Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.Cl.Cl.Cl.[NH:21]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.COCCO>CCOCC>[N:21]1([C:2]2[C:3]3[CH2:13][CH2:12][CH2:11][C:10]4[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=4[C:4]=3[N:5]=[C:6]([NH2:8])[N:7]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: C1CNCCNCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: CCOCC
Product: Nc1nc2c(c(N3CCNCCNCC3)n1)CCCc1ccccc1-2
Temperature: 110 °C
Reaction time: 19 h

Procedure:
The product from Example 68A (52 mg, 0.212 mmol) was treated with 1,4,7-triazonane trihydrochloride (202 mg, 0.847 mmol), treated with Hunig's base (554 μl, 3.17 mmol), treated with 2-methoxyethanol (2116 μl), stirred at 110° C. for 19 hours, cooled, diluted with Et2O (25 mL), washed with 0.1 M NaOH (2×10 mL), washed with brine, dried (MgSO4), filtered, concentrated and purified by chromatography on silica gel (eluting with 2, 10 and 50% (9:1 MeOH:concentrated NH4OH) in CH2Cl2) to provide the title compound. 1H NMR (CD3OD) δ 2.08-2.24 (m, 2H), 2.40 (t, J=6.94 Hz, 2H), 2.67 (t, J=6.74 Hz, 2H), 2.94 (s, 4H), 3.10-3.16 (m, 4H), 3.71-3.77 (m, 4H), 7.24-7.29 (m, 1H), 7.32-7.41 (m, 2H), 7.63-7.68 (m, 1H); MS (M+H)+ m/z 339.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].[Cl:18][C:19]1[S:23][C:22]([CH:24]=[CH:25][S:26](Cl)(=[O:28])=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[S:23][C:22]([CH:24]=[CH:25][S:26]([N:14]2[CH2:15][CH2:16][N:11]([CH2:10][CH2:9][NH:8][C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[CH3:1])[C:12](=[O:17])[CH2:13]2)(=[O:28])=[O:27])=[CH:21][CH:20]=1
Reactant: Cc1cnccc1NCCN1CCNCC1=O
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Product: Cc1cnccc1NCCN1CCN(S(=O)(=O)C=Cc2ccc(Cl)s2)CC1=O
Yield: 32.5 %

Procedure:
1-[2-(3-Methylpyridin-4-yl-amino)-ethyl]-piperazin-2-one (38 mg, 0.16 mmol), EXAMPLE 94, is reacted with 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride (40 mg, 0.16 mmol), EXAMPLE 3, using the same procedure as described in EXAMPLE 719. Reverse phase HPLC purification gives the title compound (29 mg, 0.052 mmol) as a white solid. MS m/z 441, 443 (M+H); 1H NMR (CD3OD, 300 MHz) δ8.08 (d, 1H), 7.98 (s, 1H), 7.56 (d, 1H), 7.30 (d, 1H), 7.02 (s, 1H), 7.00 (d. 1H), 6.78 (d, 1H), 3.87 (s, 2H), 3.70-3.50 (m, 8H), 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)C(=O)COc1ccc(Cl)cn1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cn1

Procedure:
A mixture of 10.5 g (0.046 mole) of 1-(5-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, prepared above, and 8.37 g (0.047 mole) N-bromosuccinimide (NBS) in 300 ml. carbon tetrachloride, with stirring, was irradiated and heated with a sunlamp until all of the NBS was consumed (about 45 min.). The reaction mixture was cooled, filtered, and the filtrate washed with aqueous sodium bisulfite and dried. After removal of the solvent, there was obtained a quantitative yield of 1-bromo-1-(5-chloro-2-pyridinyl-oxy)-3,3-dimethyl-2-butanone, a light yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C>CN(C=O)C>[OH:45][CH2:44][CH2:43][O:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:24]5[CH2:32][C:31]6[C:26](=[CH:27][C:28]([CH3:33])=[CH:29][CH:30]=6)[C:25]5=[O:34])[C:19]=4[CH3:35])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(O)ccc5c34)c1C)C2
