Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].C(O)C>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:12][OH:13]
Reactant: O=Cc1ccc(F)cc1F
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(F)cc1F
Yield: 83.5 %

Procedure:
In a fashion similar to that for preparation 13, 2,4-difluorobenzaldehyde (5.00 g, 35.2 mmol), hydroxylamine hydrochloride (2.94 g, 42.3 mmol), NaOH (7.04 g, 88.0 mmol; as a 50% solution by weight in water), ethanol (15 ml), H2O (15 ml), and ice (30 g) gave 2,4-difluorobenzaldehyde oxime (4.62 g, 84%) which was used without purification.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[Mg]Cl.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:9])=[CH:20][C:19]([CH3:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccccc1[Mg]Cl
Reactant: Cc1ccc(C(=O)NC(C)(C)C)cn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2C)c(C(=O)NC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
38.9 ml (38.9 mMol) o-Tolylmagnesium chloride solution (1M in THF) were added over 15 minutes to a solution of 2.5 g (10.1 mMol) N-tert.-butyl-6-methyl-nicotinamide in 12.5 ml THF cooled to 0° C. The suspension obtained was stirred overnight at room temperature, then one more hour at 50° C. After cooling to 0° C., 2.1 ml (51.9 mMol) methanol were added over 30 minutes (exothermic!), followed after 10 minutes by 3.5 g (15.6 mMol) 2,3-dichloro-5,6-dicyano-benzoquinone. After one hour at room temperature, the reaction mixture was concentrated under reduced pressure to a still stirrable oil, heated to 50° C. and 100 ml tert.-butyl-methylether were added. The suspension was stirred 30 minutes at reflux, 1 hour at room temperature and filtered. The filtrate was evaporated and the residue was purified by flash chromatography (50 g SiO2, eluent:AcOEt/n-heptane 2:1) to yield 3.1 g (84.5%) N-tert.-butyl-6-methyl-4-o-tolyl-nicotinamide as a light brown resinous solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([CH2:17][OH:18])[C:10]=3[OH:19])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[C:30]([CH3:32])=[CH2:31]>C1COCC1>[C:29]([O:18][CH2:17][C:11]1[CH:12]=[C:13]([O:15][CH3:16])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:19])(=[O:33])[C:30]([CH3:32])=[CH2:31]
Reactant: COc1cc(CO)c(O)c(-n2nc3ccc(F)cc3n2)c1
Reactant: C=C(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCc1cc(OC)cc(-n2nc3ccc(F)cc3n2)c1O
Temperature: -5 °C
Reaction time: 1 h

