Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26]([OH:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C>CO>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26]([OH:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]1
Reactant: CCOC(=O)C1(O)CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Solvent: CO
Product: CCOC(=O)C1(O)CCC(c2ccc(O)cc2O)CC1
Reaction time: 1 h
Yield: 21.4 %

Procedure:
A solution of one isomer of ethyl 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-hydroxycyclohexanecarboxylate (25 mg, 0.05 mmol) in methanol (2 ml) was stirred rapidly with Amberlyst A-26 (100 mg) for 18 hr. After this time the reaction mixture was filtered. The resin was then stirred rapidly for 1 hr in a solution of methanol (2 ml) and glacial acetic acid (5 drops). The reaction mixture was filtered and the combined filtrates concentrated in vacuo. Purification via flash column chromatography (SiO2, ethyl acetate/petrol, 2:1) afforded the title compound (3 mg, 21%) as a white solid. δH (d4-MeOH) 1.29 (3H, t), 1.61-1.69 (2H, m), 1.73-1.98 (6H, m), 2.81-2.90 (1H, m), 4.18 (2H, q), 6.21-6.27 (2H, m), 6.91 (1H, d); m/z (ES−) 279 (M−H)−.
Reaction SMILES: [H-].[Na+].[CH:3]([S:5]([CH3:8])(=[O:7])=[O:6])=[CH2:4].[CH2:9]([O:11][CH2:12][C:13]1[N:14]([CH2:26][C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:10].O>O1CCCC1>[CH2:9]([O:11][CH2:12][C:13]1[N:14]([CH2:26][C:27]2([O:33][CH2:4][CH2:3][S:5]([CH3:8])(=[O:7])=[O:6])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH3:10]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCCCC1
Reactant: C=CS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 25 mg, 0.62 mmol) followed by methyl vinyl sulfone (1.30 g, 12.4 mmol) were added to a stirred solution of 1-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclohexanol (2.1 g, 6.2 mmol) in tetrahydrofuran (25 mL). The reaction mixture was heated at reflux for 2 hours and additional methyl vinyl sulfone (1 equivalent) and sodium hydride (60% dispersion in oil, spatula tip full) were added. The mixture was allowed to stir overnight at room temperature. Water (50 mL) was added and a precipitate formed that was removed by filtration. The filtrate was extracted with dichloromethane (2×50 mL). The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford an oil that was purified by flash chromatography (silica gel, eluted with 5% methanol in dichloromethane) to provide 0.45 g of 2-(ethoxymethyl)-1-({1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-1H-imidazo[4,5-c]quinoline as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:14]([C:12]1[C:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: C=CCCCCCCC
Product: CCCCCCCCCc1cccc(Nc2ccccc2)c1CCCCCCCCC
Yield: 71 %

