Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:3].[CH3:31][C:32]1[NH:33][CH:34]=[CH:35][N:36]=1>CO.[Cu-]=O>[CH3:3][CH:2]([O:4][C:5](=[O:30])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:33]3[CH:34]=[CH:35][N:36]=[C:32]3[CH3:31])[CH:15]=2)[N:10]([C:26](=[O:28])[CH3:27])[C@@H:9]([CH3:29])[CH2:8]1)[CH3:1]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: Cc1ncc[nH]1
Agent: O=[Cu-]
Solvent: CO
Product: CC(=O)N1c2ccc(-n3ccnc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 37 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 52) (500 mg, 1.2 mmol), 2-methylimidazole (99 mg, 1.2 mmol) and copper(I) oxide (10 mg, 0.126 mmol) in methanol (10 mL) was stirred in air at room temperature for 24 h. A further portion of copper(I) oxide (10 mg, 0.126 mmol) was added and stirring was continued for 48 h. The reaction mixture was then filtered through celite and most of the solvent were removed in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(2-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (167 mg, 0.451 mmol, 37%) as a colourless foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:28]3[C:27]4[CH:26]=[CH:25][C:24](Br)=[CH:23][C:22]=4[N:21]=[C:20]([NH2:30])[C:19]=3[N:18]=[C:17]2[CH2:31][O:32][CH2:33][CH3:34])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].B1([C:42]2[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=2)OCCCO1.C(O)CC.C(=O)([O-])[O-].[Na+].[Na+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:28]3[C:27]4[CH:26]=[CH:25][C:24]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)=[CH:23][C:22]=4[N:21]=[C:20]([NH2:30])[C:19]=3[N:18]=[C:17]2[CH2:31][O:32][CH2:33][CH3:34])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: c1cncc(B2OCCCO2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCO
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Temperature: 105 °C
Yield: 64.1 %

Procedure:
tert-Butyl[4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate (1.15 g, 2.1 mmol), triphenylphosphine (0.005 g), pyridine-3-boronic acid 1,3-propanediol cyclic ester (0.365 g, 2.2 mmol), and n-propanol (3.67 mL) were combined. Aqueous sodium carbonate (2M, 1.12 mL) and water (0.6 mL) were added to the mixture and the flask was flushed with nitrogen. Palladium(II) acetate (0.0013 g) in toluene (0.200 mL) was added, and the flask was again flushed with nitrogen. The flask was sealed and heated in an oil bath at a temperature of 105° C. for 16 hours. The reaction was allowed to cool to room temperature and the mixture was diluted with dichloromethane and water. The layers were separated and the aqueous fraction was extracted with dichloromethane. The organic fractions were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography eluting with a gradient of CMA/chloroform and subsequent recrystallization from acetonitrile yielded 0.725 g of tert-butyl{4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-ylmethyl]benzyl}carbamate as flocculent white crystals, m.p. 195.5–197.0° C.
Reaction SMILES: [CH2:1]1[C@@H:5]2[CH:6]3[C:11](=[O:12])[O:10][C:8](=[O:9])[CH:7]3[C@H:2]1[CH:3]=[CH:4]2.C1(C)C=CC=CC=1.COC1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.[CH3:44][OH:45]>C(Cl)(Cl)(Cl)Cl>[CH3:44][O:45][C:11]([C@@H:6]1[C@H:5]2[CH2:1][C@H:2]([CH:3]=[CH:4]2)[C@@H:7]1[C:8]([OH:10])=[O:9])=[O:12]
Reactant: CO
Reactant: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Solvent: Cc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)[C@H]2C=C[C@@H]1C2
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
The starting material (a) was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-5-Norbornene-endo-2,3-dicarboxylic anhydride (4.104 g, 25 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (500 mL). The mixture was stirred for 20 min. Quinine (8.92 g, 27 5 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.04 mL, 75 mmol) was added. The mixture was stirred at −55° C. for 20 h. Upon warming to 25° C., the mixture was concentrated in vacuo to a thick oil. The oil was dissolved in ethyl acetate (400 mL), washed with 1.0 M aqueous hydrochloric acid solution (2×400 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1R,2S,3R,4S)-3-(methoxycarbonyl)bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (4.8 g, 24.5 mmol, 98%), as a clear waxy solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (1H, d, J=8.5 Hz), 1.33 (1H, d, J=8.8 Hz), 3.00 (1H, s), 3.03 (1H, s), 3.21-3.30 (2H, m), 3.45 (3H, s), 6.02-6.04 (1H, m), 6.14-6.16 (1H, m), 11.86 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>N1CCCCC1.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:4]2[CH2:5][CH2:6][CH2:10][CH2:2][CH2:3]2)=[N:4][C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(Br)c(Cl)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: NC(=O)c1cc(Br)c(N2CCCCC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Temperature: 70 °C
Yield: 189.4 %

