Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[CH2:5][CH:6]([OH:11])[CH2:7][CH2:8][CH:9]=[CH2:10])[CH3:2].[H-].[Na+].[CH3:17]I.[Cl-].[NH4+]>O.CN(C=O)C>[CH2:13]([O:12][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([O:11][CH3:17])[CH2:7][CH2:8][CH:9]=[CH2:10])[CH3:14]
Reactant: CI
Reactant: C=CCCC(O)CC(OCC)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(CC(OCC)OCC)OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
DMF (30 mL) was added to 1,1-diethoxy-hept-6-en-3-ol obtained in Preparation Example 57-(1) (3.07 g), and the mixture was cooled in an ice bath under a nitrogen atmosphere. Then, sodium hydride (60% 699 mg) was added, followed by stirring for 10 minutes. Methyl iodide (1.8 mL, specific gravity: 2.28 g/cm3) was added, followed by stirring for one hour and 50 minutes. Then, the mixture was warmed to room temperature and further stirred for one hour and 30 minutes. Sodium hydride (60%, 300 mg) and methyl iodide (0.9 mL, specific gravity: 2.28 g/cm3) were further added, followed by stirring for two hours and 30 minutes. Then, water and a saturated ammonium chloride solution were slowly added, followed by stirring for a while. After extraction with ethyl acetate, the organic layer was sequentially washed with a saturated ammonium chloride solution, water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.98 g).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([N:46](C([C@H]2N(C(C(O)C)=O)CCC2)=O)[CH3:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4].C(Cl)(Cl)Cl>CO>[CH3:1][CH2:2][C@@H:3]([C@H:5]1[NH:37][C:35](=[O:36])[C@@H:34]([NH:38][C:39]([C@H:41]([NH:46][CH3:47])[CH2:42][CH:43]([CH3:44])[CH3:45])=[O:40])[C@@H:33]([CH3:60])[O:32][C:30](=[O:31])[C@H:29]([CH2:61][C:62]2[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=2)[N:28]([CH3:70])[C:26](=[O:27])[C@H:25]2[N:21]([CH2:22][CH2:23][CH2:24]2)[C:19](=[O:20])[C@H:18]([CH2:71][CH:72]([CH3:74])[CH3:73])[NH:17][C:15](=[O:16])[C@@H:14]([CH3:75])[C:12](=[O:13])[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10][C:8](=[O:9])[CH2:7][C@@H:6]1[OH:79])[CH3:4]
Reactant: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)O)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)NC)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O

Procedure:
A similar isolation scheme was employed later during large scale production of didemnin B for biological testing. The dichloromethane extract was obtained as before with only minor modifications due to scale-up. Prep LC employed an isocratic chloroform:methanol solvent system ranging from 98:2 to 96:4 depending on the condition of the reusable PrepPak cartridge. This allowed the use of the built-in refractive index detector to monitor elution of the didemnins. Fractions obtained through this procedure were chromatographed on a reversed phase (ODS) PrepPak cartridge with 77:23 methanol:water, again monitoring with the refractive index detector. Pooling of the appropriate fractions gave yields of didemnins A-C similar to those obtained with the original procedure. Didemnins D and E could only be separated by HPLC as above.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].C(O)C.[CH3:11][C:12]1[NH:13][CH:14]=[C:15]([CH:17]=O)[N:16]=1>C(O)C.C(O)(=O)C>[CH2:6]([O:5][C:1](=[O:4])[NH:2][N:3]=[CH:17][C:15]1[N:16]=[C:12]([CH3:11])[NH:13][CH:14]=1)[CH3:7]
Reactant: Cc1nc(C=O)c[nH]1
Reactant: CCOC(=O)NN
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)NN=Cc1c[nH]c(C)n1

Procedure:
A solution of 16.68 gm. of ethyl carbazate in 50 ml. of hot ethanol is added to a solution of 16.50 gm. of 2-methyl-4-imidazolecarboxaldehyde in 100 ml. of hot ethanol containing 2 drops of acetic cid. The reaction is carried out as described in Example 32 giving the desired product, m.p. 210.5°-211.5° C.