Procedure:
A commercial nonene yielded 59% dialkylate when reacted for 10 hours with diphenylamine under the conditions of Example 1. The nonene, after passing in the vapor phase over a 75 cc catalyst bed of F-24 at 650° F. for 5 seconds, was converted to a high reactivity alkene which yielded 71% dinonyl diphenylamine under the reaction conditions of Example 1 after 10 hours reaction time.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15]Br)=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH3:25][NH2:26]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH:26][CH3:25])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CBr
Solvent: CO
Product: CNCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 71.5 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.27 mmol) and methylamine (40% in water, 1.1 ml, 1.397 mmol) in methanol (12 ml) was stirred at room temperature during four hours. The solvents were evaporated under reduced pressure, and water and ethyl acetate added to the residue. After stirring, the organic phase was separated and evaporated under reduced pressure. The residue was dissolved in diethyl ether and precipitated with pentane, to give 0.31 g of 6-nitro-2,2-dimethyl-3-(methylamino)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 128° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:13]([N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].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.O>[CH2:13]([N:20]1[CH:24]=[C:23]([C:2]2[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:22]=[N:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2cnn(Cc3ccccc3)c2)OC1(C)C
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: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cnn(Cc3ccccc3)c2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with 5-bromo-2-methoxy-3-nitropyridine (3.58 g, 15.36 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.23 g, 18.43 mmol), potassium carbonate (4.24 g, 30.72 mmol), 1,4-dioxane (50 mL) and water (5 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium(0) (1.77 g, 1.53 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred and heated in an oil bath to 100° C. After 3 days, the mixture was cooled, filtered through diatomaceous earth (Celite®) and the filter cake was washed with methylene chloride (300 mL). The combined filtrate and washings were concentrated in vacuo and the residue was purified by flash chromatography (20-50% ethyl acetate in hexanes) to give the title compound (3.70 g, 84%) as a yellow solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[NH:14])=[CH:8][C:7]=2[O:16][CH3:17])=[CH:4][N:3]=[CH:2]1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>CN(C)C=O>[CH3:17][O:16][C:7]1[CH:8]=[C:9]([NH:12][C:13]2[NH:15][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][N:14]=2)[CH:10]=[CH:11][C:6]=1[C:5]1[O:1][CH:2]=[N:3][CH:4]=1
Reactant: COc1cc(NC(=N)N)ccc1-c1cnco1
Reactant: O=C(CBr)c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(-c3ccccc3)[nH]2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The product of Example 243, Part A, 4-Oxazol-5-yl-3-methoxyphenylguanidine, 243A (150 mg, 0.65 mmol) and phenacylbromide (128 mg, 0.65 mmol) were dissolved in N,N-dimethylformamide (0.25 mL) and stirred at room temperature for 3 days. The reaction mixture was evaporated and purified by prep RPHPLC to yield 5 mg (2%, a significant portion of the product was spilled during isolation) of the title compound. LCMS conditions J, retention time=1.62 min, (90%), M+H+=333.17. (100%).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:20])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:6][CH:5]=1>CO>[C:16]([O:15][C:13]([NH:12][CH2:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:21])=[O:2])=[CH:5][N:6]=1)[OH:20])=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)c1ccc(C(O)CNC(=O)OC(C)(C)C)nc1
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(O)c1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
6-(2-tert-Butoxycarbonylamino-1-hydroxy-ethyl)-nicotinic acid methyl ester (137.3 mg, 0.450 mmol) was dissolved into 3 mL of MeOH. To this was added LiOH monohydrate (56.5, 1.350 mmol). The reaction stirred at room temperature overnight. The reaction mixture was concentrated on a rotary evaporator, dissolved into 2 mL of water, and brought to pH 4 with AcOH. The mixture was extracted into 3×10 mL of EtOAc and the organic fractions combined. The organic phase was washed with 2×20 mL H2O and 1×20 mL of brine, dried MgSO4, filtered and concentrated to give 130 mg of 6-(2-tert-butoxycarbonylamino-1-hydroxy-ethyl)-nicotinic acid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:24])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]=[S:26]1(=[O:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21](=[O:22])[NH:39][C:36]3[CH:37]=[CH:38][C:33]([CH2:32][N:29]4[CH2:28][CH2:27][S:26](=[O:25])(=[O:40])[CH2:31][CH2:30]4)=[CH:34][CH:35]=3)=[CH:19][CH:20]=2)[C:12]([CH3:24])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 118 h
Yield: 82.6 %