Procedure:
A solution of 5-bromo-6-chloro-2-(4-(morpholine-4-carbonyl)phenylamino)nicotinamide (200 mg, 0.454 mmol) in piperidine (1 ml) was stirred at rt for 2 h and heated to 70° C. for 1 h. The mixture was diluted with CH2Cl2, washed with water three times, and concentrated. The residue was purified by chromatography (ISCO, hexane/ethyl acetate gradient, 40 g silica gel column) to give 210 mg of 5-bromo-2-(4-(morpholine-4-carbonyl)phenylamino)-6-(piperidin-1-yl)nicotinamide as a white solid. LCMS: (M+H)+=488.02, 489.96 (Br pattern). 1H NMR (400 MHz, CDCl3-MIX) δ ppm 11.11 (1H, s), 7.89 (1H, s), 7.76 (2H, d, J=8.79 Hz), 7.38 (2H, d, J=8.79 Hz), 3.72 (8H, br. s.), 3.46-3.52 (4H, m), 1.73 (6 H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([OH:12])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C=O)C>C(Cl)Cl>[CH2:20]([O:12][C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[N:5][CH:4]=[CH:3][C:2]=2[Cl:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: Oc1cnc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Clc1ccnc2cc(OCc3ccccc3)cnc12
Temperature: 65 °C

Procedure:
A pyrex reaction tube was charged with 8-chloro-1,5-naphthyridin-3-ol (165 mg, 914 μmol), potassium carbonate (631 mg, 4568 μmol), 1-(chloromethyl)benzene (376 μl, 4568 μmol) and 3.7 mL DMF. The tube was sealed and the mixture was heated at 65° C. for 3 h. The reaction was diluted with DCM and washed with water. The organic portion was dried, filtered, and concentrated. The crude material was purified by silica gel chromatography, 0-25% EtOAc in DCM to provide product as a white solid. MS: [M+H]=271.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:13]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=2[C:15]#[N:16])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Reactant: Cc1ccc(F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
Combine 4-fluoro-2-nitro-phenylamine (2.9 g, 18.50 mmol), 2-fluoro-5-methyl-benzonitrile (2.5 g, 18.50 mmol) and lithium hydroxide monohydrate (2.4 g, 57.20 mmol) in methyl sulfoxide (DMSO, 40 ml). Heat the resulting mixture to 55° C. for 40 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture and collect the precipitate. Chromatograph the solid using flash chromatography and elute with mobile phase: 90% hexanes, 5% ethyl acetate, and 5% dichloromethane. Obtained 2.267 g of the title compound (8.36 mmol, 45% yield) as an orange amorphous solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:12]3[CH2:14][O:13]3)[CH:9]=2)[C:4](=[O:15])[O:3]1.Cl.[N:17]1([C:23](=[O:36])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:27][CH:26]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CCO>[OH:13][CH:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:15])[O:3][CH:2]([CH3:1])[CH2:11]2)[CH2:14][N:20]1[CH2:19][CH2:18][N:17]([C:23](=[O:36])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH:35]=[N:34][N:33]=[N:32]3)=[CH:29][CH:30]=2)[CH2:22][CH2:21]1
Reactant: CC1Cc2cc(C3CO3)ccc2C(=O)O1
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC1Cc2cc(C(O)CN3CCN(C(=O)Cc4ccc(-n5cnnn5)cc4)CC3)ccc2C(=O)O1

