Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9](F)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:3]=1[NH:4][CH3:5].[C:14]1([CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:22]1([CH:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:21][C:9]2[CH:8]=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[C:3]([NH:4][CH3:5])[C:2]=2[F:1])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CNc1c([N+](=O)[O-])ccc(F)c1F
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CNc1c([N+](=O)[O-])ccc(NC(c2ccccc2)c2ccccc2)c1F
Temperature: 200 °C
Yield: 29.6 %

Procedure:
A mixture of 2,3-difluoro-N-methyl-6-nitroaniline (2.66 g), 1,1-diphenylmethanamine (5.18 g), diisopropylethylamine (4.56 g) and butan-1-ol (26.6 mL) was heated at 200° C. for 2 hr using a microwave reactor. To the reaction mixture was added saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.47 g).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([Cl:20])=[O:13])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[CH:4]=1)#[N:2]
Reactant: CCn1cc(C#N)c2ccc(C(=O)O)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C#N)c2ccc(C(=O)Cl)cc21
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.42 g, 1.96 mmol) in CH2Cl2 (15 mL) is cooled to 0° C. The suspension is treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92 mmol) is added via syringe during 2 minutes after which the ice bath is removed and the reaction mixture is allowed to warm to ambient temperature during 1.5 h during which time the reaction becomes a yellow solution. The solution is then concentrated in vacuo to afford 0.46 g (quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+].O=O.C1(OC)C=CC=CC=1>O.[Cu]I>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:14]#[N:15])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: [C-]#N
Agent: [Cu]I
Agent: O=O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 153 °C

Procedure:
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (1.01 g, 5.3 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.00 g, 20.6 mmol), powdered sodium cyanide (1.27 g, 25.1 mmol, 97% purity), oxygen-free 4-picoline (1.92 g, 20.6 mmol) and oxygen-free anisole (10 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 153° C. for 12 h and allowed to cool to room temperature overnight. The solid reaction mixture was then heated at 125° C. and more anisole (10 mL) was added. A solution of sodium cyanide (0.505 g, 10.0 mmol) in water (20 mL) was added to the reaction mixture at about 105° C., and then the mixture was taken out of the glovebox and allowed to cool to room temperature while stirring. The reaction mixture was filtered, and the solid collected was washed with water (2×10 mL, 1×5 mL) and toluene (2×10 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (3.66 g).
Reaction SMILES: CN(C)[N:3]=[CH:4][CH:5]=[C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:9]1([C:7]2[NH:3][CH:4]=[CH:5][C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)N=CC=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A mixture of 3.1 g (0.011 mole) of 4-dimethylhydrazono-1,2-diphenyl-2-buten-1-one, 11.2 g (0.064 mole) sodium hydrosulfite in 75 ml ethanol and 37.5 ml water was heated at reflux for three hours. The mixture was cooled and poured into 300 ml ice water. The white crystalline produce was collected, washed with water and air dried to give 1.9 g (79%), m.p. 130°-1°, identical to product obtained via the decarboxylation, Method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].S(Cl)([Cl:41])=O>>[Cl:41][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCS(C)(=O)=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 0 °C
Yield: 88 %

