Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1.[CH2:12]([NH2:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:20][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=[C:6]([Cl:11])[N:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: Nc1ccnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ccnc(Cl)c1C(=O)NCCc1ccccc1
Temperature: 20 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
4-Amino-2-chloro-nicotinic acid (1 g, 5.795 mmol) was dissolved in DMF (30 mL) and dichloromethane (50 mL). Phenethylamine (0.87 mL, 6.954 mmol, 1.2 equiv.) was added followed by TEA (1.21 mL, 8.693 mmol, 1.5 equiv.) and HBTU (2.64 g, 6.954 mmol, 1.2 equiv.) and the reaction stirred at 20° C. for 12 hours. The reaction mixture was then diluted with dichloromethane and the aqueous layer was extracted with 20% isopropyl alcohol/dichloromethane. The combined organic portions were washed with 0.5N NaOH solution, NH4Cl solution, water, brine, dried over anhydrous MgSO4, filtered and concentrated. The crude material was purified by column chromatography using 2:1 ethyl acetate:hexane to provide 1.23 g (77%) of product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])=[CH2:2].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CCOCC>[C:17]([O:10][C:6]1[CH:5]=[C:4]([C:1]([CH3:3])=[CH2:2])[CH:9]=[CH:8][CH:7]=1)(=[O:19])[CH3:18]
Reactant: C=C(C)c1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)c1cccc(OC(C)=O)c1
Yield: 94.6 %

Procedure:
250 g (1.86 mol) m-isopropenylphenol and 15 mL (0.19 mol) pyridine were placed in a four-neck flask equipped with a stirrer, reflux condenser, addition funnel, and thermometer. While stirring with cooling on a water bath, 200 mL (2.12 mol) acetic anhydride was dripped in. The reaction mixture was then diluted with ether and washed with water to neutrality. Drying and distillation afforded 310 g (1.76 mol) of the target material. The yield was 94%. The properties of this product are reported below.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(O[C:9](=[O:11])[CH3:10])(=O)C.[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[C:12]1([S:18]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:9](=[O:11])[CH3:10])=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
To a suspension of AlCl3 (144 g, 1.08 mol) in CH2Cl2 (1070 mL) was added acetic anhydride (54 mL). The mixture was stirred for 15 minutes before a solution of 1-(phenylsulfonyl)indoline (46.9 g, 0.180 mol) in CH2Cl2 (1070 mL) was added dropwise. The mixture was stirred for 5 h and was quenched by the slow addition of crushed ice. The organic layer was separated and the aqueous layer was extracted with CH2Cl2. The combined organics were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated under vacuum to obtain 1-(1-(phenylsulfonyl)indolin-5-yl)ethanone (42.6 g).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.[CH2:12](O)[CH3:13]>>[NH:1]1[C:5](=[O:7])[CH2:4][CH2:3][C@H:2]1[C:8]([O:10][CH2:12][CH3:13])=[O:9]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@@H]1CCC(=O)N1

Procedure:
A mixture of ethanol and glutamic acid was initially charged in a stirred vessel (A). The fraction of glutamic acid was 0.1% of the ethanol fraction. The mixture was conveyed continuously through the reactor (C) at a pressure of 72 bar by a suitable pump (B). The tubular reactor (C) was heated to a temperature of 260° C. by the heater (D). A carrier stream of pure ethanol from the reservoir (F) was heated to the same temperature using the preheater (G). At the mixing point (H), the carrier stream was mixed with the reactant stream (ratio 50/50) and fed to the reactor (C). The preheating temperature selected was so high that there was already reaction temperature at the mixing point, so that the temperature gradient in the reactor (C) was sufficiently small to prevent carbonization at the wall. The residence time in the tubular reactor (C) was 40 sec. With the aid of the control valve (E), the pressure was kept at the target value mentioned. At the outlet of the system, the reacted solution was introduced into 1 molar HCl. According to HPLC, 50% product yield (ethyl pyroglutamate) was obtained.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl:27][C:28]1[N:33]=[C:32]([Cl:34])[C:31]([CH2:35]I)=[CH:30][N:29]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:26])[CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][C:31]1[C:32]([Cl:34])=[N:33][C:28]([Cl:27])=[N:29][CH:30]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COC(=O)Cc1ccccc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of phenylacetic acid methyl ester (1.50 g, 10.0 mmol) (Aldrich) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-phenyl-propionic acid methyl ester as a colorless oil. (Yield 1.00 g, 64.5%).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Br:11])[C:3]=1[CH3:12].[Cu][C:14]#[N:15]>CN1CCCC1=O.ClCCl>[Br:11][C:4]1[C:3]([CH3:12])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: Cc1c(Br)ccc([N+](=O)[O-])c1Br
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1c(Br)ccc([N+](=O)[O-])c1C#N
Temperature: 150 °C

