Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C=CC=CC=1.[C:32](Cl)(=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>C(N(CC)CC)C>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]([NH:25][C:32](=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([CH3:24])[CH3:23])=[O:19])[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)(N)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C)(C)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 4 h

Procedure:
In a 500 ml, three-neck, round-bottom flask equipped with a thermometer, stirrer and dropping funnel were placed 26 g (0.75 mole) of 2-amino-2-methylpropyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate, 200 ml of benzene and 8.2 g of triethylamine. To this stirred mixture was added 22.5 g (0.075 mole) of stearoyl chloride, and the mixture stirred for 4 hours. The triethylamine hydrochloride was removed by filtration and the solvent was stripped off. The residue was dissolved in hot hexane. After crystallization, filtration and drying, the title compound melted at 46°-48° C.
Reaction SMILES: P(=O)(O)(O)O.[Cl:6][C:7]1[S:11][C:10]([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.C(O)(=O)C>O>[Cl:6][C:7]1[S:11][C:10]2[CH2:12][CH2:13][CH2:14][C:15](=[O:17])[C:9]=2[CH:8]=1
Reactant: O=C(O)CCCc1ccc(Cl)s1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2sc(Cl)cc21
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
First 0.096 ml (1.41 mmol) of orthophosphoric acid and then 4.12 g (20.14 mmol) of 4-(5-chloro-2-thienyl)butanoic acid are added to 5 ml of acetic acid, and the mixture is stirred at 120° C. for 2.5 h. The cooled reaction mixture is added to water and extracted with dichloromethane, and the extract is washed with 2 M NaOH. After washing with water, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The residue is extracted with diethyl ether. Undissolved crystals are filtered off with suction and discarded. The ether phase is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate). This gives 1.07 g of 2-chloro-6,7-dihydro-1-benzothiophen-4(5H)-one.
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[N:5]=[C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=[C:7]2[N:8]=1.[CH3:14]OS(=O)(=O)OC>CO>[CH3:14][S:3][C:4]1[N:8]=[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[N:5]=1
Reactant: Sc1nc2cccccc-2n1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc2cccccc-2n1
Temperature: 45 °C
Yield: 81.9 %

Procedure:
38 g of potassium hydroxide was dissolved in 800 ml of methanol and then 100 g of 2-mercaptocycloheptimidazole was added thereto and stirred under heating at an internal temperature of about 45° C. Next, 131.2 g of dimethylsulfuric acid was dropwise added and further stirred under heating at an internal temperature of about 45° C. for 1 hour. After the solvent was evaporated off to some degree under reduced pressure, one liter of water was added, and the resulting solution was extracted with chloroform (0.5 liter×2). Then, the chloroform layer was dried with anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure until the chloroform solution became 200 ml. Next, one liter of hexane was added to the thus concentrated solution whereby a precipitate crystallized out. This was separated by filtration and dried. 89 g of colorless crystals was obtained.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:13]2[C:17]([C:18]([O:20]C)=[O:19])=[C:16]([C:22]([O:24]C)=[O:23])[S:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].Cl>O>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C:13]2[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:22]([OH:24])=[O:23])[S:15][N:14]=2)[CH:4]=[C:3]([C:2]([F:1])([F:27])[F:26])[CH:8]=1
Reactant: COC(=O)c1snc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C(=O)O

Procedure:
A mixture of 14.7 g (0.0356 mol) of dimethyl 3-(α,α,α,α',α',α'-hexafluoro-3,5-xylyl)-4,5-isothiazoledicarboxylate, 7.2 g (0.18 mol) of NaOH, and 45 ml of water was held at reflux for 2 hours, was cooled, extracted twice with ether, and acidified with 30 ml (0.36 mol) of concentrated HCl The resultant mixture was extracted three times with ether; these ether extracts were combined, dried (CaSO4), and concentrated under vacuum to 12.8 g (93.4%) of white solid, m.p 193°-193.5° with decomposition.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:30]=[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:30]=[C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:20]
Reactant: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCCCCCCCOc1ccc(C(=O)c2ccccc2)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 120 °C
Reaction time: 6 h
Yield: 37 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), 2-hydroxy-4-n-octoxybenzophenone (652 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. for 6 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (85 mg, yield 33%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[CH:11]=[CH:10]1>C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([N:1]2[C:12](=[O:13])[CH:11]=[CH:10][C:9]2=[O:14])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1cccc(O)c1
Solvent: CC(=O)O
Product: O=C1C=CC(=O)N1c1cccc(O)c1
Temperature: 25 °C
Yield: 37 %