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C(=O)N(c1cccc(-c3ccc(C(N)=O)c4[nH]c5cc(OCCO)ccc5c34)c1C)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 7-hydroxy-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 40-2, 30 mg, 0.065 mmol) and potassium carbonate (36 mg, 0.260 mmol) in DMF (1.0 mL) was stirred at rt for 30 min, then was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (62.2 mg, 0.260 mmol) and heated at 90° C. for 4 h. The mixture was filtered, the filtrate was treated with hydrogen chloride (4 M in dioxane, 1 mL) and the solution was stirred at rt overnight. The solution was concentrated under vacuum and the residue was purified by preparative HPLC to provide 7-(2-hydroxyethoxy)-4-(2-methyl-3-(6-methyl-1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an off-white solid (16.5 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 11.39 (1H, s), 8.17 (1H, br. s.), 7.94 (1 H, d, J=7.9 Hz), 7.53-7.65 (3H, m), 7.49 (3H, t, J=7.8 Hz), 7.27-7.39 (2H, m), 6.99 (1H, d, J=7.7 Hz), 6.92 (1H, d, J=8.8 Hz), 6.59 (1H, dd, J=8.8, 2.4 Hz), 4.75-4.98 (3H, m), 3.95-4.07 (2H, m), 3.69-3.80 (2H, m), 2.44 (3H, s). Mass spectrum m/z 506.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)=[C:21]2[CH2:34][CH2:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37].C(=O)([O-])[O-].[K+].[K+].CO>CC(C)=O.C(OCC)(=O)C>[F:14][C:13]([F:16])([F:15])[C:5]1[CH:4]=[C:3]([CH2:2][N:41]2[CH2:42][CH2:43][N:38]([C:36](=[O:37])[CH2:35][CH2:34][C:21]3[C:20]4[C:24](=[CH:25][CH:26]=[C:18]([Cl:17])[CH:19]=4)[NH:23][C:22]=3[C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[CH2:39][CH2:40]2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCNCC1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12)N1CCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
1-(Bromomethyl)-3,5-bis(trifluoromethyl)benzene (83 mg) was added to a mixture of 1-{3-[5-chloro-2-(4-chlorophenyl)-1H-indol-3-yl]-1-oxopropyl}piperazine (Description 30, 35 mg) and potassium carbonate (36 mg) in acetone (3 mL) and the mixture was stirred at room temperature for 2 h. Methanol (1 mL) and ethyl acetate (10 mL) were added and the mixture was washed with water. The organic fraction was filtered through a plug of silica in a Bond Elut™ cartridge, eluting with hexane/EtOAc (80:20 increasing to 60:40), to give the title compound as a colorless solid (49 mg, 89%). 1H NMR (360 MHz, CDCl3) δ2.16-2.19 (2H, m), 2.33-2.36 (2H, m), 2.59-2.63 (2H, m), 3.15-3.20 (2H, m), 3.28-3.30 (2H, m), 3.53 (2H, s), 3.58-3.61 (2H, m), 7.13 (1H, dd, J 8.7, 1.8 Hz), 7.25 (1H, d, J 8.3 Hz), 7.36-7.53 (6H, m), 7.77 (2H, s), and 8.51 (1H, s). m/z (ES+) 628, 630 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(OC(NC(CNC1C=CC=CC=1N)C(O)=O)=O)(C)(C)C.[C:54]([O:57][CH2:58]C)(=[O:56])[CH3:55]>CN(C)C=O>[CH3:58][O:57][C:54](=[O:56])[CH2:55][N:14]1[C:15](=[O:16])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]1=2
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: CC(C)(C)OC(=O)NC(CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)CNc2ccccc21
Reaction time: 18 h
Yield: 71 %

Procedure:
3(S)-tert-Butoxycarbonylamino-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of 2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of dimethylformamide and stirred for 18 hours. The reaction was poured into 700 ml of ethyl acetate and washed four times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 ethyl acetate/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H, m), 1.45 (9H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.[C:53]1([C:59]2[N:63]=[C:62]([N:64]3[CH2:69][CH2:68][NH:67][CH2:66][CH2:65]3)[S:61][N:60]=2)[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.Cl>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:67]2[CH2:68][CH2:69][N:64]([C:62]3[S:61][N:60]=[C:59]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[N:63]=3)[CH2:65][CH2:66]2)=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 5.8 %

Procedure:
