Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1([C:7]2C=CC=C[C:8]=2[CH2:9][OH:10])C=CC=CC=1.[C:15]1([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][OH:26])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:9]([O:26][CH2:25][C:24]1[CH:23]=[CH:22][C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:28][CH:27]=1)(=[O:10])[CH:8]=[CH2:7]
Reactant: OCc1ccc(-c2ccccc2)cc1
Reactant: OCc1ccccc1-c1ccccc1
Product: C=CC(=O)OCc1ccc(-c2ccccc2)cc1

Procedure:
The same process as in Synthetic Example 1 was conducted except that the ortho-phenylbenzyl alcohol in Synthetic Example 1 was changed to para-phenylbenzyl alcohol Consequently, 22.4 g of para-phenylbenzyl acrylate was obtained. The obtained para-phenylbenzyl acrylate was solid at ordinary temperature and had a melting point of 32° C. and a refractive index of 1.5920 at 40° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH3:13][C:14]1[C:22]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][NH:18]2.C([BH3-])#N.[Na+].[OH-].[Na+]>>[CH3:13][C:14]1[C:22]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][CH2:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[CH2:25]2)=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][NH:18]2
Reactant: Cc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Reactant: O=Cc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(O[C@@H]2CCC[C@H](NCc3ccncc3)C2)ccc2[nH]ncc12
Reaction time: 0.17 h
Yield: 42.6 %

Procedure:
Isonicotinaldehyde (42.8 μl, 0.45 mmol) and acetic acid (0.23 mL, 4.08 mmol) were added to a methanolic solution (5 ml) of the cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.41 mmol) obtained in Example 411, and the resulting mixture was stirred for 10 minutes. Then, sodium cyanoborohydride (28.2 mg, 0.45 mmol) was added thereto and stirred for 2 hours. An aqueous sodium hydroxide solution was added to the reaction solution, followed by extraction with chloroform (three times), and the extract solution was dried over anhydrous magnesium sulfate. The residue was purified by a silica gel chromatography (ethyl acetate, methanol (5% aqueous ammonia): chloroform=10/100) to obtain N-{cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-N-(pyridin-4-ylmethyl)amine (58.7 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[NH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][N:34]=2)[CH2:29][CH2:28][CH2:27]1.[N:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][N:44]=2)[CH:39]=[CH:38][CH:37]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[NH:34]1[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:31][CH2:32][CH2:33]1.[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:44]3[C:45]4[C:40](=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:41][CH2:42][CH2:43]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:13])=[O:14])=[CH:16][C:17]=1[C:22]([F:25])([F:23])[F:24]
Reactant: c1cnc2ncccc2c1
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)CCCN2
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCCc2cccnc21

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (208 mg, 0.50 mmol), 1,2,3,4-tetrahydro-[1,8]naphthyridine [(135 mg, 1.0 mmol) 1,2,3,4-tetrahydro-[1,8]naphthyridine was prepared freshly from 1,8-napthyridine via hydrogenation over Pt2O], BOP (486 mg, 1.1 mmol), DIEA (185 mg, 1.4 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 4-chloro-N-[5-chloro-2-(3,4-dihydro-2H-[1,8]naphthyridine-1-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: MS m/z: 531.0 (M+H).
Reaction SMILES: N1([CH:7]=[C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)CCCCC1.[CH3:24][C:25](=[O:28])[CH:26]=[CH2:27].C(O)(=O)C>C(O)C>[O:28]=[C:25]1[CH2:24][CH2:7][C:8]2([CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:13]2)[CH:27]=[CH:26]1
Reactant: C=CC(C)=O
Reactant: O=C(OCc1ccccc1)N1CCC(=CN2CCCCC2)CC1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
To a solution of EXAMPLE 265A (15.88 g) in ethanol (300 mL) was added but-3-enone (3.89 g). The mixture was stirred at reflux overnight. Then acetic acid (30 mL) was added to the mixture which was stirred at reflux again overnight. The mixture was then concentrated under vacuum and the residue was diluted with ethyl acetate (400 mL) and washed with water and brine and dried over Na2SO4. After filtration and evaporation of the solvent, column purification gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[OH:19])[CH:3]=1.Br[CH2:21][CH2:22][OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[C:12]=2[O:19][CH2:21][CH2:22][OH:23])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1O
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1cccc(C=O)c1OCCO
Reaction time: 22 h
Yield: 83 %