Procedure:
A 54.57 gram portion of m-aminophenol (0.50 mole) and 650 milliliters of acetic acid were added to a reactor and maintained under a nitrogen atmosphere with stirring. The stirred solution was maintained at 25° C., then 49.03 grams of maleic anhydride (0.50 mole) dissolved in 100 milliliters of acetic acid was added to the reactor and heating to 110° C. commenced. The 110° C. reaction temperature was maintained for 14 hours (50,400 s), then the product was dried under vacuum by rotary evaporation at 120° C. for 30 minutes (1800 s) to a dark brown solid. The crude product was extracted with two 250 milliliter portions of o-dichlorobenzene at 120° C. The combined extracts were maintained at 2° C. for 24 hours (86,400 s) then the light yellow orange colored crystalline product was recovered by filtration and dried under vacuum at 60° C. for 24 hours (86,400 s) to provide 35.0 grams of N-(3-hydroxyphenyl) maleimide. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[NH:9][CH2:10][CH2:11][N:12]([C:22]2[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)[N:23]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](Cc3ccccc3)C2)nc(-c2ccncc2)cc1=O
Yield: 81.4 %

Procedure:
To a solution of (S)-2-benzylpiperazine (48 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was added triethylamine (0.10 mL, 0.74 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (55 mg, 0.248 mmol) at room temperature. After refluxing for 24 h, the resulting mixture was concentrated in vacuo. The residue was partitioned between dichloromethane and saturated sodium bicarbonate aqueous solution, and the organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by a reverse phase chromatography eluting 0.05% TFA in water-acetonitrile to afford (S)-2-(3-benzylpiperazin-1-yl)-3-methyl-6-(4-pyridyl) pyrimidin-4-one (73 mg 81%), which was treated with 4 N hydrogen chloride in ethyl acetate to yield its dihydrochloride salt as a yellow powder.
Reaction SMILES: OO.[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:5])[CH3:4].S([O-])([O-])=[O:16].[Na+].[Na+]>C(O)(=O)C>[C:3]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=1[O-:16])(=[O:5])[CH3:4]
Reactant: O=S([O-])[O-]
Reactant: CC(=O)NCCc1ccccn1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)NCCc1cccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
30 wt % Hydrogen peroxide (80.3 ml) was added dropwise to a solution of 2-(2-acetylaminoethyl)pyridine (64.5 g) in acetic acid (65 ml) at 70°-75° C. and the mixture was stirred at the same temperature for 8 hours. After the mixture was ice-cooled and the mixture was added to a mixture of sodium sulfite (56.9 g) in ice water (200 ml). The solvent was removed by concentration in vacuo and the residue was extracted with a tetrahydrofuran. The extract solution was dried over magnesium sulfate and evaporated to give 2-(2-acetylaminoethyl)pyridine N-oxide (70.82 g).
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:13]1[CH:14]=[N:15][CH:16]=[C:17](Cl)[C:18]=1[CH2:19][CH:20]([C:22]1[C:27]2[CH2:28][C:29](C)(C)[O:30][C:26]=2[C:25]([O:33][CH3:34])=[CH:24][CH:23]=1)O>CO>[CH3:34][O:33][C:25]1[C:26]2[O:30][CH2:29][CH:28]([CH3:1])[C:27]=2[C:22]([CH2:20][CH2:19][C:18]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(C(O)Cc2c(Cl)cncc2Cl)c2c1OC(C)(C)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(CCc2ccncc2)c2c1OCC2C
Yield: 68.4 %