Reaction SMILES: [C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH2:6])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[CH:19][CH:18]=1.CCOCC>C(Cl)Cl>[C:1]([N:5]([C:7]([C:9]1[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)=[O:8])[NH:6][C:27]([NH:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)(=[O:24])=[O:25])=[O:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cccc(C(=O)N(NC(=O)NS(=O)(=O)c2ccc(Cl)cc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N'-t-butyl-N'-3-toluoyl hydrazine (4.03 g, 0.02 mol) in methylene chloride (25 ml) under nitrogen was added 4-chlorobenzenesulfonyl isocyanate (5 g, 80%, 0.02 mol) at room temperature. The exothermic reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to give an oil. A precipitate appeared after treating with ether. The pure product was collected by suction-filtration and washed with a small amount of ether affording 4.8 g of 1-t-butyl-1-(3-toluoyl)-4-(4-chlorobenzenesulfonyl)semicarbazide as a white solid: m.p. 184°-188° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][N:11]=[C:4]2[CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[N:5]2[C:6]([CH3:8])=[CH:7][C:2]([C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=3[CH3:30])[C:23]([NH:22][CH:19]3[CH2:20][CH2:21]3)=[O:40])=[CH:3][C:4]2=[N:11][N:10]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Cl)cc2nnc(-c3ccccc3Cl)n12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C)n2c(-c3ccccc3Cl)nnc2c1
Temperature: 140 °C
Yield: 239.9 %

Procedure:
In a microwave tube was placed 7-chloro-3-(2-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridine (0.061 g, 0.22 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.086 g, 0.29 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.013 g, 0.018 mmol) and sodium carbonate monohydrate (0.16 g, 1.3 mmol) in 1 mL of DME and 0.4 mL of water. The mixture was heated in the microwave at 140° C. for 15 min. Water was then added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 220 mg of a brown oil. The crude material was purified by silica gel chromatography (0-5% MeOH in DCM) to afford the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 417.2 (M+1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:32]=[N:31][C:18]3[N:19]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:20][CH2:21][C:22]([C:24](O)=[O:25])=[CH:23][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:44][N:45]([CH2:52][C:53]1[CH:59]=[CH:58][C:56]([NH2:57])=[CH:55][CH:54]=1)[CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1>ClCCl.N1C=CC=CC=1.O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:32]=[N:31][C:18]3[N:19]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:20][CH2:21][C:22]([C:24]([NH:57][C:56]4[CH:58]=[CH:59][C:53]([CH2:52][N:45]([CH3:44])[CH:46]5[CH2:51][CH2:50][O:49][CH2:48][CH2:47]5)=[CH:54][CH:55]=4)=[O:25])=[CH:23][C:17]=3[CH:16]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOCCOc1ccc(-c2cnc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxylic acid (130 mg) in dichloromethane (10 ml) were added a drop of DMF. Then, oxalyl chloride (0.034 ml) was added thereto, and the mixture was stirred for 1 hour under a nitrogen atmosphere. The resulting solution was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (85 mg) in pyridine (10 ml) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the resulting residue was purified by basic silica gel column chromatography (methanol:ethyl acetate=1:8) to give 3-[4-(2-butoxyethoxy)phenyl]-9-isobutyl-N-[4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-8,9-dihydro-7H-pyrido[2,3-b]azepine-6-carboxamide (167 mg) (Compound 4) as a yellow amorphous material.