Procedure:
A solution of 4-chloro-2-(3-formyl-2-hydroxyphenoxy)benzonitrile (0.30 g, 1.1 mmol), 2-bromoethanol (0.10 mL, 0.18 g, 1.4 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were heated with stirring in dry DMF (3 mL) at 50° C. After 22 h, 2-bromoethanol (0.19 mL, 0.33 g, 2.7 mmol) was added, and stirring continued for an additional 24 h at 50° C. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (3×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-[3-formyl-2-(2-hydroxyethoxy)phenoxy]benzonitrile (0.29 g, 83%) as a tan oil, which was used without further purification.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(C1CCCC1=O)(=O)C.[CH2:21]([N:23](CC)CC)[CH3:22].C(N)C>CO>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:23][CH2:21][CH3:22])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CC(=O)C1CCCC1=O
Agent: CCN
Solvent: CO
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Yield: 66.7 %

Procedure:
First, 5.0 g (31 mmol) of L-glutamic acid-γ-methyl ester was suspended in 15 mL of methanol. To this, 4.3 g (34 mmol) of 2-acetyl-cyclopentanone and 3.1 g (31 mmol) of triethylamine were added. The mixture was heated at 60° C. for 2 hours. Subsequently, 20 g (310 mmol) of 70% ethylamine was added to the mixture and the same procedure as in Example 1 was performed to obtain 3.6 g of theanine (yield: 66.7%). The obtained theanine had the same purity as high as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][OH:26])=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:19]4[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][O:26][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:21][CH:20]=4)[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cccc3nc(Nc4ccc(OCCO)cc4)nn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-c2cccc3nc(Nc4ccc(OCCOS(C)(=O)=O)cc4)nn23)cc1
Temperature: 0 °C

Procedure:
2-{4-[5-(4-Methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenoxy}-ethanol (XX-011) (0.48 g, 1.26 mmol) was dissolved in dichloromethane (20 mL). Triethyl amine (0.805 mL, 5.8 mmol) was added and the mixture cooled to 0° C., then methanesulfonyl chloride (0.39 mL, 5.05 mmol) was added dropwise and the reaction was allowed to warm to room temperature. The reaction mixture was washed with 5% sodium hydrogencarbonate, dried over magnesium sulfate and concentrated in vacuo and used without further purification. LCMS method: 1, RT: 5.11 min, MI: 455 [M+1].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=1.[CH:16]1(CO)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([CH2:1][O:2][C:3](=[O:15])[C@H:4]([CH3:14])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([Cl:13])[CH:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Reactant: OCC1CCCCC1
Product: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)OCC1CCCCC1