Procedure:
A sealed tube containing 3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one (72 mg, 35 mmol), 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (109 mg, 0.35 mmol), DIEA (0.2 mL) and EtOH (3 mL) was heated to 80 C for 12 hours. The excess solvent was removed and the crude product purified via MPLC (35% EtOAc/Hex-60% EtOAc/Hex) to give 6-[1-hydroxy-2-(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)ethyl]-3-methyl-3,4-dihydro-1H-isochromen-1-one. LC-MS (IE, m/z): 477 [M+1]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]2[S:33][CH2:32][CH:31]([CH2:34]I)[CH2:30][C:29]=2[CH:36]=1>CN(C)C=O>[F:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:34][CH:31]3[CH2:30][C:29]4[CH:36]=[C:25]([F:24])[CH:26]=[CH:27][C:28]=4[S:33][CH2:32]3)[CH2:3][CH2:4]2)=[O:9])=[CH:15][CH:14]=1
Reactant: Fc1ccc2c(c1)CC(CI)CS2
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CC2CSc3ccc(F)cc3C2)CC1
Temperature: 23 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2.178 kg (10.5 mol) p-fluorophenyl 4-piperidinyl ketone hydrochloride (R. L. Duncan et al., J. Med. Chem. 13, 1 (1970)), 1.008 kg (9.96 mol) triethylamine and 25 1 dimethylformamide is added a solution of 3.053 kg (9.9 mol) (6-fluoro-3,4-dihydro-2H-1-benzothiopyran-3-yl)methyl iodide in 9 1 dimethylformamide with stirring at 23° C. over 45 min. The suspension is stirred for 3 days at ambient temperature. The reaction is filtered and the filtrate concentrated at 80° C./4 mbar. The resulting oil is poured into a mixture of 20 1 water and 24 1 ethyl acetate, cooled to 5° C. and basified to pH 10 with concentrated ammonium hydroxide. The organic layer is separated, the aqueous solution extracted further with ethyl acetate, and the combined organic solutions washed with water and brine, dried over sodium sulfate and activated carbon, filtered, and concentrated at 50° C./ 4 mbar. The residue is triturated with heptane, filtered, washed twice with heptane, dried in vacuo and dissolved in dichloromethane. The solution is filtered from the insolubles, stirred with 1.27 kg Kieselgel 60 for 30 min., then filtered and evaporated at 45° C./4 mbar to give the title compound as a solid, m.p. 121°-124° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[C:25](F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].C1COCC1.[CH:39]1[CH:43]=[C:42](CC(Cl)=O)[S:41][CH:40]=1>O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:30][CH3:31])=[C:21]([NH:23][C:24](=[O:29])[CH2:25][C:40]4[S:41][CH:42]=[CH:43][CH:39]=4)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)cc1NC(=O)Cc1cccs1
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A solution of N-[5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (250 mg, 0.56 mmol) and 1M LiOH (1.30 mL, 1.39 mmol) in 10:1 THF:H2O (5 mL) was heated at 50° C. overnight. After removal of THF by rotary evaporation, the reaction mixture was redissolved in EtOAc and washed with water (25 mL) and brine (25 mL). The organic layer was dried over MgSO4. Following filtration, the solvent was removed by rotary evaporation. After high vacuum removal of the residual solvent, the crude mixture was dissolved in THF (5 mL) and to this was added thiophene-2-acetylchloride (0.10 mL, 0.84 mmol). After overnight stirring, water (0.5 mL) was added and THF removed by rotary evaporation. The reaction mixture was redissolved in DCM (25 mL) washed with saturated NaHCO3 (10 mL), water (10 mL) and brine (10 mL). Organics were dried over MgSO4, filtered and filtrate concentrated under reduced pressure to afford the desired amide (210 mg, 79%) as an off-white solid. ES-LC/MS m/z=476 [M+H]−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].I[CH3:21].[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: CI
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-(4-fluoro-3-nitro-phenyl)-benzamide (1.60 g, 6.15 mmol) in anhydrous DMF was added iodomethane (3.49 g, 24.60 mmol, 1.53 ml) under argon. 60% Sodium hydride (0.37 g, 9.23 mmol) was then added portionwise to the cooled solution (0° C.) and the reaction mixture was then stirred at room temperature for 24 h. The solution was poured slowly into water and the aqueous layer was extracted 3× with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography, eluting with hexane/ethyl acetate (4:1) to give N-(4-fluoro-3-nitro-phenyl)-N-methyl-benzamide. (1.47 g, 87%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=1>CN1CCCC1=O.O>[F:29][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[O:27][CH3:28])[CH2:20][CH2:19][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=2[C:5]2[CH2:14][N:13]([CH3:15])[CH2:12][CH2:11][C:6]1=2
Reactant: COc1ccc(CCBr)cc1F
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cc1F
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 4632.5 %

