Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].S(OC)(O[CH3:15])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:15])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccccc1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1C(C)C

Procedure:
2-Isopropylphenol (300 g), 262 ml of dimethyl sulfate, and 1500 g of potassium carbonate in 1 liter of acetone are stirred mechanically and refluxed for61/2 hours. The mixture is filtered and the filter cake washed with acetone. The combined filtrate is stripped, the residue is redissolved in ether, then extracted with 2N sodium hydroxide (twice) and brine (once). The ether is dried, filtered, and stripped to leave an oil which is distilled under high vacuum to afford 2-isopropylanisole, b.p. 39°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([OH:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][OH:15])=[CH:5][CH:4]=1.C(O)(=O)C.[Se](=O)=O>CC(O)C>[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH:14]=[O:15])(=[O:16])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(O)c2ccccc2CO)cc1
Agent: O=[Se]=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1ccc(C(=O)c2ccccc2C=O)cc1

Procedure:
A solution of 26 g. of 4'-methoxy-2-hydroxymethylbenzhydrol in 140 ml. of acetic acid and 14.5 g. selenium dioxide was refluxed for 2 hours. The mixture was filtered and the filtrate was made basic. An oil separated which crystallized on standing and was collected. Recrystallization from a mixture of methylene chloride and petroleum ether gave off-white platelets melting at 90°-91°. Ultraviolet maxima (2-propanol) at 221 mμ (ε = 21,600), 258 mμ (ε = 12,400) and 292 mμ (ε = 17,000); infrared absorption (CHCl3) at 1660 cm-1 and at 1700 cm-1.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[C:14]1([C@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([C@H:20]([NH:22][CH2:2][C:3]2[NH:4][C:5](=[O:13])[C:6]3[CH2:12][O:11][CH2:10][CH2:9][C:7]=3[N:8]=2)[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Solvent: CCO
Product: C[C@@H](NCc1nc2c(c(=O)[nH]1)COCC2)c1ccccc1
Temperature: 65 °C
Yield: 28.1 %

Procedure:
To 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (50 mg, 0.249 mmol) in ethanol (2 mL) was added (R)-1-phenyl-ethylamine (66 mg, 0.545 mmol, 2 eq) and the solution was heated at 65° C. for 15 h. The cooled solution was concentrated under vacuum and the resulting oil was taken up in methanol, added to a strong cation exchange (SCX) column and washed with methanol (50 mL). The product was eluted with 1 N ammonia in methanol (50 mL) and concentrated under vacuum. The crude product was absorbed onto Silica Gel (500 mg), added to a Biotage SNAP-10 g column and eluted with 1% to 10% methanol in dichlormethane over 12 column volumes to give: 2-[((R)-1-phenyl-ethylamino)-methyl]-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (20 mg, 28% yield). Exact mass calculated for C16H19N3O2 285.15. found 286.5 (ESI, M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:13][NH2:14].[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH:14][CH3:13]
Reactant: CN
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2,4-Dimethoxybenzaldehyde (5.0 g) was dissolved in methanol (60 mL), and a 40% methanol solution (9.3 mL) of methylamine was added at room temperature. The mixture was stirred at room temperature for 1 hr, and sodium borohydride (1.37 g) was added by small portions under ice-cooling. The mixture was stirred at room temperature for 3 hr, treated with 1 mol/L hydrochloric acid under ice-cooling, and methanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate, basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane:ethyl acetate=4:1→2:1) to give the title compound as a colorless oil (yield 4.41 g, 81%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8](O)([CH3:10])[CH3:9].C=CC>C(C1C=C(O)C=CC=1)(C)C>[CH:8]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])([CH3:10])[CH3:9]
Reactant: Oc1ccccc1
Reactant: CC(C)O
Agent: CC(C)c1cccc(O)c1
Solvent: C=CC
Product: CC(C)c1ccccc1O

