Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][NH:15][C:13]=2[N:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[CH:20]([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Si:1]([NH:8][C:9]1[N:10]=[C:11]([Cl:18])[C:12]2[CH:17]=[CH:16][N:15]([CH:20]([CH3:22])[CH3:21])[C:13]=2[N:14]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)I
Reactant: CC(C)(C)[Si](C)(C)Nc1nc(Cl)c2cc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Cl)nc(N[Si](C)(C)C(C)(C)C)nc21
Yield: 99.1 %

Procedure:
2-(t-Butyl-dimethylsilanyl)amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (CXXII) (5 g, 17.7 mmol), 2-iodopropane (4.5 g, 26.6 mmol) and K2CO3 (4.3 g, 26.6 mmol) in DMF (20 mL) were reacted at ambient temperature for 15 h. After addition of H2O (50 mL) to the reaction mixture, the aqueous solution was extracted with EtOAc (300 mL) and the organic layer was washed with a brine solution (50 mL) and dried with Na2SO4. The solvents were removed in vacuo and the residue was purified by flash column chromatography (pet ether/EtOAc=10/1 to 5/1) to afford 2-(t-butyl-dimethylsilyl)amino-4-chloro-7-i-propyl-pyrrolo[2,3-d]pyrimidine (CXXXIII, 5.7 g, 100%) as a light yellow oil. LCMS: (ESI) m/z=325 (M+H)+.
Reaction SMILES: [Mg].[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12](Cl)[CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)[CH3:3].C(Br)(C)C.O=O.C(=O)=[O:28].S(=O)(=O)(O)O>O.C(OCC)C>[CH2:2]([N:4]([CH2:19][CH3:20])[CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:28])[CH:13]=[CH:14][CH:15]=2)[C:10]([NH2:18])=[N:9]1)[CH3:3]
Reactant: CCN(CC)CCCn1nc(N)c2c(Cl)cccc21
Reactant: O=C=O
Agent: O=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CC(C)Br
Solvent: CCOCC
Product: CCN(CC)CCCn1nc(N)c2c(O)cccc21
Reaction time: 12 h
Yield: 40 %

Procedure:
To 20 ml of diethyl ether solution containing 600 mg of magnesium powder was added dropwise a mixed solution consisting of 2.81 g of 1-(3-diethylaminopropyl)-3-amino-4-chloroindazole obtained by the same method as described in Example 1, 2.06 g of iso-propyl bromide and 20 ml of diethyl ether. Into the solution were introduced dried oxygen gas and dried carbon dioxide gas for 10 hours so as to reflux the solution, and the solution was left to stand for 12 hours. The pH of the solution was adjusted to 4.0 by adding dropwise sulfuric acid to the solution at 0° C. The solution was added with 50 ml of water and filtered. To the aqueous layer of the filtrate was added an aqueous potassium carbonate solution to separate crystals. The crystals were obtained by filtration and dried to give 1.01 g of 1-(3-diethylaminopropyl)-3-amino-4-hydroxyindazole having the following analytical values in a yield of 40%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[Si:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(O)cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cn1

Procedure:
A solution of 10.9 g 5-hydroxypicoline, 8.85 g imidazole and 29.9 mL of t-butyldiphenylsilylchloride in 500 mL of CH2Cl2 was stirred for 4 days at 25° C. The mixture was washed with H2O, brine, dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica gel chromatography (EtOAc/Hexane 10:90) to afford the pure title compound as an oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:16]([CH3:30])[NH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].[CH2:39](Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)=[C:16]([CH3:30])[N:15]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:14]=2)=[O:12])=[CH:31][CH:32]=1)(=[O:4])=[O:3]
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1c(-c2cccc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 5, 50 mg, 0.108 mmol), K2CO3 (27 mg, 0.193 mmol) and benzyl bromide (0.015 mL, 0.129 mmol) in DMF (0.5 mL) is stirred for 30 min at 80° C. (microwave). The reaction mixture is diluted with MeOH, filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 28 mg (47% of theory); ESI mass spectrum: [M+H]+=555; Retention time HPLC: 1.16 min (Z003—001).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:28])=[O:4].[OH-].[Li+].[OH-].[Na+]>>[CH3:28][C:6]1[C:7]2[C:12]([NH:13][C:14]3[C:15]([O:20][CH:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[N:11][CH:10]=[N:9][C:8]=2[S:27][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3OC3CCOCC3)c2c1C
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)sc2ncnc(Nc3cccnc3OC3CCOCC3)c12

