 (m, 1H), 3.08 (m, 3H), 3.21 (m, 1H), 3.65 (m, 1H), 4.18 (br d, J=11.4, 1H), 7.06 (br d, 1H), 7.09 (br d, 1H). 19F NMR −64.6. LC/MS 4.40 min, [M+1]+ 360.