Procedure:
To a mixture of 2,6-dibromo-3-nitrotoluene (1.0 g, 3.4 mmol) in 14 ml of N-methylpyrrolidinone was added 0.323 g of freshly prepared copper (I) cyanide. The reaction was stirred and heated at a temperature of 150° C. under a nitrogen atmosphere for a period of three hours. After this period, the reaction mixture was cooled to room temperature, diluted with dichloromethane, and washed with 10% aqueous sodium thiosulfate solution. The organic layer was separated, dried, and concentrated under vacuum to remove the solvent. The residue was chromatographed on silica gel, eluting with 20% ethyl acetate/80% hexane, to afford 0.293 g of 3-bromo-2-methyl-6-nitrobenzonitrile as a yellow-white crystalline solid, mp 116°-118° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9](O)=[O:10]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]([Cl:3])=[O:10]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1Br
Reactant: O=S(Cl)Cl
Product: CCCCCCCOc1ccc(C(=O)Cl)cc1Br

Procedure:
11 g of thionyl chloride was added to 14.5 g (0.046 mol) of the 3-bromo-4-n-heptyloxybenzoic acid prepared in Step II and was gently refluxed for two hours. Excess thionyl chloride was removed by distillation or vacuum distillation to yield 14.2 of 3-bromo-4-n-heptyloxybenzoyl chloride. The yield was calculated to be 92.3%.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH2:23]=O>C(O)=O>[CH3:23][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH3:22])[N:12]=2)=[O:10])[CH2:4][CH2:3]1
Reactant: C=O
Reactant: CCCn1nc(C(=O)NC2CCNCC2)c2ccccc21
Agent: Cl
Solvent: O=CO
Product: CCCn1nc(C(=O)NC2CCN(C)CC2)c2ccccc21
Yield: 18 %

Procedure:
To N-(4-piperidyl)-1-n-propylindazole-3-carboxamide hydrochloride (0.32 g) obtained in Example 20 were added formic acid (0.7 ml) and a 36% aqueous solution of formaldehyde (0.3 ml), and the mixture was stirred at room temperature for 5 hours. Then formic acid (4 ml) and a 36% aqueous solution of formaldehyde (1.6 ml) were further added, and the mixture was heated under reflux for 2.5 hours. The reaction solution was distilled off under reduced pressure, and to the residue were added chloroform and aqueous ammonia. After extraction with chloroform, the chloroform layer was washed with-saturated aqueous sodium chloride, dried over anhydrous potassium carbonate, and distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol:aqueous ammonia=90:10:2) to give the title compound (0.06 g). Yield=18%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]=1[C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)c(-c2ccccc2Cl)s1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccccc2Cl)s1

Procedure:
5 g of the compound obtained in stage 23D) are added to 100 ml of CH2Cl2, cooling is carried out at −50° C. and 41.8 ml of 1M solution of BBr3 in CH2Cl2 are added. The temperature is allowed to return to 20° C. and then 20 ml of methanol are added. The mixture is concentrated to dryness and the residue is taken up in CH2Cl2, washed with water, dried over MgSO4 and concentrated to dryness. After purifying by chromatography on silica (heptane up to heptane/AcOEt 75/25), 4.57 g of the expected compound are obtained.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[C:13]([C:15]1[CH:16]=[C:17]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14].CI.Cl>C1COCC1>[C:13]([C:15]1[CH:16]=[C:17]([CH:22]([CH3:1])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:18]=[CH:19][C:20]=1[F:21])#[N:14]
Reactant: CC(C)NC(C)C
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)OC(C)(C)C)c1ccc(F)c(C#N)c1
Temperature: 0 °C

Procedure:
To a stirred solution of diisopropylamine in 2 ml of THF at −78° C. was added n-butyl lithium (0.61 ml). The reaction was stirred for 30 minutes after which time a solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (0.300 g) in THF (2 ml) was added dropwise over 20 minutes at −78° C. The reaction was warmed to 0° C. and then transferred a flask containing 2 ml THF and MeI (0.080 ml). The reaction was acidified with 2M HCl and extracted with ethyl acetate. The combined organics were then washed with brine and dried over MgSO4. The concentrated product was purified by silica gel chromatography using a solvent system of 5% to 50% ethyl acetate/hexanes to provide tert-butyl 2-(3-cyano-4-fluorophenyl)propanoate (0.140 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[C:9](=[O:16])[NH:10][CH:11]=[C:12]([F:15])[C:13]=1[I:14].Br[CH2:18][CH2:19][C@@:20]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1.C(O)(C)(C)C>[F:7][C:8]1[C:9](=[O:16])[N:10]([CH2:18][CH2:19][C@@:20]([CH3:30])([S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:11]=[C:12]([F:15])[C:13]=1[I:14]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Reactant: O=c1[nH]cc(F)c(I)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)c(F)c1=O)S(C)(=O)=O
Reaction time: 72 h
Yield: 32 %