Procedure:
Prepared analogously to 1.2. from 5-methyl-4-[2-(tetrahydro-pyran-4-yloxy)-pyridin-3-ylamino]-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester. Lithium hydroxide was replaced by sodium hydroxide (2M).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:18]=[C:17]([O:27][CH2:28][CH2:29][C:30]([OH:32])=O)[C:16]=2[O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:42][C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:44]=1[NH2:45]>>[CH3:42][C:43]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[C:44]=1[NH:45][C:30](=[O:32])[CH2:29][CH2:28][O:27][C:17]1[C:16]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])=[C:15]([NH:14][S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:18]=1
Reactant: Cc1cccc(C)c1N
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)O
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCOCC2)nc1OCCC(=O)Nc1c(C)cccc1C

Procedure:
The procedure described in Example 3 was repeated by use of 3-[6-(4-t-butylphenylsulfonylamino)-5-(2-methoxyphenoxy)-2-morpholino-4-pyrimidinyloxy]propionic acid and 2,6-dimethylaniline, to thereby obtain the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH2:27][CH3:28].Cl>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:9][CH2:10][N:11]([CH2:26][CH2:27][CH3:28])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:15]([F:18])([F:16])[F:17]
Reactant: OC1(c2ccc(F)c(C(F)(F)F)c2)CCNCC1
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(O)(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
Preparation according to Example 2: 4-[4-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.4 g, 1.52 mmol), acetonitrile (20 ml), potassium carbonate (0.42 g, 3.0 mmol), iodopropane (0.18 ml, 1.82 mmol). Yield: 0.31 g, 67%. The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 179-181° C. MS m/z (relative intensity, 70 eV) 305 (M+, 5), 276 (bp), 258 (52), 256 (23), 185 (50).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29](=[O:42])[N:30]([CH3:41])[C:31]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17](I)[C:10]=12.[F:43][C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[F:1][C:2]1[CH:3]=[C:4]([C:28]2[C:29](=[O:42])[N:30]([CH3:41])[C:31]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32][CH:33]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:16]=[C:17]([C:47]3[CH:48]=[CH:49][C:44]([F:43])=[CH:45][CH:46]=3)[C:10]=12
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
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: [Cl-]
Solvent: C1COCCO1
Product: COc1ccc(Cn2nc(-c3ccc(F)cc3)c3c(Oc4ccc(-c5cnc(Nc6ccccc6)n(C)c5=O)cc4F)ccnc32)cc1
Temperature: 110 °C
Reaction time: 0.58 h

Procedure:
A suspension of 5-(3-fluoro-4-(3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.025 g, 0.0371 mmol; prepared according to the procedure of Example 86, Step E), 4-fluorophenylboronic acid (0.006 g, 0.04 mmol), Pd(PPh3)4 (0.002 g, 0.002 mmol) and lithium chloride (0.006 g, 0.15 mmol) in dioxane (1 mL) and 2 M aqueous Na2CO3 (1 mL) was stirred at 110° C. for 35 minutes and then at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to yield 0.031 g crude product as a yellow gum. The crude material was used without further purification in the following step. LRMS (APCI pos) m/e 643 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C(C)(C)OB(/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)O1>O1CCOCC1.O>[CH3:9][O:8][C:5]1[C:4]([O:10][CH3:11])=[CH:3][C:2](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:7][N:6]=1
Reactant: COc1cc(Br)cnc1OC
Reactant: CC1(C)OB(/C=C/c2ccccc2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(/C=C/c2ccccc2)cnc1OC
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture of 5-bromo-2,3-dimethoxypyridine (0.50 g, 2.29 mmol), tripotassium phosphate (1.95 g, 9.17 mmol), tetrakistriphenylphosphine (0.27 g, 0.23 mmol) and (E)-4,4,5,5-tetramethyl-2-styryl-1,3,2-dioxaborolane (0.53 g, 2.29 mmol) was diluted with dioxane (6 ml) and water (1 ml) and heated in a microwave for 1 hour at 100° C. The reaction mixture was partitioned between ethyl acetate and water and the organics were dried (MgSO4), filtered and concentrated in vacuo to give yellow oil. The oil was purified by column chromatography (SiO2; 0-10% ethyl acetate in petrol) gave 2,3-dimethoxy-5-[(E)-2-phenylethenyl]pyridine as a colourless oil (116 mg, 21%).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:25]=[C:24]([NH2:26])[CH:23]=[CH:22][C:5]=1[O:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:9][CH:8]=1
Reactant: [H][H]
Reactant: CCCCCCCCOc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCOc1ccc(Oc2ccc(N)cc2N)cc1
Yield: 85 %