To a solution of a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1; 150.0 mg; 0.38 mmol; 1.0 eq.) in DMF (1.5 mL) was added 3-phenyl-5-piperazino-1,2,4-thiadiazole (93.2 mg; 0.38 mmol; 1.0 eq.) and the resulting reaction mixture was stirred at RT for 14 h. An aqueous solution of HCl (1N) was added and the resulting mixture was extracted with EtOAc, dried over MgSO4, filtered and evaporated to give an oil. This residue was taken up in CD3OD. The precipitate was filtered off and the mother liquids were evaporated and the resulting residue was then purified by chromatography (SiO2, gradient from 2/1 to 1/1 c-hex/EtOAc in about 30 min) to give the title product as a colorless oil (10 mg; 5.8%). M+(ESI): 459.0. HPLC (Condition A): Rt: 4.5 min (HPLC purity: 98.5%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Li])CCC.C[Si](Cl)(C)C.[C:17]([C:20]1[CH:24]=[C:23]([CH3:25])[O:22][C:21]=1[CH3:26])(=[O:19])[CH3:18].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:26][C:21]1[O:22][C:23]([CH3:25])=[CH:24][C:20]=1[C:17]([C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1])([OH:19])[CH3:18]
Reactant: Cc1cscn1
Reactant: CC(=O)c1cc(C)oc1C
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(C)(O)c2scnc2C)c(C)o1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
4-Methylthiazole (6.51 g) in dry tetrahydrofuran (50 ml) was stirred under an atmosphere of dry nitrogen and cooled to -70° C. and n-butyllithium (2.5M solution in hexane, 29 ml) was added dropwise. After 30 minutes trimethylsilylchloride (7.14 g) was added and the mixture was allowed to warm to room temperature. After 30 minutes the mixture was again cooled to -70° C. and n-butyllithium (2.5M solution in hexane, 29 ml) was added dropwise. After 30 minutes 3-acetyl-2,5-dimethylfuran (10 g) was added dropwise. The mixture was stirred at -70° C. for 1 hour and was then allowed to warm to room temperature. After 30 minutes, aqueous sodium hydrogen carbonate was added and the mixture was extracted with diethylether. The combined extracts were washed, dried and evaporated to give the title compound which was recrystallised from diethylether. M.p. 100.5°-101.5° C.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:19][CH:20]3[O:24]C(=O)[N:22]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[CH2:21]3)[C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([Br:18])=[CH:12][CH:11]=3>C1COCC1.O.CCOC(C)=O>[Br:18][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH:20]([OH:24])[CH2:21][NH:22][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:8]3[C:16]([C:15]=2[CH:14]=1)=[CH:17][C:5]([Br:4])=[CH:6][CH:7]=3
Reactant: O=C1OC(Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CN1c1ccncc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: OC(CNc1ccncc1)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound of Example 41 was prepared as follows. LiOH.H2O (0.0157 g, 0.373 mmol) was added to 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(pyridin-4-yl)oxazolidin-2-one (0.0187 g, 0.0373 mmol) in a mixture of 428 μL THF and 48 μL H2O (v/v=9:1). The mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with 30 mL EtOAc and washed with brine 3×30 mL. The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which did not require purification (0.0013 g white solid, 7.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[OH-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:17]([O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCOc1ccc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of 5-chloro-8-hydroxyquinoline (1 mmol, 180 mg) in aqueous NaOH (0.25 M, 8 mL; 2 mmol) containing tetrabutylammonium bromide as the phase-transfer catalyst (0.1 mmol, 33 mg) was stirred for 30 min., and allyl bromide (1 mmol, 85 μL) and benzene (8 mL) were added and the reaction mixture was stirred vigorously at 50° C. for 14 h. The reaction mixture was partitioned between water (15 mL) and EtOAc (15 mL) after cooling to room temperature and the extraction was repeated twice. The organic layers were combined and washed with 1 M NaOH solution (15 mL) and concentrated. The crude product was purified by flash-column chromatography over silica gel using 1:2 hexanes-ether as eluent to afford quinoline 3a as a light-brown solid (170 mg, 64%).