Procedure:
Organic compound mixtures enriched in meta-isopropylphenol are prepared by alkylating phenol with isopropanol or propylene to form mixtures of isopropylphenol isomers and by subsequently selectively cracking the para-isopropylphenol isomer from such a mixture over a ZSM-5 type cracking catalyst. Concentration of the para-isomer is thereby selectively reduced relative to the meta-isomer and the meta-isopropylphenol isomer can be further separated from the remaining mixture by fractionation procedures.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[CH3:16][S:17]SC.CI>C1COCC1>[Cl:1][C:2]1[C:3]2[S:10][C:9]([S:17][CH3:16])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Cl)c2s1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF (11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at −78° C. and the mixture was stirred for 15 min at the same conditions. A solutions of dimethyl disulfide (160 uL, 1.77 mmol) and MeI (110 μL, 1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture was stirred for 2 h at −78° C., quenched with saturated aqueus NH4Cl solution, and extracted with DCM. The extract was dried over anhydrous Na2SO4 and concentrated to afford the title compound 280 (210 mg, 82% yield) as a yellowish solid. MS (m/z): 217.0(M+H) (found).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:45]=[CH:44][C:38]2[O:39][CH2:40][CH2:41][CH2:42][O:43][C:37]=2[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[O:39]1[C:38]2[CH:44]=[CH:45][C:35]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:21][CH:22]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:36][C:37]=2[O:43][CH2:42][CH2:41][CH2:40]1
Reactant: [O-]B([O-])Oc1ccc2c(c1)OCCCO2
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc5c(c4)OCCCO5)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3,4-dihydro-2H-1,5-benzodioxepin-7-yl borate (123 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 6 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 66) (194 mg).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+].O>CO.O1CCCC1>[C:15]1([C:13](=[O:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)c2cccc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(OCC(=O)c2cccc3ccccc23)cc1
Yield: 51.3 %

Procedure:
To a hot solution of 4-[2-(1-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.128 g) in methanol (3 mL) and tetrahydrofuran (0.5 mL) was added 1N sodium hydroxide (0.8 mL) followed by water (15 mL). The solvents were removed under reduced pressure, then the solution was acidified with 1N hydrochloric acid (1 mL) and extracted with dichloromethane (1×20 mL, 1×10 mL). The combined organic layers were washed with water, dried (MgSO4) and evaporated and the resulting yellow solid (0.107 g) was crystallized from ethyl acetate-hexane to provide 0.063 g of 4-[2-(1-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 141°-143° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[S:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH:47][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:46][C:42]=2[C:41]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[CH:40][CH:39]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(C)c3)nc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 406 (M+Na+, 46), 384 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[S:11][C:7]=2[CH:6]=1.O.[Cl-].[NH4+]>C(O)C>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:19]=[CH:18][C:8]3[N:9]=[C:10]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[S:11][C:7]=3[CH:6]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2s1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)c(F)c1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
To a suspension of N-[6-(2-fluoro-4-nitrophenoxy)-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (1.15 g, 3.07 mmol) in ethanol (50 mL)/water (10 mL) were added ammonium chloride (1.64 g, 30.7 mmol) and reduced iron (856 g, 15.3 mmol), and the mixture was heated under reflux for 4 hr. The reaction mixture was cooled to room temperature, filtered through celite, and washed with a mixed solution of ethanol/water. The solvent was evaporated under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran. The combined organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate/diisopropyl ether and collected by filtration to give the title compound (644 mg, 61%) as a pale-yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:31][CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)[CH:14]=[CH:15][CH:16]=1.O.NN>C(O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:31][CH:32]1[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]1)[C:11]1[CH:12]=[C:13]([C:17]#[C:18][CH2:19][NH2:20])[CH:14]=[CH:15][CH:16]=1
Reactant: CN1CCC(OC(c2cccc(C#CCN3C(=O)c4ccccc4C3=O)c2)c2nc3ccccc3[nH]2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCC(OC(c2cccc(C#CCN)c2)c2nc3ccccc3[nH]2)CC1
Reaction time: 0.08 h