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-methyl-biphenyl-4-carboxylic acid (500 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl) -phenylamine (367 mg), triethylamine (0.64 ml) and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (869 mg) in dry DMF (20 ml) was stirred at 20 C for 118 h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol; 1:1 removed high Rf impurities and further elution with ethyl acetate gave the title compound as a pale yellow solid (693 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][CH:3]=1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH:14]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH:8][CH2:14][CH:13]([O:16][CH3:17])[O:12][CH3:11])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: COC(C=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CNCCc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a solution of 4-fluorophenethylamine (2.00 mL, 15.0 mmol) and dimethoxyacetaldehyde (60% solution in water, 2.53 mL, 16.83 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (4.28 g, 20.20 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by the addition of saturated sodium bicarbonate (50 mL). The mixture was extracted with ethyl acetate (3×100 mL) and the combined organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluted with ethyl acetate/hexane to afford N-(4-fluorophenethyl)-2,2-dimethoxyethanamine as a colorless oil in 52% yield (1.78 g): 1H NMR (300 MHz, CDCl3) δ 7.14-7.10 (m, 2H), 6.97-6.91 (m, 2H), 4.43-4.40 (m, 1H), 3.35 (s, 6H), 2.89-2.81 (m, 2H), 2.76-2.71 (m, 4H); MS (ES+) m/z 228.2 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9]Br.C1CCN2C(=NCCC2)CC1>C1COCC1>[I:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: BrCc1ccccc1I
Reactant: c1nc[nH]n1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Ic1ccccc1Cn1cncn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.4 %

Procedure:
To a stirring solution of 1,2,4-triazole (1.02 g, 14.8 mmol) and 2-iodobenzyl bromide (6.05 g, 20.3 mmol) in THF (10 mL) was added a solution of DBU (2.65 g, 17.4 mmol) in THF (2 mL) dropwise over a 1 hour period. The mixture was stirred at ambient temperature for 12 hours after which it was filtered. The filtrate was concentrated in vacuo and the resultant residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 50-60% ethyl acetate/isohexane to give the title compound as a white solid (1.45 g). 1H NMR (360 MHz, CDCl3): δ 8.15 (1H, s), 8.00 (1H, s), 7.89 (1H, d, J=7.9 Hz), 7.36 (1H, t, J=7.6 Hz), 7.13 (1H, d, J=7.7 Hz), 7.08-7.04 (1H, m), 5.43 (2H, s).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:8]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[Br-:30].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1>[Br:30][CH2:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:8]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N(Cc2ccccc2)S(C)(=O)=O)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reaction time: 6 h

Procedure:
A solution of N-{5-acetyl-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl) methanesulfonamide (J. Med Chem 1977, 20, 687-92) (1.18 g) in THF (50 ml) was treated with phenyltrimethylammonium tribromide (1.08 g) at <10° and stirred for 6 h. The reaction mixture was quenched with chilled water and then filtered. The filtrate was partitioned between diethyl ether and water, the organic phase was dried (MgSO4) and the solvent was removed in vacuo. The mixture was purified by column chromatography on silica (SPE bond elut, gradient 0 to 45% EtOAc-cyclohexane) to afford the title compound. LCMS RT=3.48 min
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O>>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][N:24]1[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[C:22]([C:20]2[CH:19]=[CH:18][N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:14][CH:13]=3)[N:21]=2)[CH:26]=[N:25]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Reactant: CN(C)CCO
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)cnn2CCN(C)C)cc1

Procedure:
The title compound is prepared as described in Example 54 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and 2-dimethylamino-ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:9]2)=[CH:4][CH:3]=1.[CH3:23]OC(OC)OC>>[CH3:23][NH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:22])[NH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH2:20][CH3:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCCOc1ccccc1-c1nc2cc(N)ccc2c(=O)[nH]1
Reactant: COC(OC)OC
Product: CCCOc1ccccc1-c1nc2cc(NC)ccc2c(=O)[nH]1