Procedure:
Following transesterification General Procedure AB above and using N-(3,4-dichlorophenyl)alanine methyl ester (from Example A9 above) and cyclohexylmethanol (Aldrich), the title compound was prepared.
Reaction SMILES: [C:1]([C:3]([CH3:38])([CH3:37])[C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:3]([CH3:37])([CH3:38])[C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5])#[N:2]
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyano-1,2,2-trimethyl-ethyl)-amide (120 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added TFA (0.75 mL). The reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h then concentrated. The residue was taken up in 10% MeOH/CH2Cl2 and water was added. The resultant precipitate was collected via filtration then triturated with EtOAc to afford 77 mg (84%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-cyano-1,2,2-trimethyl-ethyl)-amide as a light yellow powder. MS: (M+H)+=422; mp=322-328° C.; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.78 (s, 1H), 8.99 (s, 1H), 8.38 (s, 1H), 8.34 (d, J=9.1 Hz, 1H), 8.01 (d, J=9.6 Hz, 1H), 7.86 (d, J=1.5 Hz, 1H), 7.19 (dd, J=8.6, 1.5 Hz, 1H), 4.20-4.34 (m, 1H), 4.04 (s, 3H), 1.31 (d, J=6.6 Hz, 3H), 1.28 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: [CH2:1]1[O:8][C@@H:7]2[O:9][C@H:2]1[CH:3]=[CH:4][C:5]2=[O:6].[K].[BH4-].[Na+].[C:13]([OH:16])(=O)[CH3:14]>C(O)C1C=CC=CC=1.C(O)C>[CH2:13]([O:16][C@@H:3]1[C@H:2]2[CH2:1][O:8][C@H:7]([O:9]2)[C:5](=[O:6])[CH2:4]1)[C:14]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: CC(=O)O
Reactant: O=C1C=C[C@H]2CO[C@@H]1O2
Agent: [BH4-]
Agent: [K]
Agent: [Na+]
Solvent: CCO
Solvent: OCc1ccccc1
Product: O=C1C[C@H](OCc2ccccc2)[C@H]2CO[C@@H]1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,6-anhydro-4-O-benzyl-3-deoxy-β-D-erythro-hexopyranos-2-ulose in benzyl alcohol was prepared as described in Example 6, except that 0.088 g of levoglucosenone were used as starting material and, 5 min after the addition of potassium benzoxide, a suspension of sodium borohydride (0.073 g) in ethanol (4 ml) was added to the mixture, which was then stirred for 0.5 h at room temperature, made neutral with acetic acid, evaporated under vacuum, and the resulting white residue transferred to a short column of silica, which was eluted with a gradient of ethyl acetate/hexane (from 1:2 to 2:1). The fractions found by t.l.c. to contain the title compound A were combined and evaporated, to give material that spontaneously crystallized (0.106 g, 64% from levoglucosenone). 1H-Nmr spectroscopy of this material showed it to be an 9:11 mixture of the title compound A and the D-arabino isomer determined from the relative intensities of their H-3 resonances.
Reaction SMILES: [C:1]1([CH:7]([NH2:22])[CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([NH:22][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[CH:13][CH:12]=1)=[O:32])[CH3:35]
Reactant: Cc1ccc(OCCC(N)c2ccccc2)c2ccccc12
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)NC(CCOc1ccc(C)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A solution of 2.12 g (7.3 mmol) of 1-phenyl-3-(4-methyl-1-naphthalenyloxy)propanamine, 1.12 ml (8.0 mmol) of triethylamine and 100 ml of THF was cooled to approximately 0° C. under a nitrogen atmosphere. To the mixture was added 0.766 ml (8.0 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for approximately five and one-half hours and concentrated under vacuum. The residue was dissolved in diethyl ether, toluene and water. The mixture was extracted with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, water, 1N sodium hydroxide water, and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum to provide 2.74 g of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[BrH:17]>C(OCC)(=O)C>[Br:17][CH:4]1[CH2:3][CH:2]([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12]
Reactant: Br
Reactant: CC1CCC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1CC(Br)C(=O)c2ccccc21

Procedure:
Commercially available 4-methyl-1-tetralone, 32.0 grams, contained in 250 ml. of chloroform and 50 ml. of ethyl acetate is heated to boiling. A mixture of 98.3 grams of cupric bromide and 50 ml. of ethyl acetate is heated to its reflux temperature. After all of the hydrogen bromide is evolved, the mixture is maintained at its reflux temperature for an additional hour. The reaction mixture is filtered while hot, the residue washed with boiling chloroform and the combined filtrates evaporated to dryness in vacuo. The residue is dissolved in a minimum of methylene chloride, placed upon an alumina column and eluted with methylene chloride. The eluate is concentrated and the desired 2-bromo-4-methyl-1-tetralone obtained as a dark oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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.O>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][CH:18]=[CH:19]5)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2ccc3[nH]ccc3c2)cc1-c1nnc(C2CC2)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
5-Bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (200 mg, 0.71 mmol), 5-indolyl boronic acid (112 mg, 0.78 mmol), K2CO3 (290 mg, 2.13 mmol), 1,4-dioxane (10.0 mL) and water (4.0 mL) were taken in a sealed tube and degassed with nitrogen for 15 min. Then Pd(PPh3)4 (41 mg, 0.03 mmol) was added and stirred for 18 h at 100° C. The reaction mixture was diluted with ice-cold water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated under reduced pressure to get crude 3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-(1H-indol-5-yl)-pyridin-2-ylamine. Crude compound was purified by column chromatography using silica gel (100-200 mesh). The column was eluted with 30% EtOAc in petroleum ether to afford the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:14])[CH2:10][CH2:9][CH:8]=[C:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: OC1=CCCSc2ccc(Cl)cc21
Reactant: C1COCCO1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Product: O=S1CCC=C(O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The starting material is prepared as follows: The solution of 6.4 g of 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin in 65 ml of dry methanol and65 ml of dry dioxane is treated dropwise at 0° in 1 hour with the solution of 7.0 g of sodium metaperiodate in 65 ml water. The mixture is stirred at 0° for two hours after the addition period and then allowed to warm to room temperature for overnight. It is filtered and the solid rinsed with 30 ml of methanol. The combined filtrate and wash is concentrated to a smaller volume and treated with 40 ml of water. The mixture is extracted with chloroform, the extract separated, washed with water, dried and evaporated, to yield the 7-chloro-5-hydroxy-2,3-dihydro-1-benzothiepin-1-oxide boiling at 154-157/0.25 mmHg.
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]#[CH:24].C1(C)C=CC=CC=1>C(#N)C>[CH2:24]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 67.5 °C
Reaction time: 24 h