Procedure:
The resultant 1-[4-(2,4-dinitrophenoxy)phenoxy]octane (31.08 g, 0.080 mol) and ethanol (700 ml) and 10% Pd/C (1.50 g) were introduced into a 2-liter (l) reaction bottle. After hydrogen passed through the reaction under normal pressure for 4 hours, the reaction mixture was filtered and concentrated to obtain a crude product. The crude product was recrystallized by ethanol to obtain 1-[4-(2,4-diaminophenoxy)phenoxy]octane (22.33 g, 0.068 mol). Yield: 85%. Spectrum: IR (KBr) 3420, 3352, 2924, 2856, 1618, 1503, 1466, 1215, 1105, 1027 cm−1, 1H NMR (DMSO-d6, 300 MHz). δ0.8˜6.7 (m, 4H), 6.46 (d, J=8.3 Hz, 1H), 6.02 (d, J=2.0 Hz, 1H), 5.79 (dd, J=8.5, J=2.2 Hz, 1H), 4.61 (s, 2H), 4.47 (s, 2H), 3.82 (t, J=5.7 Hz, 2H), 1.70˜1.50 (m, 2H), 1.40˜1.10 (m, 10H), 0.84 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 75 MHz). δ153.5, 152.7, 151.3, 146.1, 140.9, 133.4, 121.4, 116.8, 115.3, 103.2, 101.6, 68.0, 31.5, 29.0, 28.9, 25.7, 22.3, 14.1
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[C:6]([O:20][CH3:21])[C:5]([O:22][CH:23]([F:25])[F:24])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:49])[NH:44][CH2:43]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:24][CH:23]([F:25])[O:22][C:5]1[C:6]([O:20][CH3:21])=[C:7]([C:2]([C:40]2[CH:41]=[C:42]3[C:46](=[CH:47][CH:48]=2)[C:45](=[O:49])[NH:44][CH2:43]3)=[CH:3][CH:4]=1)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: COc1c(OC(F)F)ccc(Br)c1OCc1ccc(S(N)(=O)=O)cc1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)CNC3=O)c1OCc1ccc(S(N)(=O)=O)cc1
Temperature: 85 °C
Yield: 17.9 %

Procedure:
To a stirring solution of 4-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)benzenesulfonamide (200 mg, 0.456 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h. To this cesium carbonate (444 mg, 1.368 mmol), tetrakis(triphenylphosphine) palladium(0) (26 mg, 0.022 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (141 mg, 0.547 mmol) were added and the resultant reaction mixture was heated to 80-90° C. for 3 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded the title compound as a solid (40 mg, 18%).
Reaction SMILES: O[CH:2]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25].[K+].[Br-]>ClCCl.C(OCC)(=O)C>[F:22][C:23]([F:34])([F:33])[C:24]([O:26][CH2:5][CH2:4][CH2:3][CH2:2][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:17](=[O:19])[C:20]=2[CH:21]=1)=[O:25]
Reactant: CCCC(O)c1ccc(OCc2ccsc2C(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1c2cc(CCCCOC(=O)C(F)(F)F)ccc2OCc2ccsc21
Reaction time: 48 h