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.5 g, 0.0022 mmol) was dissolved in N-methyl 2-pyrolidone (4.0 mL). Powdered potassium hydroxide (1 g, 0.008 mol) was added and heated at 100° C. for 2 h. 4-(2-Bromo-ethyl)-2-fluoro-1-methoxy-benzene (0.520 g, 0.0022 mol) was added at the room temperature and stir for 0.5 h at RT (TLC showed incomplete reaction). Reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×100 mL). Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as light yellow oil (0.038 g, 4% yield). 8-Chloro-5-[2-(3-fluoro-4-methoxy-phenyl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0038 g, 0.00010 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.00010 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.016 g, 34% yield).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[CH:7][C:6]([Br:13])=[CH:5]2.[OH-:14].[Na+]>O.P(=O)(O)(O)O>[Br:13][C:6]1[CH:7]=[N:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([OH:14])=[CH:11][C:10]=2[CH3:12]
Reactant: [OH-]
Reactant: Cc1cc(N)cc2cc(Br)cnc12
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(O)cc2cc(Br)cnc12
Temperature: 180 °C

Procedure:
6-Amino-3-bromo-8-methylquinoline (12 g) was suspended in a mixture of water (5 ml) and phosphoric acid (60 ml) and heated in a sealed glass tube to 180° C. for 3 days. The mixture was cooled to ambient temperature, diluted with water then taken to pH 3-4 with aqueous (2M) sodium hydroxide. The precipitate formed was filtered from solution, washed with cold water and sucked to dryness to give 3-bromo-6-hydroxy-8-methylquinoline, 11.0 g, as a grey solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>ClCCl.N1C=CC=CC=1>[C:16]([O:1][CH2:2][C@@H:3]([C@@H:5]1[C@:13]2([CH3:14])[C@H:8]([C@@H:9]([OH:15])[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)[CH3:4])(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C[C@@H](CO)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](COC(=O)C(C)(C)C)[C@H]1CC[C@H]2[C@@H](O)CCC[C@]12C
Temperature: 0 °C

Procedure:
The compound of Example 3D (0.58 g, 2.7 mmol) was dissolved in 4 mL of dichloromethane and 2 mL of pyridine; the solution was cooled to 0° C., and 0.39 mL of pivaloyl chloride was added dropwise over 5 minutes. The resultant mixture was stirred at 0° C. for 2.5 hours, then it was quenched with water, and the mixture was concentrated in vacuo with the bath maintained below ambient temperature. The crude material was partitioned between ether and 0.5 N aqueous HCl; the organic phase was washed with 0.5 N aqueous HCl, then brine, and dried over Na2SO4. The solvents were removed in vacuo; the residue (0.96 g) was carried forward without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([N:21](COCC)[C:22]3[N:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)(=[O:20])=[O:19])=[C:13]([F:33])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[ClH:39].O>CO>[ClH:17].[ClH:39].[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:9]=2[O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([S:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]([F:28])=[CH:26][N:27]=3)(=[O:20])=[O:19])=[C:13]([F:33])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOCN(c1ncc(F)cn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N)c2)cc1F
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(-c2cc(Cl)ccc2Oc2cc(F)c(S(=O)(=O)Nc3ncc(F)cn3)cc2Cl)ccn1
Temperature: 60 °C