Procedure:
The esterification was carried out using the product. In a 250 ml round bottom flask equipped with a magnetic stirrer and nitrogen inlet was dissolved 5.06 g (17.5 mmol) 2-(5-fluoro-2H-benzo[d][1,2,3]triazol-2-yl)-6-(hydroxymethyl)-4-methoxyphenol in 60 ml anhydrous THF. Triethylamine (8.7 ml, 62 mmol)) was added and the mixture was cooled to −10-0° C. Methacryloyl chloride (2.26 g, 21.6 mmol) was added dropwise and the mixture was stirred for 1 hr at −10° C. followed by 20 hours at ambient temperature. The salts were filtered and rinsed with 100 ml THF (≧99.9%, anhydrous containing inhibitor, Aldrich). Diethyl ether (100 ml) was added to the filtrate, which was washed with 1N HCl and water, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the desired product, which was recrystallized in ethanol to give 2.5 g (40%) of a yellow solid. 1H NMR (CDCl3) delta: 11.03 (s, 1H, phenol OH), 7.94 (m, 1H, Ar—H benzotriazole ring), 7.87 (s, 1H, Ar—H phenol ring), 7.53 (m, 1H, Ar—H benzotriazole ring), 7.29 (m, 1H, Ar—H benzotriazole ring), 7.05 (s, 1H, Ar—H phenol ring), 6.21 (s, 1H, C═C—H trans), 5.61 (s, 1H, C═C—H cis), 5.39 (s, 2H, Ar—CH2), 3.89 (s, 3H, Ar—OCH3), 2.01 (s, 3H, C═C—CH3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:17][OH:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[H-].[Na+].[CH3:21]I>C(COC)OC>[CH3:21][O:18]/[N:17]=[C:9](/[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])\[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: ON=C(Cc1cccnc1)c1ccc(F)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CO/N=C(\Cc1cccnc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2',4'-difluoro-2-(3-pyridyl)acetophenone oxime in 25 ml of dimethoxyethane is treated in portions with 0.50 g of sodium hydride dispersion (55% in oil) and the mixture is stirred at room temperature for 30 minutes. 1.8 g of methyl iodide is then added and the mixture is heated to reflux temperature. After 4 hours, it is cooled to room temperature, poured onto ice and extracted with ethyl acetate, and the organic phase is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. After separation by column chromatography on silica gel, (E)-2',4'-difluoro-2-(3-pyridyl)acetophenone O-methyloxime [1H-NMR (CDCl3, 200 MHz): 4.05 ppm (s, CH3O--N=)] is obtained first and then (Z)-2',4'-difluoro-2-(3-pyridyl)acetophenone O-methyloxime [1H-NMR (CDCl3, 200 MHz): 3.91 ppm (s, CH3O--N=)].
Reaction SMILES: [NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([O:25]CC)=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:28])[C:3]=1[F:29].OS(O)(=O)=O>CC(O)=O.O>[NH2:1][C:2]1[C:21]2[C:20](=[O:22])[C:19]([C:23]([OH:25])=[O:24])=[CH:18][N:7]3[C@@H:8]([CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([F:28])[C:3]=1[F:29]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)c(N)c3c1=O)OC[C@@H]2Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Nc1c(F)c(F)c2c3c1c(=O)c(C(=O)O)cn3[C@@H](Cc1ccccc1)CO2
Temperature: 0 °C
Yield: 94.5 %

Procedure:
To a suspension of ethyl (3S)-8-amino-9,10-difluoro-2,3-dihydro-7-oxo-3-phenylmethyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (100 mg, 0.250 mmol) in a mixture of AcOH (0.6 mL) and water (0.5 mL), was added H2SO4 (0.1 mL), the whole mixture was heated under reflux for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were suspended in water, filtered, and dried in vacuo to give (3S)-8-amino-9,10-difluoro-2,3-dihydro-7-oxo-3-phenylmethyl-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid (88.0 mg, 95%) as a yellow powder.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:18])[CH:2]=[CH2:3].Cl>[OH-].[K+].C(O)C>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:18])=[CH:2][CH3:3]
Reactant: C=CCc1cc(Oc2ccc(F)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC=Cc1cc(Oc2ccc(F)cc2)ccc1O
Temperature: 25 °C

Procedure:
A solution of 2-allyl-4-(4-fluorophenoxy)phenol, from above, in saturated KOH/ethanol (65 mls) was refluxed for 18 hrs. It was then cooled to r.t. and acidified to pH2 by that addition of 10% HCl. The aqueous solution was then extracted with ethylacetate (3×200 mls). The organics were combined, dried with MgSO4 and concentrated to afford 17.52 g of 2-(1-propenyl)-4-(4-fluorophenoxy)phenol as a brownish oil which was used as is.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)([CH2:7][C:8]#[CH:9])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=1.[CH3:31]N(C=O)C>>[O:1]=[C:2]1[N:6]([CH3:31])[C:5]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)([CH2:7][C:8]#[CH:9])[C:4](=[O:18])[N:3]1[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=1
Reactant: C#CCC1(c2ccc(OC)cc2)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Reactant: CN(C)C=O
Product: C#CCC1(c2ccc(OC)cc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
Following the procedure of Example 159, a solution of 380 mg of 4-[2,5-dioxo-4-(4-methoxyphenyl)-4-(2-propynyl)imidazolidin-1-yl]-2-trifluoromethylbenzonitrile in 9 mL of DMF is treated to produce 580 mg of crude product which is purified by chromatography over silica while eluting with (90/10 then 85/15) heptane/ethyl acetate mixture. 320 mg of product are obtained in the form of a white solid (Yd=81%).
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N+:15]([O-])=O)([CH3:6])[C:3]([OH:5])=[O:4].[H][H]>O1CCCC1.[Ni]>[CH3:6][C:2]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[NH2:15])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: [H][H]
Reactant: CC(C)(Nc1cc(Cl)ccc1[N+](=O)[O-])C(=O)O
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(Nc1cc(Cl)ccc1N)C(=O)O