Procedure:
7-amino-2-(2-propoxyphenyl)-4(3H)-quinazolinone (0.5 g) was heated under reflux in trimethylortho-formate (5 ml) for 22 hours. The reaction mixture was evaporated to dryness, the residue dissolved in dry tetrahydrofuran and treated with sodium borohydride (0.3 g) and 4A molecular sieves for 24 hours. The reaction mixture was partitioned between water and dichloromethane, the organic layer separated, dried (magnesium sulphate) and evaporated. The residue was recrystallized from dichloromethane-diethyl ether to give 7-methylamino-2-(2-propoxyphenyl)-4(3H)-quinazolinone 0.17 g, m.p. 204°-205° C.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:6][C:7]1=[N:8][C:9](=[O:19])[S:10]/[C:11]/1=[CH:12]\[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[C:4]#[CH:5].C(=O)([O-])[O-].[K+].[K+].C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:31]=1)(=O)C.O>CN(C=O)C>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:16]2[CH2:17][CH2:18][CH:13](/[CH:12]=[C:11]3/[C:7]([NH:6][CH2:3][C:4]#[CH:5])=[N:8][C:9](=[O:19])[S:10]/3)[CH2:14][CH2:15]2)=[C:32]([C:38]([F:39])([F:40])[F:41])[CH:31]=1
Reactant: CC(=O)Oc1ccc(CBr)c(C(F)(F)F)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(O)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of (5Z)-4-(prop-2-yn-1-ylamino)-5-(piperidin-4-ylmethylidene)-1,3-thiazol-2(5H)-one dihydrochloride (2 g) in DMF (20 mL) were added potassium carbonate (3.45 g) and 4-(bromomethyl)-3-(trifluoromethyl)phenyl acetate (1.84 g). The reaction mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the residue in methanol (20 mL) was added potassium carbonate (858 mg), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and the solid was recrystallized from ethyl acetate/heptane to give the title compound (0.75 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[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].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[S:44]1[CH:48]=[CH:47][C:46]([CH2:49][C:50](O)=[O:51])=[CH:45]1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:50](=[O:51])[CH2:49][C:46]3[CH:47]=[CH:48][S:44][CH:45]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C(O)Cc1ccsc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(Cc1ccsc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3-thiopheneacetic acid (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc: CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-3-yl-acetamide (0.7 g, 80%) as a white solid: mp 163-165° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.39 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.55 (s, 2H), 4.71 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.04-7.06 (m, 1H), 7.28-7.29 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.67 (m, 1H), 7.76-7.83 (m, 2H), 8.60 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ21.95, 30.90, 36.88, 37.83, 48.83, 121.87, 122.35, 125.76, 127.11, 128.67, 131.51, 133.18, 134.67, 135.82, 139.17, 166.91, 167.44, 169.78, 170.23, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.37; H, 3.98; N, 10.05; S, 7.83.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[NH2:17]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(Nc2ccccc2CC(=O)O)cc(C(F)(F)F)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methoxy-5-(trifluoromethyl)aniline to yield 2-[(3-methoxy-5-(trifluoromethyl)phenyl)amino]phenylacetic acid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][OH:10])[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15].[CH3:17]I.[H-].[Na+].Cl>O1CCCC1>[OH:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:17])[C:6]([CH:11]([CH3:12])[CH3:13])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1cc(C(C)C)c(CO)cc1CO
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(CO)c(C(C)C)cc1C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
31.5 g (0.14 mol) of the compound from Example 3 and 9.6 ml (0.15 mol) of methyl iodide are added under a nitrogen atmosphere to 8.9 g (0.3 mol) of sodium hydride (80% strength in paraffin oil) in 500 ml of tetrahydrofuran. After stirring for 2 h at 80° C., the mixture is cautiously hydrolyzed using 30 ml of dilute hydrochloric acid, the solvent is distilled off, and the residue is taken up in methylene chloride, washed with water, dried and chromatographed on silica gel (230-400 mesh, ethyl acetate/petroleum ether 1:2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:10][CH:9]=2)=[CH:4][CH:3]=1.IC.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[N:14][C:15]=3[NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:10]([CH2:32][CH:29]3[CH2:31][CH2:30]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: O=c1c(-c2ccc(Cl)cc2)c[nH]c2ccnc(NCc3ccccc3)c12
Solvent: CI
Product: O=c1c(-c2ccc(Cl)cc2)cn(CC2CC2)c2ccnc(NCc3ccccc3)c12

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-benzylamino-1,6-naphthyridine and iodomethane was replaced with cyclopropylmethyl bromide. MS 426 (M+1)+.