Procedure:
6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (3.6 g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF (1.8 ml) was added under argon and the mixture was heated at reflux for 1.5 hours. The thionyl chloride was eliminated by several azeotropic distillations using toluene. The solid residue was suspended in ice/water and a saturated solution of sodium hydrogen carbonate was added to adjust the mixture to pH7. The solid was collected by filtration, washed with water and dried in a vacuum dessicator over phosphorus pentoxide to give 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g, 88%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]([F:41])([F:40])[F:39].O>CN(C=O)C>[F:39][C:38]([F:40])([F:41])[C:29]1[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:35])[F:36])=[CH:33][C:28]=1[CH2:27][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) was added a solution of potassium carbonate (345 mg) and 2-(bromomethyl)-1,4-bis(trifluoromethyl)benzene (0.129 mL) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (156 mg).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH2:37])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[C:40]([C:48](O)=[O:49])[CH:39]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:9][C:10]([CH2:12][CH2:13][CH2:14][C@H:15]([NH:37][C:48]([C:40]1[CH:39]=[N:38][C:47]2[C:42]([CH:41]=1)=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:16]([O:18][C@@H:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:20][C:21]([NH2:23])=[O:22])=[O:17])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@@H](N)CCCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC[C@@H](CC(N)=O)OC(=O)[C@H](CCCC(=O)OCc1ccccc1)NC(=O)c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (3S)-3-[(2S)-5-benzyloxycarbonyl-2-aminopentanoyl]oxyhexadecanamide hydrochloride (1.79 g), 3-quinolinecarboxylic acid (630 mg) and 1-hydroxybenzotriazole (536 mg) in N,N-dimethylformamide (40 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (616 mg) at 0° C., and the mixture was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate (200 ml) and washed with 0.5N hydrochloric acid (200 ml), 10% aqueous citric acid (200 ml), saturated aqueous sodium bicarbonate (200 ml) and brine, successively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give (3S)-3-[(2S)-5-benzyloxycarbonyl-2-{(3-quinolyl)carbonylamino}pentanoyl]oxyhexadecanamide (2.16 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:10])[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1B(O)O.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH3:10])[NH:9][C:13]1[CH:12]=[CH:11][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc2ccccc2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CN(Nc1ccc2ccccc2c1)C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 45.1 %

Procedure:
A mixture of N-methyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 1; 1.50 g, 10.26 mmol), 2-naphthaleneboronic acid (Lancaster; 1.90 g, 11.05 mmol), copper(II) acetate (1.90 g, 10.46 mmol) and triethylamine (3.6 mL, 25.8 mmol) in 1,2-dichloroethane (40 mL) was heated in an oil bath at 50° C. for 45 min. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 120 g column, eluting with 15-20% ethyl acetate/hexanes, to give N-methyl-N′-naphthalen-2-yl-hydrazinecarboxylic acid tert-butyl ester (1.26 g, 45%) as an orange oil that partially solidified. The Boc region of the 1H NMR spectrum integrated high, but the material was used directly in subsequent steps without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>C(O)C>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])=[CH:37][CH:38]=1
Reactant: C1COCCN1
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCOCC2)cn1
Reaction time: 18 h
Yield: 34.3 %

Procedure:
To a solution of morpholine (9.00 g, 103 mmol) in 400 mL ethanol was added N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (10.0 g, 52.2 mmol), 1-hydroxybenzotriazole (7.00 g, 51.8 mmol), and 6-aminonicotinic acid (6.00 g, 43.4 mmol). After stirring for 18 hours, the resulting solid was filtered. This was triturated with a mixture of 100 mL methanol and 100 mL dichloromethane to yield (6-Amino-pyridin-3-yl)-morpholin-4-yl-methanone (3.08 g, 14.9 mmol). MS (ESI) 208.1 (M+H)+.
Reaction SMILES: [H-].[Na+].F[C:4]1[C:22]([CH3:23])=[C:21]([F:24])[C:20]([F:25])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7].O>O1CCOCC1>[CH:16]1([N:15]2[C:4]3[C:5](=[CH:19][C:20]([F:25])=[C:21]([F:24])[C:22]=3[CH3:23])[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)cc2c1=O
Yield: 78.1 %

Procedure:
To the cooled mixture of 55% sodium hydride (50 mg) in anhydrous dioxane (2 ml) was added ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate (300 mg) slowly with stirring. After stirring for 30 minutes at room temperature, to the reacting mixture was added water (5 ml), the resulting precipitate was collected by filtration, washed with water and recrystallized from methanol to give the title compound (220 mg) as white needles.
Reaction SMILES: Br[C:2]1[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[CH:19]1([CH:25]=[CH:26]B(O)O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1(/[CH:25]=[CH:26]/[C:2]2[C:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[N:7][C:6]=23)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1nn2cccnc2c1Br
Reactant: OB(O)C=CC1CCCCC1
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1/C=C/C1CCCCC1

Procedure:
The product from Example 148A and 2-cyclohexylethenylboronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.38 (s, 1H), 8.96 (dd, J=6.9, 1.7 Hz, 1H), 8.53 (dd, J=4.1, 1.7 Hz, 1H), 7.00 (dd, J=6.9, 4.0 Hz, 1H), 6.58 (dd, J=16.1, 6.8 Hz, 1H), 6.30 (dd, J=16.1, 1.2 Hz, 1H), 2.04-2.14 (m, 1H), 1.58-1.84 (m, 5H), 1.46 (s, 9H), 1.07-1.41 (m, 5H); MS (ESI) m/z 341 (M−H)−.
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[OH-].[Na+].I[CH2:13][CH2:14][CH3:15].Cl>O.CN1CCCC1=O>[OH:9][C:8]1[CH:7]=[C:5]([OH:6])[N:4]=[C:2]([S:3][CH2:13][CH2:14][CH3:15])[N:1]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: CCCI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCSc1nc(O)cc(O)n1