Procedure:
Using a one-liter autoclave, 53.4 g (0.206 mol) of 2-methyl-(5'-chloro-2'-nitroanilino)-propionic acid in solution in 500 ml of tetrahydrofuran are hydrogenated in the presence of 17 g of Raney nickel. Hydrogen pressure in the cold: 120 kg. Temperature 60° C. Duration: 1 hour. Pressure drop:
Reaction SMILES: C(S[C:4]1[NH:5][C:6](=[O:13])[C:7]2[CH2:12][S:11][CH2:10][C:8]=2[N:9]=1)C.Cl.CC(O)=[O:17]>O>[NH:9]1[C:8]2[CH2:10][S:11][CH2:12][C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:17]
Reactant: CCSc1nc2c(c(=O)[nH]1)CSC2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2c(c(=O)[nH]1)CSC2
Yield: 80 %

Procedure:
To the suspension of 2-(ethylthio)thieno[3,4-d]pyrimidin-4-(3H, 5H, 7H)-one (2.88 g, 13.45 mmol) in water (20 mL) was added 2.0 mL of cone. HCl and 4.0 mL of AcOH. The reaction was heated at reflux overnight then cooled and the solid collected by filtration, washed with water and methanol, evaporated and dried to obtain a white solid thieno[3,4-d]pyrimidine-2,4-(1H, 3H, 5H, 7H)-dione (1.80 g, 80%). Without further purification, the crude product was used directly in the next step.
Reaction SMILES: [N:1]1[N:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.C1(O)C=CC=CC=1.[CH3:28][O:29][C:30](=[O:34])[CH:31](Br)[CH3:32]>>[N:1]1[N:2]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:31]([CH3:32])[C:30]([O:29][CH3:28])=[O:34])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=2)[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=[N+]([O-])c1cc(Cn2cc3ccccc3n2)ccc1O
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1ccc(Cn2cc3ccccc3n2)cc1[N+](=O)[O-]

Procedure:
Using 4-((2H-indazol-2-yl)methyl)-2-nitrophenol as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (d, J=6.82 Hz, 3H) 3.66 (s, 3H) 5.24 (q, J=6.82 Hz, 1H) 5.66 (s, 2H) 7.00-7.08 (m, 1H) 7.19-7.29 (m, 2H) 7.54-7.63 (m, 2H) 7.71 (d, J=8.34 Hz, 1H) 7.94 (d, J=2.02 Hz, 1H) 8.52 (s, 1H). ESI-MS: m/z 356.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3](C(=O)N)[N:4]=[CH:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]4[O:20][CH2:21][O:22][C:16]=4[CH:15]=3)=[CH:9][CH:8]=2)=[CH:5][NH:4][N:3]=1
Reactant: NC(=O)n1ncc(-c2ccc(Cc3ccc4c(c3)OCO4)cc2)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1n[nH]cc1-c1ccc(Cc2ccc3c(c2)OCO3)cc1
Yield: 74.5 %

Procedure:
To a suspension of 3-amino-2-carbamoyl-4-[4-(3,4-methylenedioxyphenylmethyl)phenyl]pyrazole (2.0 g) in methanol (20 ml) was added 5N sodium hydroxide solution (2.0 ml), and the mixture was refluxed for 1 hour. The solvent was distilled away under reduced pressure, and thereto was added water (50 ml) under ice-cooling. The mixture was neutralized (pH 7 to 8) with 10% hydrochloric acid, and the precipitate was separated by filtraltion, washed with chloroformdiethyl ether to give the title compound (1.3 g, 74.0%).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][O:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc(O)c1
Reactant: Fc1cccc(CBr)c1
Product: Oc1cccc(OCc2cccc(F)c2)c1
Yield: 7 %