Procedure:
A solution of 2-(3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-phenyl}prop-2-ynyl)isoindole-1,3-dione (70 mg) and hydrazine hydrate (70 μL) in ethanol (0.7 mL) is stirred a room temperature for 3 hours. Ethanol is removed under reduced pressure and 1N hydrochloric acid in water is added to the organic residue and stirred for 5 minutes. The mixture is filtered, cake washed with ethyl acetate. The filtrate is extracted by dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure The residue purified by chromatography (dichloromethane/methanol/ammonia from 90/10/1) to afford 3-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenyl}prop-2-ynylamine melting at 101° C.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>O1CCOCC1.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>[CH2:26]([C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[C:4]([Cl:23])[CH:3]=1)[CH:25]=[CH2:24]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=CCc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(OC)ccc(F)c1F
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (0.82 g) in 1,4-dioxane (40 mL) were added allyltri(n-butyl)tin (0.74 mL) and tetrakis(triphenylphosphine)palladium(0) (0.46 g), and the reaction vessel was equipped with a reflux condenser, and the reaction mixture was stirred at 120° C. under an argon atmosphere overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−3/1) to give 4-allyl-2-chloro-5-(2,3-difluoro-6-methoxybenzyl-oxy)-1-nitrobenzene (0.68 g). This material was dissolved in tetrahydrofuran (20 mL). To the solution were added water (10 mL), 50% aqueous N-methylmorpholine-N-oxide solution (0.96 mL) and osmium(VIII) oxide, microencapsulated (about 10%, 0.23 g), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/4) to give 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-(2,3-dihydroxy-propyl)-1-nitrobenzene (0.29 g). The title compound was prepared in a similar manner to that described in Reference Example 170 using this material instead of 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-(1,3-dihydroxy-2-propoxy)-1-nitrobenzene.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:33])[F:32])[CH:24]=2)[CH2:15][CH:16](O)[C:17]([F:20])([F:19])[F:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:42])CC)C>ClCCl>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][CH:16]([F:42])[C:17]([F:18])([F:19])[F:20])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:35])([F:34])[CH:31]([F:32])[F:33])[CH:24]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Solvent: ClCCl
Product: FC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 3-[(3-phenoxyphenyl)[[3-(1,1,2,2-tetrafluoroethoxy) phenyl]-methyl]amino]-1,1,1-trifluoro-2-propanol (474 mg, 0.00094 mol) in 4.5 mL of dichloromethane at 0° C. was added (diethylamino)sulfur trifluoride (378 mg, 0.0023 mol). The reaction mire was warmed to room temperature and stirred for 2 h, then quenched with water and extracted with dichloromethane. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 1:9 ethyl acetate in hexane to afford 240 mg (50%) of the desired N-(3-phenoxyphenyl)-N-(3,3,3,2-tetra-fluoropropyl)-3-(1,1,2,2-tetrafluoroethoxy)benzenemethanamine product as a yellow oil. HRMS calcd. for C24H19F8NO2: 506.1366 [M+H]+, found: 506.1368. 1H NMR (CDCl3) δ 7.26 (m, 3H), 7.20 (m, 5H), 6.87 (d, 2H), 6.62 (d, 1H), 6.50 (s, 1H), 6.49 (d, 1H), 5.87 (t, 1H), 4.89 (d, 1H), 4.77-4.52 (m, 1H), 4.73 (d, 1H), 4.60 (s, 2H). 19F NMR (CDCl3) δ −69.83 (t, 3F), −88.63 (s, 2F), −137.19 (dt, 2F), −228.82 (1F).
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[NH2:34][C:35]1[C:36]([F:57])=[C:37]([C:41]2[N:42]=[C:43]([C:53]([CH3:56])([CH3:55])[CH3:54])[S:44][C:45]=2[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([NH2:52])[N:47]=2)[CH:38]=[CH:39][CH:40]=1.[S:58]1[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59]1>>[NH2:52][C:48]1[N:47]=[C:46]([C:45]2[S:44][C:43]([C:53]([CH3:54])([CH3:56])[CH3:55])=[N:42][C:41]=2[C:37]2[C:36]([F:57])=[C:35]([NH:34][S:63]([C:60]3[CH:61]=[CH:62][S:58][CH:59]=3)(=[O:65])=[O:64])[CH:40]=[CH:39][CH:38]=2)[CH:51]=[CH:50][N:49]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1ccsc1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccsc3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (80 mg, 0.233 mmol) and 3-thiophenesulfonyl chloride (47 mg, 0.256 mmol), the title compound was obtained as a white solid (68 mg, 56% yield). MS (ESI): 490.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[C:12]([N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]>CCOC(C)=O.CCCCCC>[C:12]([N:15]1[CH2:20][CH2:19][C:18]2([CH2:10][C:9](=[O:11])[C:3]3[C:2]([OH:1])=[CH:7][CH:6]=[CH:5][C:4]=3[O:21]2)[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: CC(=O)N1CCC(=O)CC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)N1CCC2(CC1)CC(=O)c1c(O)cccc1O2