Procedure:
Water (670 ml) was added to 2-thiobarbituric acid (200 g). The resulting mixture was stirred and sodium hydroxide (126.3 g) was added in portions. The mixture was stirred for 40 mm. then diluted with water. 1-Methyl-2-pyrrolidinone (400 ml) and 1-iodopropane (140.9 ml) were then added. The resulting slurry was stirred at 20° C. for 22 h. The pH of the mixture was then adjusted to 6.5 by addition of 1M HCl (600 ml) over 30 min, then to pH 2.5 by the addition of 6 M HCl (180 ml) over a further 30 min. The resulting slurry was stirred for 18 h and the product was isolated by filtration and washed successively with water (4×100 ml), ethanol (200 ml) and water (2×200 ml). The product was dried under reduced pressure overnight at 50° C. to yield the title product as a white powder (185 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[CH:13][N:12]=[C:11]([C:22]([NH2:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>ClCCl>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([C:22]([NH2:24])=[O:23])=[N:12][CH:13]=1
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a solution of 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg, 0.078 mmol) in dichloromethane (2 mL) at rt was sequentially added methanesulfonyl chloride (22.35 mg, 0.195 mmol) and pyridine (0.016 mL, 0.195 mmol). The mixture was stirred at room temperature for 1 hr and then at 50° C. in a closed vial for 30 min. The mixture was concentrated. The residue was diluted with MeOH (1.5 mL) and subjected to prep. reverse phase HPLC purification. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution to pH 9, and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (4.81 mg, 0.012 mmol, 15.00% yield) as a pale solid. LCMS (M+H)+=399.03. 1H NMR (500 MHz, DMSO-d6) δ: 11.85 (s, 1H), 10.03 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.67-7.63 (m, 2H), 7.50-7.43 (m, 2H), 7.19 (d, J=7.7 Hz, 1H), 6.92 (dd, J1=8.8 Hz, J2=2.2 Hz, 1H), 3.02 (s, 3H).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]([O:20][CH3:21])=[CH:10][CH:9]=2.[Br:22]Br.C(=O)([O-])O.[Na+]>O>[Br:22][C:12]1[C:11]([O:20][CH3:21])=[CH:10][CH:9]=[C:8]2[C:13]=1[C:14]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:6]([CH3:5])[NH:7]2
Reactant: BrBr
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C)[nH]c2ccc(OC)c(Br)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an acetic acid (12 mL) solution of methyl [2-methyl-5-(methyloxy)-1H-indol-3-yl]acetate (300 mg), bromine (206 mg) was added and the mixture was stirred at room temperature for one hour. To the reaction mixture, water and an aqueous saturated sodium hydrogen carbonate solution were added, followed by extraction with ethyl acetate. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution, water and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=65:35→60:40) to obtain the titled compound having the following physical properties (134 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:29][C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([F:25])[CH:27]=1
Reactant: O=Cc1cccc(F)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1cccc(C=C(Br)Br)c1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred cooled (ice/salt, 0°) solution of carbon tetrabromide (48.82 g) in anhydrous CH2Cl2 (200 ml) was added portionwise over 3 minutes, triphenylphosphine (77.1 g), maintaining the temperature below 10°. The resulting orange suspension was stirred at 0° for 1 hour before adding to it, 3-fluorobenzaldehyde (7.8 ml). After the addition was complete, the suspension was stirred at 0° for 1 hour then quenched by the addition of water (75 ml). The organic phase was separated and washed with brine (75 ml), dried (Na2SO4) and evaporated to dryness. The residual gum was poured into cyclohexane (1L) and stirred for 30 minutes. The organic phase was decanted and the residue taken up into CH2Cl2 and poured into cyclohexane (1L). This procedure was repeated twice more and the combined organic phases concentrated to ˜100 ml and passed through silica gel. The filtrate was concentrated to give the title compound as a mobile yellow oil (24 g, 100%).
Reaction SMILES: Cl[C:2]([F:7])([F:6])[C:3]([O-])=O.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C@H:39]2[CH2:44][CH2:43][C@H:42]([C:45](=O)C)[CH2:41][CH2:40]2)[CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][CH3:32].CCCCCCC>CN(C=O)C>[F:6][C:2]([F:7])=[CH:3][CH2:45][C@H:42]1[CH2:43][CH2:44][C@H:39]([C@H:36]2[CH2:37][CH2:38][C@H:33]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:34][CH2:35]2)[CH2:40][CH2:41]1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(C)=O)CC2)CC1
Reactant: O=C([O-])C(F)(F)Cl
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=C(F)F)CC2)CC1
Temperature: 80 °C