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.O>CN(C)C=O>[Si:25]([O:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:20])/[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:9]([O:21][CH3:22])[C:8]([CH3:23])=[C:7]2[C:3]=1[C:4](=[O:24])[O:5][CH2:6]2)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: COC(=O)CC/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate (Tetrahedron, 28, 4395, 1972) (10.0 g) in dimethylformamide (75 ml) was added t-butyldimethylsilyl chloride (4.97 g) and imidazole (2.24 g). The mixture was heated at 50° C. for 1 hour, then left at room temperature for 24 hours, then poured into water and extracted with ethyl acetate. The extract was washed twice with water, dried over magnesium sulfate and evaporated under vacuum to give methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -4-methyl-4-hexenoate as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([CH3:11])=[O:10])=[CH:6][CH:7]=1.ON1C(=O)N(O)C(=O)N(O)[C:14]1=[O:23].N(C(C)(C)C#N)=NC(C)(C)C#N.[O:36]=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:9]([O:8][C:5]1[CH:4]=[CH:3][C:2]([C:14]([OH:23])=[O:36])=[CH:7][CH:6]=1)(=[O:10])[CH3:11].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([CH3:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=O
Reactant: O=c1n(O)c(=O)n(O)c(=O)n1O
Agent: [Co+2]
Agent: [Mn+2]
Agent: CC(=O)Oc1ccc(C)cc1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
A mixture of 0.300 g of p-tolyl acetate, 0.018 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (5% by mole relative to p-tolyl acetate), 5 g of acetic acid, 0.003 g of cobalt (II) acetate 4 H2O, 0.001 g of manganese(II) acetate .4 H2O and 0.003 g of 2,2′-azobisisobutyronitrile was stirred at 100° C. in an atmosphere of oxygene gas (1 atm=0.1 MPa) for 6 hours. The resulting product in the reaction mixture was analyzed by gas chromatography and was found to yield 4-acetoxybenzoic acid in 82% yield at 85% conversion of p-tolyl acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:10]([O:12][CH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[NH:15]C(=O)C(F)(F)F)=[O:11].[N:30]([O-])=O.[Na+]>O>[N+:8](=[C:9]([CH2:25][C:26]([F:29])([F:28])[F:27])[C:10]([O:12][CH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[NH2:15])=[O:11])=[N-:30]
Reactant: NC(CC(F)(F)F)C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=C(CC(F)(F)F)C(=O)OC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
To a solution of O-(2-amino-4,4,4-trifluoro-1 -oxobutyl)-N-trifluoroacetyl-L-serine trifluoroacetate (500 mg) in water (5 ml) was added sodium nitrite (146 mg) at room temperature. After stirring for 30 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (70 mg) was added. After stirring for 6 hours at room temperature, the mixture was chromatographed on SP (trade mark, made by MITSUBISHI CHEMICAL INDUSTRIES LTD.) (50 ml) eluting successively with water and a 9:1 mixture of water and acetone to give a crude product, which was chromatographed on preparative thin layer chromatography eluting with a 65:25:4 mixture of chloroform, methanol and water to give O-(2-diazo-4,4,4-trifluoro-1-oxobutyl)-L-serine (28 mg).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:40])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:38][CH3:39])=[C:17]([O:20][C@@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@@H:23]([C:34]([NH:36][CH3:37])=[O:35])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1>O1CCOCC1.C(#N)C>[Cl:2][C:3]1[C:4]([F:40])=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:38][CH3:39])=[C:17]([O:20][C@@H:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([C:34]([NH:36][CH3:37])=[O:35])[CH2:22]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