Procedure:
A stirred suspension of 14.33 g (0.0468 mol) of 3-[4-(1-hydroxybutyl)phenoxy]methyl-2-thiophenecarboxylic acid and 150 ml of anhydrous CH2Cl2 was treated with one portion of trifluoroacetic anhydride (22.60 g, 0.107 mol). The suspended material rapidly dissolved and the stirred solution was heated under reflux for four hours. After standing two days at ambient temperature, the reaction was quenched with water (70 ml) and washed with 50 ml of 5% NaHCO3 solution. The dried (Na2SO4) organic phase was concentrated to an oil, which was further dried by azeotropic distillation of toluene. The oil was dissolved in approximately 15 ml of isopropanol, seeded with product previously prepared on a smaller scale, and stirred until a thick crystalline mass formed. The mass was triturated with isopropanol, followed by vacuum filtration. The filter cake was dried in vacuo at 40° C. to afford 15.08 g (83.8%) of almost colorless crystals, m.p. 65.5°-67° C. The material appeared pure by TLC (silica gel, ethyl acetate, Rf =0.70; dichloromethane, Rf =0.51) and the IR (KBr), 1H-NMR (CDCl3) and MS (M+,384) were consistent with structure.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)NCc2cccc3c2CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and p-anisoyl chloride (0.4 g, 2.5 mmol) in THF (30 mL) was cooled to 5° C. Triethylamine (0.5 g, 4.8 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methoxy-benzamide (0.8 g, 90%) as a white solid: mp 289-291° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.32-2.65 (m, 2H), 2.86-3.00 (m, 1H), 3.81 (s, 3H, OCH3), 4.40-4.60 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 7.02 (d, J=8.6 Hz, 2H, Ar), 7.46-7.64 (m, 3H, Ar), 7.85 (d, J=8.7 Hz, 2H, Ar), 8.93 (t, J=5.3 Hz, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.58, 31.17, 46.28, 51.59, 55.32, 113.51, 121.57, 126.25, 128.27, 129.06, 130.64, 131.58, 134.93, 140.07, 161.63, 165.81, 168.07, 170.98, 172.81; Anal. calcd. for C22H21N3O5: C, 64.86; H, 5.20; N, 10.31. Found: C, 64.51; H, 5.04; N, 10.09.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]3=[O:27])[N:13]=2)=[N:6][CH:7]=1.[OH-:35].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]([CH2:19][CH2:18][NH:17][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[C:16]([OH:27])=[O:35])[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCC(Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1)C(=O)O
Temperature: 55 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-1-carboxylate (0.070 g, 0.128 mmol) (Example 393, Steps A-C) was dissolved in 1 mL of THF and sodium hydroxide (0.963 mL, 1.93 mmol) 2M solution was added. The resulting solution was heated to 55° C. and agitated for 3 hours. Reaction was quenched with 3 mL of 2M potassium hydrosulfate solution and extracted twice with ethyl acetate. The extracts were washed with water, brine, dried and evaporated to produce the title compound. 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.60-1.74 (m, 2H), 2.64-3.08 (m, 5H), 4.65 (bs, 1H), 6.47 (s, 1H), 7.09-7.43 (m, 7H), 8.14 (s, 1H).
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C@H:43]2[CH2:48][CH2:47][C@H:46]([CH:49]=O)[CH2:45][CH2:44]2)=[CH:39][CH:38]=1)#[N:36]>C1COCC1>[O:4]1[CH2:5][CH2:6][CH2:7][O:2][CH:3]1[CH2:8][CH:9]=[CH:49][C@H:46]1[CH2:47][CH2:48][C@H:43]([C:40]2[CH:39]=[CH:38][C:37]([C:35]#[N:36])=[CH:42][CH:41]=2)[CH2:44][CH2:45]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](C=CCC3OCCCO3)CC2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A mixture of (2-(1,3-dioxan-2-yl)ethyl)triphenylphosphonium bromide (17.4 g, 38.0 millimols) with THF (100 ml) was cooled down to -20° C., followed by adding t-BuOK (4.5 g, 39.9 millimols) to the mixture, stirring for 30 minutes, dropwise adding to the mixture, a THF (35 ml) solution of trans-4-(4-cyanophenyl)cyclohexanecarbaldehyde (7.7 g, 36.1 millimols) so as to keep the temperature at -20° C. or lower, stirring the mixture at the same temperature for 2 hours, and treating the reaction product in the same manner as in Example 3, to obtain raw 4-(trans-4-(3-(1,3-dioxan-2-yl)propenyl)cyclohexyl)benzonitrile (10.3 g).
Reaction SMILES: C(C1C=C[C:6]([O:7]CCCCCOC2C=CC(C(N(C(C)C)C(C)C)=O)=C(O)C=2)=[CH:5]C=1)#N.[H-].[Na+].BrCC(OCC)=O.[C:41]([C:43]1[CH:77]=[CH:76][C:46]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][O:53][C:54]2[CH:55]=[CH:56][C:57]([C:67]([N:69]([CH:73]([CH3:75])[CH3:74])[CH:70]([CH3:72])[CH3:71])=[O:68])=[C:58]([CH:66]=2)[O:59][CH2:60][C:61]([O:63][CH2:64][CH3:65])=[O:62])=[CH:45][CH:44]=1)#[N:42].[ClH:78]>CN(C)C=O.C(O)C>[ClH:78].[CH2:64]([O:63][C:61]([CH2:60][O:59][C:58]1[CH:66]=[C:54]([CH:55]=[CH:56][C:57]=1[C:67]([N:69]([CH:73]([CH3:75])[CH3:74])[CH:70]([CH3:71])[CH3:72])=[O:68])[O:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][O:47][C:46]1[CH:45]=[CH:44][C:43]([C:41](=[NH:42])[O:7][CH2:6][CH3:5])=[CH:77][CH:76]=1)=[O:62])[CH3:65]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Reactant: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Agent: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=N)c1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OCC(=O)OCC)c2)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (0.5 g, 1.18 mmol) in 10.0 mL of N,N-dimethylformamide is treated with 60% sodium hydride (47 mg, 1.18 mmol) and ethyl bromoacetate (144 μL, 1.3 mmol), and heated at 70° C. for 2.5 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford yellow foam. The resulting ethyl 5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate in 50 mL of anhydrous ethanol at 0° C. is treated with anhydrous hydrogen chloride gas over 30 minutes. This solution is stirred at room temperature for 20 hours and concentrated in vacuo. This material is purified by chromatography on silica gel with 60% ethyl acetate/hexane as the eluent to afford ethyl 4-[5-[3-ethoxycarbonylmethoxy-4-[N,N-bis(1- methylethyl)aminocarbonyl]phenoxy]pentyloxy]benzenecarboximidoate monohydrochloride as colorless foam.