Procedure:
Another method to prepare the titled compound is as follows. 2,2,3,3-Tetrafluoro-6-aminobenzodioxane (50.2 g, 225 mmol) and potassium carbonate (43.54 g, 315 mmol) were suspended into acetonitrile (250 mL), stirred in a 1-liter three-necked flask equipped with an overhead mechanical stirrer, and treated with ˜80% propargyl bromide in toluene (33.5 g, ˜225 mmol). The mixture was slowly heated to 65-70° C. over about three hours. Stirring was continued at that temperature for 24 hours, at which time the heat was turned off and the mixture was permitted to cool to room temperature. The mixture was filtered through a glass fritted funnel, and the solids were rinsed with acetonitrile (300 mL). The filtrate was concentrated, reconcentrated thrice from hexanes, and chromatographed on silica (0 to 1 to 2 to 4% EtOAc/hexanes) to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[NH:24][CH:25]=[N:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH:19][C:22]2[N:30]=[CH:29][N:28]=[C:27]3[C:23]=2[N:24]=[CH:25][NH:26]3)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:20])=[CH:13][CH:14]=2)[N:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: NCc1cc2ccc(F)cc2nc1-c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Fc1ccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc2c1

Procedure:
Prepared according to Procedure H using (2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methanamine (0.080 g, 0.279 mmol), 6-chloropurine (0.065 g, 0.42 mmol, 1.5 eq) and DIEA (0.56 mmol, 2.0 eq) in n-butanol (3 mL). N-((2-(2-chlorophenyl)-7-fluoroquinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=225 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.49 (s, 1 H), 8.14 (s, 1 H), 8.03-8.10 (m, 2 H), 7.66-7.73 (m, 2 H), 7.47-7.56 (m, 2 H), 7.43-7.44 (m, 1 H), 7.33-7.40 (m, 1 H), 4.10-4.18 (m, 2 H), Mass Spectrum (ESI) m/e=405 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([OH:26])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25].O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:38]=2)=[CH:30][CH:29]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH2:20]([O:26][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[S:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:38]=2)=[CH:32][CH:33]=1)/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH3:25]
Reactant: CCCCCc1ccc(-c2ccc(O)cc2)s1
Reactant: CCC/C=C/CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC/C=C/COc1ccc(-c2ccc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
Triphenylphosphine (0.53 g) was added in small portions to a solution of (E)-hex-2-en-1-ol (0.20 g), 2-(4-hydroxyphenyl)-5-pentylthiophene (0.50 g), diethylazodicarboxylate (0.35 g) in dry tetrahydrofuran (15 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using a 4:1 petroleum (40-60° C.) ether/ethyl acetate mixture as eluent, followed by recrystallisation from ethanol to yield 0.10 g of 2-(4-[(E)-hex-2-enyloxy]phenyl)-5-pentylthiophene, K, 82° C., I.