Procedure:
2',5'-Dihydroxyacetophenone and 1-acetyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a yellow solid, m.p. 114°-116° C. (from EtOAc/hexane).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].C(N(CC)CC)C.O>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[O:30])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccccn4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a stirred mixture of 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and picolinoyl chloride hydrochloride (0.29 g, 1.60 mmol) in N,N-dimethylformamide (20 mL), was added triethylamine (0.67 mL, 4.80 mmol) at room temperature under nitrogen. After 18 h, water (100 mL) was added and the product was extracted with CH2Cl2 (3×150 mL). The organic layers were combined, washed with water (3×150 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration, washed with Et2O (25 mL) and dried in vacuo to give pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.31 g, 51% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 5.52 min (97.80%); mp: 229-231° C.; 1H NMR (DMSO-d6) δ 1.86-2.11 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.59 (d, J=17.0 Hz, 1H, CHH), 2.79-3.06 (m, 1H, CHH), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 4.61 (d, J=6.4 Hz, 2H, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.48 (d, J=7.7 Hz, 1H, Ar), 7.54 (s, 1H, Ar), 7.58-7.65 (m, 1H, Ar), 7.68 (d, J=7.9 Hz, 1H, Ar), 7.89-8.19 (m, 2H, Ar), 8.67 (d, J=4.5 Hz, 1H, Ar), 9.49 (t, J=6.3 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.19, 42.51, 47.11, 51.58, 122.02, 122.18, 122.93, 126.62, 127.20, 130.36, 137.81, 142.35, 143.82, 148.47, 149.89, 164.07, 167.92, 170.98, 172.85; LCMS: MH=379; Anal Calcd for C20H18N4O4+0.1H2O: C, 63.18; H, 4.83; N, 14.74. Found: C, 62.80; H, 4.86; N, 14.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][CH2:14][OH:15])[CH2:8][CH2:7][CH2:6]2.N.[Li].CO>O1CCCC1.C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH2:4][C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][CH2:14][OH:15])[C:10]=2[CH2:11][CH:12]=1
Reactant: COc1ccc2c(c1)CCCC2CCO
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC1=CCC2=C(CCCC2CCO)C1
Reaction time: 3 h
Yield: 126 %

Procedure:
A solution of 1 g (4.8 mmole) of the alcohol product from Example 3 in 15 ml of tetrahydrofuran and 15 ml of t-butyl alcohol was cooled to less than 0°, and 45 ml of distilled liquid ammonia was added. This was followed by the addition over a ten-minute period of 600 mg (86 mmole) of lithium. After three hours, methanol was added to the reaction mixture until the blue color disappeared, and the ammonia was then evaporated under a stream of nitrogen. The residue was dissolved in 5 ml of water, extracted with diethyl ether and acidified with 5% hydrochloric acid. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was chromatographed on silica gel to give 1.26 g of the title compound, contaminated with t-butanol. Structure assignment was confirmed by the proton nmr spectrum.