Procedure:
Prepared in analogy to example 8 from resorcinol and 3-fluoro-benzylbromide. Colorless oil. Yield=7%. MS: m/e=218.1 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[N:3]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3cccc(Cl)c3)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 3-chlorophenylboronic acid. LC-MS Method 3, tR=1.354 min, m/z=781.1. 1H NMR (CDCl3) 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.55-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.30-7.60 (m, 8H), 7.90-7.95 (m, 1H), 8.05 (s, 1H), 8.80-8.85 (m, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[C:32](O)=[O:33]>>[CH3:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]=1[C:32]([N:17]1[CH2:16][CH:15]2[CH:19]([CH2:20][N:13]([C:9]3[N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:12]=[CH:11][N:10]=3)[CH2:14]2)[CH2:18]1)=[O:33]
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: Cc1ccc2ccccc2c1C(=O)O
Product: Cc1ccc2ccccc2c1C(=O)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2-methyl-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. for C28H26N4O, 434.51; m/z found, 435.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([NH2:9])=[CH:7][C:6]([N+:10]([O-])=O)=[CH:5][N:4]=1)[CH3:2].[H][H]>CO>[NH2:10][C:6]1[CH:7]=[C:8]([NH2:9])[C:3]([CH2:1][CH3:2])=[N:4][CH:5]=1
Reactant: [H][H]
Reactant: CCc1ncc([N+](=O)[O-])cc1N
Solvent: CO
Product: CCc1ncc(N)cc1N

Procedure:
9 g of the nitro compound of Stage 1 are hydrogenated in methanol on platinum with hydrogen at standard pressure and at room temperature. On taking up the theoretical amount of hydrogen the mixture is filtered off from the catalyst and concentrated. The residue (6.8 g) is used in Stage 3 without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>N1C=CC=CC=1>[C:8]1([C:5]2[CH:4]=[C:3]([CH2:2][NH:1][C:15](=[O:16])[O:17][CH2:18][CH3:19])[O:7][N:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cl
Reactant: NCc1cc(-c2ccccc2)no1
Solvent: c1ccncc1
Product: CCOC(=O)NCc1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 7 g. portion of the product of Example 8 was dissolved in 50 ml. of pyridine, cooled in an ice bath, and combined with 10 ml. of ethyl chloroformate. The mixture was stirred at ice bath temperature for 1 hour and allowed to warm to room temperature while being stirred for 2 hours more. The mixture was then poured into ice water and the crude product was separated by filtration and purified by chromatography over silica gel with ethyl acetate as the eluent. The yield was 6 g. of purified [(3-phenyl-5-isoxazolyl)-methyl]carbamic acid, ethyl ester, m.p. 82°.
Reaction SMILES: S(O[CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)(C)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:26]([CH2:6][C:7]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:8]=1[O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=[N+:27]=[N-:28]
Reactant: COC(=O)c1ccc(COc2cc(Cl)ccc2COS(C)(=O)=O)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2CN=[N+]=[N-])cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74.6 %

Procedure:
To a solution of methyl 4-(2-mesyloxymethyl-5-chlorophenoxymethyl)-benzoate (628 mg; prepared in Reference Example 48.) in DMF (5.0 ml), sodium azide (530 mg) was added in a stream of argon. The mixture was stirred for 40 minutes at 60° C. The reaction mixture was diluted with ethyl acetate. The impurity was filtered with celite. The filtrate was washed, dried over and concentrated under the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=10:1) to give the title compound (404 mg) having the following physical data.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)OC(C)(C)C)=[C:19]([N+:31]([O-:33])=[O:32])[CH:18]=2)[CH2:13][CH2:12]1)([CH3:10])[CH3:9]>C(Cl)Cl>[CH:8]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([N+:31]([O-:33])=[O:32])[CH:18]=2)[CH2:15][CH2:16]1)([CH3:10])[CH3:9]
Reactant: CC(C)N1CCN(c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115 %