Procedure:
Cesium carbonate (1.90 g, 5.84 mmol) was added to a solution of the 3,5-difluoro-4-iodopyridin-2(1H)-one (1.0 g, 3.9 mmol) and ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate, T1, (1.45 g, 5.06 mmol) in tetrahydrofuran:t-butanol (1:1, 50 mL). The resulting suspension was heated to reflux and was stirred at this temperature for 72 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (3×50 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography on an Analogix SF15-24 g column using an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS) m/z 463.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (s, 3H) 1.58 (s, 3H) 2.20 (dt, J=13.90, 7.00 Hz, 1H) 2.52-2.62 (m, 1H) 3.14 (s, 3H) 4.00 (t, J=7.61 Hz, 2H) 4.05-4.22 (m, 2H) 7.94 (dd, J=4.20, 2.05 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:46])[N:18]3[C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([O:12][C:13]2[C:22]([C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:27]=3)=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH2:16][C@H:17]([CH3:46])[N:18]3[C:41]([CH:43]2[CH2:45][CH2:44]2)=[O:42])[CH2:11][CH2:10][CH2:9]1
Reactant: C[C@H]1CCc2c(ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c2OC2CCC2)N1C(=O)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-c3cnn(C4CCNCC4)c3)c2OC2CCC2)N1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a 0° C. solution of (S)-tert-butyl 4-(4-(5-cyclobutoxy-1-(cyclopropanecarbonyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.032 g, 0.060 mmol) in dichloromethane (2.0 mL). The ice bath was removed, and the mixture stirred at rt for 1.5 h. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The layers were separated and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-(5-cyclobutoxy-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.022 g, 85%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.57-0.71 (m, 1H), 0.78-0.91 (m, 1H), 0.92-1.04 (m, 1H), 1.13 (d, J=6.45 Hz, 3H), 1.19-1.45 (m, 3H), 1.53-1.71 (m, 2H), 1.79-2.42 (m, 11H), 2.74-2.92 (m, 2H), 2.94-3.09 (m, 1H), 3.30 (br d, J=12.61 Hz, 2H), 4.04-4.21 (m, 1H), 4.28 (ddt, J=11.43, 7.62, 3.96, 3.96 Hz, 1H), 4.66-4.84 (m, 1H), 7.12 (d, J=8.21 Hz, 1H), 7.28 (d, J=8.21 Hz, 1H), 7.81 (s, 1H), 7.88 (s, 1H). MS (ESI, pos. ion) m/z 435 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:15]COCC>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCOCC
Product: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (3.00 g, 11.2 mmol) in Et2O (50 mL) was added a solution of CH2N2 in Et2O (2M, 50 mL, 100 mmol) at rt and the mixture was stirred for 10 min, concentrated and purified by CC (PE/EA=10/1) to give compound P42a (2.51 g, 80%) as a colorless oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:20])[CH2:16][CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][NH:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Reactant: CC(C)CCN
Product: CC(C)CCNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
Using the general method of Example 41, 4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and then reacted with isoamylamine (10.5 g, 0.12 mole) to provide the crude product as a yellow solid. This solid was recrystallized from hexane to provide the desired product as a solid, m.p. 99°-100° C. Analysis: Calculated: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 64.8; % H, 6.6; % N, 16.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][Cl:11]>C1(C)C=CC=CC=1>[Cl:11][CH2:10][CH2:9][CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: ClCCCN1CCOCC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
To a solution of morpholine (2.00 g, 23.0 mmol) in toluene (200 mL), was added 1-bromo-3-chloropropane (4.55 mL, 45.9 mmol) and the mixture was stirred for 4 h at 70° C. Insoluble materials were removed by filtration and the filtrate has been concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane=70/30→100/0) to give the title compound (1.27 g, 68%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](Cl)=[O:8])=[C:5]([CH3:10])[O:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[N:24][C:25]=3[NH2:27])[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:30][CH2:29]3)[N:19]=2)=[CH:14][C:13]=1[O:41][CH3:42]>N1C=CC=CC=1>[NH2:27][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:20]([C@H:28]3[CH2:33][CH2:32][C@@H:31]([N:34]4[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]4)[CH2:30][CH2:29]3)[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:10])=[O:8])=[C:13]([O:41][CH3:42])[CH:14]=3)[C:26]=12
Reactant: Cc1noc(C)c1C(=O)Cl
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1c(C)noc1C
Reaction time: 5 h