Procedure:
To a solution of 4-[2-(2-aminopyridin-4-yl)-4-chlorophenoxy]-5-chloro-N-(ethoxymethyl)-2-fluoro-N-(5-fluoropyrimidin-2-yl)benzenesulfonamide (Preparation 15, 67 mg, 0.12 mmol) in methanol (1 mL) was added a 2.0 M solution of hydrogen chloride in water (1 mL, 2.00 mmol). The reaction mixture was heated at 60° C. for 6 hours then concentrated in vacuo. The residue was freeze dried from acetonitrile-water to afford the title compound as a white solid (69 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:17]([NH2:19])[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[NH:23][CH:24]=[N:25]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:17]([NH:19][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:18])[C:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccs1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2ccc(F)cc2nc1-c1cccs1

Procedure:
Prepared according to Procedure H using (1S)-1-(7-fluoro-2-(thiophen-2-yl)-quinolin-3-yl)ethanamine (0.078 g, 0.286 mmol), 6-chloropurine (0.053 g, 0.344 mmol, 1.2 eq) and DIEA (0.58 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(7-fluoro-2-(thiophen-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=8 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 8.62 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 8.00-8.07 (m, 1H), 7.62-7.73 (m, 3 H), 7.43-7.51 (m, 1H), 7.18 (m 1H), 1.78 (d, J=7.04 Hz, 3H), 1H), Mass Spectrum (ESI) m/e=391 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH2:6].CC1C=CC(C)=CC=1N.[C:20](OC(=O)C)(=[O:22])[CH3:21].C([O-])(=O)C.[K+]>C(Cl)(Cl)Cl>[OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:7]([CH3:10])=[CH:8][CH:9]=1)[NH:6][C:20]([CH3:21])=[O:22]
Reactant: Cc1ccc(CO)cc1N
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cc1ccc(C)c(N)c1
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(CO)ccc1C
Yield: 114.1 %

Procedure:
To a solution of an approximately 1:1 mixture of 3-(hydroxymethyl)-6-methylaniline, (8.05 g, 58.8 mmol) (2) and 2,5-dimethylaniline in chloroform (290 mL), was added acetic anhydride (20 mL, 206 mmol) and potassium acetate (20 g, 202 mmol). The resulting mixture was heated to its reflux temperature for 2 hours. The mixture was then concentrated and purified by a flash column chromatography (1:1 of hexane-ethyl acetate) which also removed the by-product from Example 61 to give the title compound (12.02 g, 92%). TLC Rf: 0.52 (ethyl acetate); MS (electrospray) 222 (M+1); 1H N MR (CDCl3) δ 2.09 (s, 3H), 2.21 (s, 3H), 2.25 (s, 3H), 5.06 (s, 2H), 7.00 (br s, 1H, NH), 7.08 (d, 1H, J=7.6 Hz), 7.18 (d, 1H, J=7.6 Hz), 7.81 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)([O-:3])=[O:2].[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:14])=[C:8]([S:10]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)(=[O:12])=[O:11])[CH:9]=1)([O-:3])=[O:2]
Reactant: c1c[nH]cn1
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)n1ccnc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
2.36 g of 5-nitro-2-methyl-phenylsulfonyl chloride (0.01 mol) and 1.36 g of imidazole (0.02 mol) were dissolved in 15 ml of pyridine, and the mixture was stirred at 50° C. for 3 hours to react. After the reaction, the reaction mixture was poured into water, and extracted with chloroform. The chloroform layer was washed with water and dehydrated. Evaporation of chloroform gave 1.70 g of 1-(5-nitro-2-methyl-phenylsulfonyl)-imidazole of the m.p. 119°-120° C.