Procedure:
p-Toluenesulfonic acid (1.0 g) was added to a solution (50 ml) of Compound 45a (2.0 g) obtained in Step A of Example 45 in methanol at room temperature, followed by heating under reflux. The reaction solution was cooled and then the solvent was distilled off under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added to the residue, followed by extraction with chloroform. The organic layer was washed with a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give Compound 57 (1.0 g, 48.2%) as a pale-yellow oily substance.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9](=[O:12])[NH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>CC(C)=O>[C:1]1([C:7]2[S:8][C:9](=[O:12])[N:10]([CH2:21][C:20]#[CH:19])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#CCBr
Reactant: O=c1[nH]nc(-c2ccccc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCn1nc(-c2ccccc2)sc1=O
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To the solution of 2-phenyl-1,3,4-thiadiazolin-5-one (3 g, 16.85 mmole) in dry acetone (30 ml) under nitrogen with magnetic stirring was added potassium carbonate (3 g, 22 mmole), followed by propargyl bromide (3 g, 80% in toluene, 20 mmole) at room temperature. The mixture was refluxed for one hour. The reaction mixture was cooled down to room temperature and the solid was filtered off by suction-filtration. The filtrate was diluted with ether (200 ml) and washed with water (2×50 ml) and brine. The organic layer was dried over sodium sulfate. After the drying agent was filtered off the filtrate was concentrated to about 5 ml. Hexane was added to precipitate out the product. The product was collected by suction-filtration and washed with a little hexane to afford 2 g of 2-phenyl-4-propargyl-1,3,4-thiadiazolin-5-one as a powder. m.p.=73°-75° C.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9]([OH:20])([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:8][CH2:7]1)=O)C.[OH-].[K+]>C(O)CCC>[OH:20][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(O)(c2ccc(Cl)c(Cl)c2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: OC1(c2ccc(Cl)c(Cl)c2)CCNCC1
Yield: 90 %

Procedure:
A mixture of 64.2 g of 1-ethoxycarbonyl-4-hydroxy-4-(3,4-dichlorophenyl)piperidine (X-1) and a solution of 72.4 g of KOH in 700 ml of nBuOH is refluxed for 2 hours and evaporated. The reaction mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated. The resulting crystalline residue is recrystallized from ethyl acetate to prepare 44.7 g (Yield: 90.0% of the compound (II-1). mp. 144.5°-146.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[C@H:12]([CH2:17][NH2:18])[CH2:11]2)=[CH:4][CH:3]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH:29]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:39][N:38]1[C:34]([C:30]2[CH:29]=[C:28]([NH:27][C:26]([NH:18][CH2:17][C@H:12]3[C@@H:13]([CH3:16])[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:11]3)=[O:25])[CH:33]=[CH:32][CH:31]=2)=[N:35][N:36]=[N:37]1
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: C[C@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(CCc2ccc(F)cc2)C[C@H]1CNC(=O)Nc1cccc(-c2nnnn2C)c1
Reaction time: 18 h
Yield: 75.2 %

Procedure:
A solution of cis-1-[2-(4-fluorophenyl)ethyl]-4-methyl-piperidin-3-ylmethylamine (54 mg, 215 μmol) and [3-(1-methyl-1H-tetrazol-5-yl)phenyl]-carbamic acid phenyl ester (64 mg, 215 μmol) in N,N-dimethylformamide (2 mL) was treated with triethylamine (60 μL, 431 μmol). After 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane containing 0.3% aqueous ammonium hydroxide, to provide an amorphous solid (73 mg, 75%). 1H NMR (300 MHz, CDCl3) δ7.95 (s, 1H), 7.64 (d, J=7 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.29 (m, 1H), 7.11 (m, 2H), 6.97 (t, J=9 Hz, 2H), 4.17 (s, 3H), 3.42 (m, 1H), 3.26 (m, 1H), 3.1-2.5 (m, 8H), 2.1-1.6 (m, 4H), 0.99 (d, J=7 Hz, 3H). Mass spec (AP+) m/z 452.1 (M+H+).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]([CH3:31])([CH3:30])[CH2:12][C:13]1[N:14]([CH2:27][CH2:28][CH3:29])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH2:27][CH2:28][CH3:29])[C:13]([CH2:12][C:11]([NH:10][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])([CH3:31])[CH3:30])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.3 %