Procedure:
TFA (3 mL) was slowly added to a stirred solution of tert-butyl (4-(4-isopropylpiperazin-1-yl)-2-nitrophenyl)carbamate (1.2 g, 3.29 mmol) in dry DCM (5 mL) under argon atmosphere at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 12 hr. Reaction progress was monitored by LCMS, after completion of the reaction, excess solvents were removed under reduced pressure to afford a crude residue. The crude residue was repeatedly washed with ether to get the title compound (1 g, yield: 80.6%) as a red solid. MS (ESI): 265.1 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[CH3:13][C:14]1([CH3:30])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[O:15]1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([B:16]2[O:17][C:18]([CH3:20])([CH3:19])[C:14]([CH3:30])([CH3:13])[O:15]2)=[CH:29][CH:28]=1)=[O:26]
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
The title intermediate is prepared in a manner substantially analogous General Procedure E using 2-(R)-methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid (CAS 180516-87-4). The crude product is confirmed by NMR and used without further purification.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Br[CH2:7][C:8]([C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([OH:20])[CH:11]=1)=[O:9]>>[C:1]([O:4][CH2:7][C:8](=[O:9])[C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13]([OH:19])=[C:12]([OH:20])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: [Na+]
Product: CC(=O)OCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
1.26 g of sodium acetate are added to a solution of 1.35 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone in 25 ml of alcohol and heated to boiling under reflux. After 6 hours, the reaction mixture is filtered from separated sodium bromide and evaporated. The residue is dissolved in ethyl acetate. The solution is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated at 50°. There is obtained (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate of m.p. 166°-168° (from ethyl acetate/ether).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[CH3:34][C:35]([OH:39])([C:37]#[CH:38])[CH3:36].C(N(CC)CC)C>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:12][C:13]3[C:14]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:31])([F:32])[F:33])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][C:17]=4[CH3:23])[N:3]=[C:2]([C:38]#[C:37][C:35]([CH3:36])([OH:39])[CH3:34])[C:10]=12
Reactant: C#CC(C)(C)O
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(C#CC(C)(C)O)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A suspension of 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.0569 g, 0.102 mmol) and copper(i) iodide (0.00387 g, 0.0203 mmol, 0.2 eq) in DMF (2 mL) was treated with 2-methyl-3-butyn-2-ol (0.0984 mL, 1.02 mmol, 10 eq), triethylamine (0.0282 mL, 0.203 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (0.0117 g, 0.0102 mmol, 10 mol %) under Ar. The mixture was stirred under Ar at rt for 45 min. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on a 40 g of Redi-Sep™ column using 0 to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 14 min as eluent to provide 4-(4-amino-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methylbut-3-yn-2-ol [PI3Kδ IC50=116 nM] as a tan solid. 1H NMR (DMSO-d6) δ ppm 8.21 (1 H, s), 8.02 (1H, s), 7.87 (1 H, d, J=7.8 Hz), 7.77-7.82 (1 H, m), 7.65 (1 H, d, J=6.7 Hz), 7.57-7.62 (2 H, m), 7.51-7.57 (1 H, m), 7.26-7.32 (1 H, m), 5.76 (1 H, s), 5.44 (2 H, s), 2.60 (3 H, s), 1.46 (6 H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].[BrH:19].C1(C)C=CC=CC=1>O>[Br:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: Br
Reactant: OCCCCCCCCCCCCCCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: OCCCCCCCCCCCCCCCCBr
Yield: 45.8 %

Procedure:
First, 10 g of 1,16-hexadecanediol, 26 g of 48% hydrobromic acid, and 400 ml of toluene were placed in a 1 L flask. The reaction mixture was stirred under reflux for 48 hours while water in the system was removed. The reaction mixture was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=9/1) and recrystallized from hexane to obtain 5.7 g of 16-bromo-1-hexadecanol (Y: 46%). The compound thus obtained had a purity of 95% by GC.