Reaction SMILES: [CH:1]1[C:10]([OH:11])=[C:6]([CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][C:2]=1[CH3:3].C(O)(=O)C.S(=O)(=O)(O)O.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>O.CCCCCC>[CH3:22][C:21]([C:5]1[C:6]([CH:7]([CH3:9])[CH3:8])=[C:10]([OH:11])[CH:1]=[C:2]([CH3:3])[CH:4]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C(C)C)c(O)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: Cc1cc(O)c(C(C)C)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
Thymol (360.0 g, 2.4 mol) was added to a cooled (0° C.) mixture of acetic acid (600 mL) and sulfuric acid (144 mL). The mixture was allowed to warm to 20°-25° C., after which, t-butanol (228 mL, 2.4 mol) was added dropwise over a one hour period. The mixture was stirred at 25° C. for one hour. An additional portion of t-butanol (114 mL, 1.2 mol) was then added dropwise over a one hour period. The mixture was stirred at 25° C. for 4 hours after which the mixture was poured into hexane (1 L) and water (1 L) and the layers separated. The aqueous layer was extracted with hexane (2×100 mL). The combined extracts were washed with water (3×200 mL), saturated sodium bicarbonate solution (2×100 mL), water (200 mL) and brine (2×100 mL). The solvents were evaporated and the residue distilled to provide 262 g (bp 135°-145° C., 6 mm) of material which was crystallized from hexane to give 215.2 g (43% yield, GLC purity 99.5%) of 4-(1,1-dimethylethyl-2-(1-methylethyl)-5-methylphenol; mp 75.5°-76.5° C.; 1H-NMR (CDCl3)δ 1.24 (6H, d, J=7 Hz), 1.38 (9H, s), 2.42 (3H, s), 2.95-3.42 (1H, m), 4.67 (1H, broad s), 6.48 (1H, s), 7.13 (1H, s); IR (CHCl3)νmax 3575, 3340, 2940, 1605, 1670, 1490, 1450, 1400 cm-1 ; MS m/e 206, 191, 149, 121; UVλmax (ethanol) 223 nm (ε=5650), 253 nm (ε=2260).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]3[C:11]([CH3:24])=[N:12][C:13]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)=[C:8]3[CH:7]=[N:6][C:5]=2[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[C:10]2[N:9]3[C:11]([CH3:24])=[N:12][C:13]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:18][CH:19]=4)=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(c(Br)cn3[Si](C(C)C)(C(C)C)C(C)C)n12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3[nH]cc(Br)c3n12
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a mixture of 2-(4-(8-bromo-1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.300 g, 0.554 mmol; Preparation #AD.1) in THF (5 mL) was added TBAF (0.504 mL, 0.554 mmol). The mixture was stirred at about rt for about 1 h and then was partitioned between DCM (50 mL) and water (25 mL). The layers were separated and the aqueous phase was extracted with DCM (3×20 mL). The combined organic phases were washed with brine (100 mL) and then the solid was collected by filtration to give 2-(4-(8-bromo-1-methyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.082 g, 39%). LC/MS (Table 2, Method a) Rt=1.87 min.; MS m/z: 387 (M+H)+. Syk IC50=A.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([C:10](=[O:12])[CH3:11])[N:4]2[C:3]=1[CH3:13].[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C[O-].[Na+]>C1COCC1>[CH3:1][C:2]1[S:6][C:5]2=[N:7][CH:8]=[C:9]([C:10](/[CH:11]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[N:4]2[C:3]=1[CH3:13]
Reactant: CC(=O)c1cnc2sc(C)c(C)n12
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1sc2ncc(C(=O)/C=C/c3ccccc3)n2c1C
Temperature: 0 °C

Procedure:
A solution of 1-(2,3-dimethylimidazo[2,1-b]thiazole-5-yl ethanone (See procedures from Preparation 6) (Formula D-1) (0.87 g) in THF (25 mL) was treated with benzaldehyde (0.52 mL) and sodium methoxide (0.11 g). After 18 hours trace 1-(2,3-dimethylimidazo[2,1-b]thiazol-5-yl ethanone remained and additional benzaldehyde (0.2 mL) was added. After an additional 2.5 hours the reaction was diluted with ice water and precipitated 2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone (FIG. D-2) (1.03 g) was filtered. Crystallization from isopropanol solution gave pure 2,3-Dimethyl-(2-phenyl-E-ethenyl)imidazo[2,1-b]thiazol-5-yl methanone (FIG. D-2), m.p. 189-190°.