Procedure:
A nitrogen-purged 1-L three-neck flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 16.4 g (107.7 mmol) of sodium chlorodifluoroacetate, 28.3 g (107.7 mmol) of triphenylphosphine and 200 ml of DMF, and the mixture was heated up to 80° C. while stirring. A solution of 15.0 g (53.9 mmol) of 1-(trans-4-(trans-4-pentylcyclohexyl)-cyclohexyl)acetaldehyde dissolved in 100 ml of DMF was added dropwise at 80 to 110° C., and the solution was stirred at 100° C. for 2 hours. The reaction mixture was transferred into a 2-L beaker, and 500 ml of heptane was added thereto. Insoluble materials were separated by filtration by means of a glass filter, and 300 ml of water was added thereto. The separated heptane layer was washed twice with 300 ml of water and dried over anhydrous magnesium sulfate. The solvent was distilled of under reduced pressure, and then the concentrated residue was purified by means of a silica gel column chromatography with heptane as a developing solvent to obtain 14.1 g of 1,1-difluoro-3-(trans-4-(trans-4-pentylcyclohexyl)cyclohexyl)-1-propene.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH2:20])[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=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>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:18]([NH:20][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[N:24]=[CH:25][NH:26]4)[CH3:19])[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccnc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccnc1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(pyridin-3-yl)-quinolin-3-yl)ethanamine (0.067 g, 0.236 mmol), 6-chloropurine (0.044 g, 0.283 mmol, 1.2 eq) and DIEA (0.48 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(7-fluoro-2-(pyridin-3-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=23 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.99 (s, 1 H), 8.57-8.65 (m, 2 H), 8.33 (d, J=7.83 Hz, 1 H), 8.16 (s, 1 H), 8.08 (s, 1 H), 7.85-7.96 (m, 2 H), 1.62 (d, 3 H), Mass Spectrum (ESI) m/e=402 (M+1).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH2:6][CH:5]1[CH:4]([C:9]([OH:11])=O)[CH2:3][CH:2]2[C:12]([OH:14])=O.C(OC(=O)C)(=O)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[CH2:29][CH2:28]1>O>[N:34]1[CH:35]=[CH:36][CH:37]=[N:38][C:33]=1[N:30]1[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][CH2:23][N:22]2[C:12](=[O:14])[CH:2]3[CH2:3][CH:4]([CH:5]4[CH2:6][CH2:7][CH2:8][CH:1]43)[C:9]2=[O:11])[CH2:28][CH2:29]1
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Reactant: O=C(O)C1CC(C(=O)O)C2CCCC12
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1C2CC(C(=O)N1CCCCN1CCN(c3ncccn3)CC1)C1CCCC21

Procedure:
Bicyclo[3.3.0]-octane-2,4-dicarboxylic acid (1.6 g., 8.1 mmole) was converted to the anhydride by refluxing for three hours in 100 ml. of acetic anhydride. The excess reagent was removed in vacuo. Two hundred fifty (250) ml. of xylene was added along with 1.9 g. (8.1 mmole) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine. The mixture was refluxed under nitrogen for 48 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuo and the residue filtered through 75 g. of silica gel with 2% ethanol/chloroform as eluent. Removal of solvent and recrystallization of the residue from isopropanol with the addition of 4N isopropanolic HCl, followed by a second recrystallization from isopropanol, gave 750 mg. of white solid title compound as hydrochloride, one quarter hydrate, m.p. 188°-189° C.