Procedure:
3,5-dimethyl-4-isoxazolecarbonyl chloride (22 mg, 0.137 mmol) was added to a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.067 mmol) in pyridine (0.5 mL). After 5 hours, the solvent was evaporated and the residue was re-crystallized from DMSO to give cis-N4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3,5-dimethyl-4-isoxazolecarboxamide (33 mg, 87%). 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.24 (m, 2H), 2.36 (m, 2H), 2.41 (s, 3H), 2.63 (s, 3H), 2.77 (m, 3H), 3.17 (s, 3H), 3.37 (bm, 8H), 3.95 (s, 3H), 4.95 (m, 1H), 7.37 (m, 2H), 8.17 (d, J=8.17, 1H), 8.30 (s, 1H), 9.26 (s, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.), MH+=560.2, Rt=2.44 min.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH3:63]>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([N:62]([CH3:63])[CH3:61])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CNC
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)N(C)C)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (60 mg, 0.09 mmol) in THF (2 mL) was added polystyrene-carbodiimide (156 mg, 0.18 mmol), 1-hydroxybenzotriazole hydrate (18 mg, 0.13 mmol) and dimethylamine (0.09 mL, 0.13 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The reaction was filtered through a micro filter and concentrated. The crude material was purified by preparative TLC (9:1, methylene chloride/methanol) to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-N,N,3-trimethyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide as a mixture of diastereomers (8.0 mg, 13%) and as a red solid: 1H NMR (500 MHz, CDCl3) δ 14.18 (s, 1H), 8.16 (s, 1H), 6.85 (d, J=9.0 Hz, 0.8H), 6.57 (s, 1H), 6.28-6.24 (m, 0.2H), 6.20 (s, 0.2H), 5.87 (s, 0.8H), 5.14-5.08 (m, 1H), 5.00-4.94 (m, 1H), 4.71-4.66 (m, 1H), 4.62-4.56 (m, 1H), 3.79 (s, 3H), 3.75-3.68 (m. 2H), 3.61 (s, 3H), 3.59-3.52 (m, 3H), 3.41 (s, 3H), 3.38-3.28 (m, 2H), 3.13 (t, J=9.0 Hz, 1H), 2.92 (s, 6H), 2.14 (s, 3H), 3.14 (d, J=6.0 Hz, 3H); MS (ESI−) m/z 709 (M−H); HPLC 95.6% (AUC), tR 11.51 min.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[O:9]1[C:13]2([CH2:18][CH2:17][CH:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:28]([CH:29]=3)=[C:27](F)[CH:26]=[CH:25][C:24]=4[CH3:31])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.C1OCCOCCOCCOCCOC1>C1COCC1.CS(C)=O>[CH:1]1([O:6][C:27]2[CH:26]=[CH:25][C:24]([CH3:31])=[C:23]3[C:28]=2[CH:29]=[C:20]([NH:19][CH:16]2[CH2:17][CH2:18][C:13]4([O:12][CH2:11][CH2:10][O:9]4)[CH2:14][CH2:15]2)[N:21]=[CH:22]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCC1
Reactant: Cc1ccc(F)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Cc1ccc(OC2CCCC2)c2cc(NC3CCC4(CC3)OCCO4)ncc12
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
In a dry box, in a microwave test tube cyclopentanol (600.0 mg, 7.0 mmol) was dissolved in 5 ml of THF. To this solution was added the NaH (273.0 mg, 11.4 mmol) at room temperature and the mixture was stirred for 30 min. N-1,4-dioxaspiro[4.5]dec-8-yl-5-fluoro-8-methylisoquinolin-3-amine (1.8 g, 5.7 mmol) mixed with 15-crown-5 ether (0.13 g, 0.57 mmol) in 15 ml of DMSO was added to above solution. The microwave test tube was capped and moved out from the dry box. The tube was placed into Microwave apparatus and heated to 140° C. for 2 hours. The crude product was purified using a silica gel column to give 263.0 mg (yield 53%). 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.89 (m, 1H), 1.17-1.40 (m, 2H), 1.57-2.02 (m, 10H), 2.05-2.29 (m, 2H), 2.47-2.63 (m, 3H), 3.54-3.78 (m, 1H), 3.90-4.06 (m, 4H), 4.64-5.02 (m, 2H), 6.46-6.77 (m, 1H), 6.79-6.98 (m, 2H), 7.20-7.43 (m, 1H), 8.91 (s, 1H). MS m/z, (APCI); 383.2 ([M+H]+).