Reaction SMILES: [F:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=[O:4].C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1>CC(O)C>[F:1][C@:2]([C:7]1[CH:8]=[CH:9][C:10]([O:13][S:14]([C:17]([F:18])([F:20])[F:19])(=[O:16])=[O:15])=[CH:11][CH:12]=1)([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: CC(F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CC(C)O
Product: C[C@@](F)(C(=O)O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Yield: 39393.9 %

Procedure:
To a solution of 1 (9.38 g, 29.7 mmol) in 2-propanol (150 ml), cinchonidine (8.73 g, 29.7 mmol) was added under vigorous stirring and the resulting mixture was left under reflux until to complete dissolution. After cooling at room temperature the formed precipitate was filtered off and the mother liquors were crystallized again from 2-propanol (50 mL). The collected precipitated salts (8.72 g) were dissolved in water (70 mL) and 37% HCl (2 mL) was added; the aqueous layer was extracted with CH2Cl2 (2×70 mL), dried over Na2SO4 and evaporated under vacuum to give the pure (2S)-2-fluoro-2-(4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)propanoic acid (3.7 g, 11.7 mol) as pale brown solid. Yield 79%. mp 91-94° C. e.e. 96% (HPLC). [α]D=+19.8 (c=0.6; CH3OH). 1H-NMR (CDCl3) δ 7.70 (d, 2H, J=7 Hz), 7.40 (d, 2H, J=7 Hz), 2.00 (d, 3H, J=23 Hz).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH2:34]([CH2:36][NH2:37])[OH:35]>>[OH:35][CH2:34][CH2:36][NH:37][C:29](=[O:30])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: NCCO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)NCCO
Yield: 80.8 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with ethanolamine (0.26 ml, 4.3 mmol) to give the title compound as a solid (170 mg, 80%), except that the mixture was heated at 45° C. for 20 hours. NMR Spectrum 1.65 (d, 3H), 3.22 (m, 2H), 3.43 (m, 2H), 4.75 (t, 1H), 5.23 (q, 1H), 5.79 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.72 (m, 3H), 8.11 (s, 1H), 8.48 (m, 1H), 8.51 (s, 2H), 9.04 (s, 1H), 10.72 (br s, 1H); Mass spectrum MH+ 490.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Clc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To 150 ml of chlorobenzene, 100.1 g (0.75 mol) of aluminum chloride was added, and further 143 g (0.75 mol) of p-toluenesulfonyl chloride was added dropwise over 1 hour. After stirred for 3 hours at 55° C., the reaction mixture was poured into 1.5 liter of water, and then the obtained crystal was filtered off and washed with n-hexane to obtain 140 g of the intended 4-methyl-4'-chlorodiphenylsulfone. NMR (heavy chloroform): δ7.9-7.8 (m, 4H), 7.5 (m, 2H), 7.3 (d, 2H), 2.4 (s, 3H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.CC1C=CC(S(O[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:23])(=O)=O)=CC=1.O>CN(C=O)C>[CH3:23][C@H:22]([NH:24][C:25](=[O:26])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][O:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1
Reactant: Oc1ccncc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 20.7 %

Procedure:
To a suspension of sodium hydride (oil, 60%, 1.61 g) in DMF (50 mL) was added 4-hydroxypyridine (3.83 g) under ice-cooling. The reaction mixture was stirred for 30 min under ice-cooling, and (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (13.3 g) was added thereto in small portions under ice-cooling. The reaction mixture was stirred for 2 hr under ice-cooling, and at 60° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[NH:4][CH:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1>C(O)C.Cl.[Fe]>[NH2:20][C:16]1[CH:15]=[C:14]([CH:3]2[C:2]([CH3:1])([CH3:23])[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=3)[NH:4]2)[CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)Cc2cc(C#N)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1(C)Cc2cc(C#N)ccc2NC1c1cccc(N)c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