4M Hydrogen chloride (7.5 ml) in dioxane was added to a stirred solution of (1) tert-butyl (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.17 g) in acetonitrile (10 ml) and stirred for 2 hours at room temperature. A second portion of 4M Hydrogen chloride (3.75 ml) in dioxane was added and the mixture stirred a further 1½ hours. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residues were purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4). The fractions containing the desired product were combined and evaporated. The resulting solids were triturated with iso-hexane/methylene chloride filtered and dried under high vacuum at 50° C. to give the title product as a white solid (1.94 g, 57%); 1H NMR Spectrum: (DMSO d6) 1.67-1.82 (m, 2H); 1.83-1.94 (m, 1H); 1.98-2.08 (m, 1H); 2.59 (d, 3H); 2.74-2.83 (m, 1H); 2.90-3.01 (m, 1H); 3.48-3.55 (m, 1H); 3.94 (s, 3H); 4.83 (br s, 1H); 7.22 (s, 1H); 7.23-7.30 (m, 1H); 7.43-7.57 (m, 2H); 7.75-7.81 (m, 1H); 7.84 (s, 1H); 8.37 (s, 1H); 9.52 (s, 1H); Mass Spectrum: (M+H)+ 460.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[C:13]12([C:23](Cl)=[O:24])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[C:13]12([C:23](=[O:24])/[CH:12]=[C:7]3\[S:8][CH:9]=[C:10]([CH3:11])[N:6]\3[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:20][CH:19]3[CH2:18][CH:17]([CH2:16][CH:15]([CH2:21]3)[CH2:14]1)[CH2:22]2
Reactant: CCCC[n+]1c(C)csc1C
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCN1C(C)=CS/C1=C\C(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 1-adamantyl carbonylchloride (31.8 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR, MS and LC/MS. MS (ESI) positive ion 332 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4](=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:5]([CH3:7])=O.[C:19]1(=[O:47])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:41])/[CH:37]=[C:38](\[NH2:40])/[CH3:39])[C:22](=[O:42])[C:21]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:20]12>CO>[CH3:7][C:5]1[NH:40][C:38]([CH3:39])=[C:37]([C:36]([O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:23]2[C:19](=[O:47])[C:20]3=[CH:46][CH:45]=[CH:44][CH:43]=[C:21]3[C:22]2=[O:42])=[O:41])[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: C/C(N)=C/C(=O)OCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCCCCCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Yield: 97.8 %

Procedure:
Prepared by a method analogous to that of Example 1(a) from 9.33 g (37.5 mmol) of 2-(3-nitrobenzylidene)-acetoacetic acid methyl ester and 15.00 g (37.5 mmol) of 3-amino-crotonic acid-(11-phthalimido-undecyl)ester. 23.18 g (98%) of yellow crystals, melting point 130°-132° C., obtained from methanol.
Reaction SMILES: [CH2:1]([O:8]CCOC1C=C(C2OC(=O)NCC2)C=CC=1OC)C1C=CC=CC=1.[CH3:27][C:28]([CH3:51])([CH:31]([OH:50])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)[CH:33]=1)[C:29]#[N:30]>>[CH3:27][C:28]1([CH3:51])[CH:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH:41]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42]3)[CH:33]=2)[O:50][C:1](=[O:8])[NH:30][CH2:29]1
Reactant: COc1ccc(C2CCNC(=O)O2)cc1OCCOCc1ccccc1
Reactant: COc1ccc(C(O)C(C)(C)C#N)cc1OC1Cc2ccccc2C1
Product: COc1ccc(C2OC(=O)NCC2(C)C)cc1OC1Cc2ccccc2C1
Yield: 75.9 %

Procedure:
According to the same procedure as in Example 1(2) to (3), using 2,2-dimethyl-3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrile instead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-described compound (yield 75.9%) was obtained as an off white solid.