Procedure:
Cyclohexanecarbonyl chloride (401 μL, 3.00 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (627 μL, 4.5 mmol) in dichloromethane (26.7 mL). After 3 hours at 0° C., the solution was stirred for 2 days at ambient temperature. More triethylamine (697 μL) and cyclohexanecarbonyl chloride (602 μL) was added. After 30 minutes, 2 M aqueous sodium carbonate was added to the solution. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (20 mL) and concentrated hydrochloric acid (2 mL) were added. The solution was heated at reflux for 4 hours, then left to stand at ambient temperature overnight, then heated at reflux again for brief periods of time during the next 2 days. In all, the solution was heated at reflux for a total of 7 hours. After cooling to ambient temperature, 2 M aqueous sodium carbonate was added to adjust the mixture to pH 10-11. The mixture was concentrated under reduced pressure to remove the methanol. Water was added and a solid was isolated from the mixture by filtration. The solid was washed with water. Chloroform was added to the solid, and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by IFC. The appropriate fractions were combined and concentrated to a white solid that was recrystallized from 50% ethyl acetate/hexanes. The crystals were isolated by filtration and dried to yield 896 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]cyclohexanecarboxamide as a white solid, mp 190-191° C.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1C)C.C([Li])(C)(C)C.CCCCC.[CH3:27][N:28](C)[C:29]#N>C1COCC1>[CH3:27][N:28]([CH3:29])[C:15]1[N:3]=[C:4]([OH:14])[C:5]2[C:6]([CH:16]=1)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2
Reactant: CN(C)C#N
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N(C)C)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1000 mg, 4.52 mmol) in THF (10 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (5316 μl, 9.04 mmol) and the solution was stirred for 0.5 h before addition of N,N-dimethylcyanamide (317 mg, 4.52 mmol) in THF (10 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl, and extracted with EtOAc. The organic layer was collected, dried over sodium sulfate, filtered, followed by removal of solvent under vacuum to give 3-(dimethylamino)-6-methoxyisoquinolin-1-ol (700 mg, 71% yield) which was carried to the next step without further purification. MS: MS m/z 219.1 (M++1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:38])[C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:38])[C:34](=[O:37])[CH2:35][OH:36])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Reactant: ClCc1ccccn1
Agent: Cl
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 57 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide to give the title compound in 57% yield; NMR spectrum (DMSO-d6) 1.20 (dd, 3H), 2.80 (d, 3H), 3.10 (m, 1H), 3.80-4.20 (m, 2H), 4.20-4.50 (m, 2H), 5.15 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.30 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (m, 1H), 7.80-7.95 (m, 2H), 8.40 (d, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum MH+ 508.2.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].O=[C:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[OH:3][N:2]=[C:10]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NO
Reactant: CCOC(=O)CCCCC(=O)c1ccc2ccccc2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(=O)CCCCC(=NO)c1ccc2ccccc2c1
Yield: 120.3 %

Procedure:
An ethanolic solution (150 ml) of ethyl 6-oxo-6-(2-naphthyl)hexanoate (15 g) was added to an aqueous solution (42 ml) of hydroxylamine hydrochloride (4.8 g) and sodium acetate (5.7 g) and the mixture was refluxed for 2 hours. The ethanol was then distilled off under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried and the solvent was distilled off. The crude residue was purified by silica gel column chromatography (hexane-ethyl acetate =10:1) to provide ethyl 6-hydroxyimino-6-(2-naphthyl)hexanoate (19 g).
Reaction SMILES: [F:1][CH:2]([F:45])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:21]1[N:25]2[CH:26]=[C:27]([C:30]3[CH:31]=[N:32][C:33]([N:36]4[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]4)=[N:34][CH:35]=3)[CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[CH3:44])[C:11]([O:13]CC1C=CC=CC=1)=[O:12].O.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[F:45][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:21]1[N:25]2[CH:26]=[C:27]([C:30]3[CH:31]=[N:32][C:33]([N:36]4[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]4)=[N:34][CH:35]=3)[CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[CH3:44])[C:11]([OH:13])=[O:12]
Reactant: Cc1nc2ccc(-c3cnc(N4CCNC(=O)CC4)nc3)cn2c1C(C(=O)OCc1ccccc1)c1ccccc1OC(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2ccc(-c3cnc(N4CCNC(=O)CC4)nc3)cn2c1C(C(=O)O)c1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of Example 311 (0.219 g, 0.358 mmol) in THF (4 mL) was added lithium hydroxide monohydrate (0.03 g, 0.716 mmol) and the mixture was stirred at room temperature for 4 h. The pH of the mixture was adjusted to ˜6 by the dropwise addition of a 10% aqueous solution of citric acid. The material was concentrated in vacuo, and the residue was washed with acetone, to furnish the title compound (0.135 g, 72%). δH (300 MHz, DMSO-d6) 8.57 (m, 3H), 7.66 (m, 1H), 7.51 (m, OH), 7.41 (dd, OH, J 9.3, 1.5 Hz), 7.23 (m, 1H), 7.09 (m, 2H), 6.99 (m, OH), 5.31 (m, OH), 3.95 (d, 4H, J 3.9 Hz), 3.20 (m, 2H), 2.25 (s, 3H). LCMS (pH 10): MH+ 523.2, RT 1.05 minutes.