To a mixture of 3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (4 g, 13 mmol) in ethanol 95% (150 mL) and 10% hydrochloric acid (10 mL) was added iron (2.18 g, 39.2 mmol). The reaction mixture was stirred at 95° C. for 6 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (0.9 g, 25%) as a yellow solid: LC/MS m/e calcd for C18H19N3 (M+H)+: 278.37, observed: 278.1.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:9]=[C:8]3[N:22]([CH3:24])[CH3:23])[CH2:3][CH2:2]1.[C:25](O)(=[O:27])[CH3:26].C(Cl)(=O)C.[OH-].[Na+]>C(OCC)(=O)C>[CH:1]1([N:4]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[N:11]=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:9]=[C:8]3[N:22]([CH3:24])[CH3:23])[C:25](=[O:27])[CH3:26])[CH2:3][CH2:2]1
Reactant: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(NC3CC3)cc12
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CC(=O)N(c1ccc2nc(-c3cccc(F)c3)cc(N(C)C)c2c1)C1CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared by acetylation at the 6-nitrogen as follows. Into a 50 mL round-bottom flask equipped with a magnetic stirrer, condenser silicone oil bath and nitrogen inlet, was placed 750 mg (2.33 mmoles) of N6-cyclopropyl-N4,N4-dimethyl-2-[3-fluorophenyl]-4,6-quinolinediamine. To this was added 5 mL of glacial acetic acid. After the material dissolved, 202 mg (2.57 mmoles, 1.1 equiv.) of acetyl chloride was added. The mixture was stirred at room temperature for 1 hr, then heated to 60° C. for 2 hr. At the end of this time the reaction was cooled and poured into a 1 L separatory funnel containing 300 mL ethyl acetate and 500 mL of 1 N NaOH solution. The organic layer was separated, washed with NaOH solution, dried over Na2SO4, filtered and concentrated. The residue was then crystallised from methylene chloride and hexane to give 550 mg (65%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:19]=[C:18]2[N:9]([CH2:10][C:11](=[O:20])[N:12]3[N:17]2[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8](=[O:21])[C:7]=1[O:22]CC1C=CC=CC=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:19]=[C:18]2[N:9]([CH2:10][C:11](=[O:20])[N:12]3[N:17]2[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8](=[O:21])[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N1CCCCN21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N1CCCCN21

Procedure:
A solution of intermediate 24, 2-benzyloxy-1,9-dioxo-5,6,7,8,9,10-hexahydro-1H-4,4b,8a, 10a-tetraaza-phenanthrene-3-carboxylic acid ethyl ester (0.396 g, 1.0 mmol) in trifluoroacetic acid (5 mL) was stirred for 18 hours. The reaction was dried in vacuo to give the title compound as an oil which partially crystallized upon standing. 1H NMR (500 MHz, CDCl3) δ ppm: 10.35 (1H, br s), 4.63 (2H, s), 4.45 (2H, q, J=7.0 Hz), 3.83–3.88 (2H, m,), 3.72–3,76 (2H, m), 1.90–1.97 (2H, m), 1.76–1.83 (2H, m), 1.43 (3H, t, J=6.7 Hz). HRMS (ESI) calcd for C13H17N4O5 (M+H) 309.1199. found 309.1207.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH:26]1([C:29]([N:31]2[CH2:36][CH2:35][CH:34]([C:37](O)=[O:38])[CH2:33][CH2:32]2)=[O:30])[CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([C:37]([CH:34]3[CH2:33][CH2:32][N:31]([C:29]([CH:26]4[CH2:28][CH2:27]4)=[O:30])[CH2:36][CH2:35]3)=[O:38])[CH2:12][C@H:11]2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH3:9])=[O:7])=[CH:24][CH:25]=1
Reactant: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)C2CC2)CC1
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)C2CCN(C(=O)C3CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 633, step 3 and 1-(cyclopropylcarbonyl)piperidine-4-carboxylic acid, and by the reaction and purification in the same manner as in Example 97, the title compound was obtained.