Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:31])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=1.I[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:31])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:18]=1)[CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Reactant: ICC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(S(C)(=O)=O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of diisopropylamine (951 μL, 6.79 mmol) in dry tetrahydrofuran (6 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (2.5 mL, 6.79 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3,4-bis-methanesulfonyl-phenyl)-acetic acid methyl ester (1.89 g, 6.17 mmol) in dry tetrahydrofuran (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL). The resulting reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (1.56 g, 7.40 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 64 h. The reaction mixture was quenched with water (150 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining residue was further diluted with water (100 mL) and then extracted with ethyl acetate (1×250 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 3/1 hexanes/ethyl acetate) afforded 2-(3,4-bis-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (1.61 g, 67%) as a yellow oil: EI-HRMS m/e calcd for C17H24O6S2 (M+) 388.1014, found 388.1014.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]3=[O:27])[N:13]=2)=[N:6][CH:7]=1.Cl>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:27])[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)C1=O
Agent: Cl
Solvent: ClCCl
Product: O=C1NCCC1Cc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reaction time: 8 h
Yield: 87.7 %

Procedure:
In a 20 mL scintillation vial, tert-butyl 3-((2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)methyl)-2-oxopyrrolidine-1-carboxylate (35 mg, 0.064 mmol) was dissolved in CH2Cl2 (1 mL) and HCl (4.0M solution in dioxane) (2.00 mL, 8.00 mmol) was added. The resulting mixture was agitated overnight. The solvents and excess HCl were evaporated, and product was obtained as yellow solid (25 mg, 87.5% yield). 1H NMR (DMSO-d6 δ 1.70-1.80 (m, 1H), 2.12-2.20 (m, 1H), 2.60-2.74 (m, 1H), 3.02 (d, 1H), 3.16-3.22 (m, 2H), 3.44-3.76 (m, 5H), 6.97 (s, 1H), 7.19-7.50 (m, 6H), 7.83 (s, 1H), 8.30 (s, 1H).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)[CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@H:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[NH:30][CH2:29]2)=[O:7])[NH2:1])=[CH:16][C:17]=1[F:22]
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)c(F)c1)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)c(F)c1)C1CCOCC1

Procedure:
The title compound was prepared from (2S,3R)-2-azido-3-(4-chloro-3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (Example 1035, step 1) using the procedures and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=663 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[F:8].[CH:11]1[CH2:16][CH2:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[F:1][C:2]1[C:3](=[O:10])[CH:4]2[CH:5]([C:6](=[O:9])[C:7]=1[F:8])[CH:13]1[CH2:14][CH2:15][CH:16]2[CH:11]=[CH:12]1
Reactant: C1=CCCC=C1
Reactant: O=C1C=CC(=O)C(F)=C1F
Solvent: CCOCC
Product: O=C1C(F)=C(F)C(=O)C2C3C=CC(CC3)C12
Temperature: 25 °C

Procedure:
A solution of 1.7 g of 2,3-difluoro-1,4-benzoquinone (G. Haufe, Perkin Transactions 1 (2002), (23), 2719-2728), 2.2 mL of 1,3 cyclohexadiene in 25 mL of Et2O was heated in a closed vessel at 50° C. for 2 h. After cooling to rt the mixture was concentrated in vacuo to obtain 1.4 g of the desired compound as mixture of stereoisomers as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][S:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][S:23][C:24]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cccc(NC[C@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CNc1cccc(C(=O)O)c1)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of 24 (1.51 g) in methanol (70 mL) was added 5% sodium hydroxide (10 mL). The solution was stirred for 18 h, concentrated in vacuo, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was extracted w/50 mL each of 2% potassium hydrogen sulfate, saturated sodium chloride, dried over magnesium sulfate and concentrated in vacuo to obtain the product. NMR (300 MHz, CDCl3) δ 7.50-7.10 (18H, m), 6.76 (1H, m,), 4.60 (1H, m), 3.82 (1H, m), 3.08 (2H, m), 2.47 (3H, m), 1.43 (9H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Clc1cc(-c2ccnc(NC3CCOCC3)n2)ccn1
Reactant: Nc1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1cccc(Nc2cc(-c3ccnc(NC4CCOCC4)n3)ccn2)c1

Procedure:
To a solution of 4-(2-chloro-4-pyridinyl)-N-(tetrahydro-2H-pyran-4-yl)-2-pyrimidinamine (i.e., the product of Step A) (500 mg, 1.7 mmol) in toluene (15 mL) was added 3-fluoroaniline (400 uL, 4.1 mmol), palladium(II) acetate (50 mg, 0.20 mmol), (±)-BINAP (100 mg, 0.16 mmol) and cesium carbonate (1.9 g, 5.8 mmol), and the resulting mixture was stirred at reflux for 4.5 h. The cooled mixture was partitioned between ethyl acetate and water, and the organic layer was washed with brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure to give a residue that was chromatographed on silica gel eluted with 15% to 85% ethyl acetate in hexanes to afford 330 mg of title compound as a solid, m.p. 190-192° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][CH2:4][CH2:3]1.C(O[CH2:14][N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:16][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[CH2:21]([N:15]1[CH2:16][CH:6]2[CH:5]([CH2:4][CH2:3][CH:2]([CH3:1])[C:7]2=[O:8])[CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC1CCC=CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCC2CN(Cc3ccccc3)CC2C1=O
Reaction time: 3 h

Procedure:
To a solution of 1 g of 6-methyl-cyclohex-2-enone in 15 cm3 of dichloromethane are added, at room temperature, 3 drops of trifluoroacetic acid, followed by 3.6 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine. The reaction mixture is brought to reflux, with stirring, for 3 hours. After cooling, potassium carbonate is added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 2 cm, height 20 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (60/40 by volume) and collecting 25 cm3 fractions. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 0.7 g of (3aRS,5RS,7aSR)-2benzyl-5-methyl-4-perhydroisoindolone is obtained in the form of a colourless oil.
Reaction SMILES: [OH:1][C:2]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15]C(=O)OCC2C=CC=CC=2)[CH2:11][CH2:10]1)([C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[CH3:3].B(Br)(Br)Br>ClCCl.CO>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:2]([C:4]2[S:5][CH:6]=[CH:7][N:8]=2)([OH:1])[CH3:3])[CH2:10][CH2:11]1
Reactant: CC(O)(c1nccs1)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(O)(c1nccs1)[C@H]1CC[C@H](N)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {trans-4-[1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]cyclohexyl}-carbamate (895 mg, 2.48 mmol) in dichlormethane at −78° C. was added boron tribromide (1.0 M in dichloromethane, 2.7 mL, 2.7 mmol) dropwise. After one hour, the solution was warmed to 0° C. Another portion of boron tribromide (1.0 M in dichloromethane, 2.7 mL, 2.7 mmol) was then added dropwise and the reaction was allowed to warm to room temperature. The solution was then carefully diluted with methanol and concentrated in vacuo. The residue was purified by chromatography on silica gel to afford 1-(trans-4-aminocyclohexyl)-1-(1,3-thiazol-2-yl)ethanol. MS ESI calc'd. for C11H19N2OS [M+H]+ 227. found 227. 1H NMR (500 MHz, DMSO-d6) δ 7.67 (d, J=3.3, 1H), 7.51 (d, J=3.2, 1H), 5.69 (s, 1H), 2.46-2.39 (m, 1H), 1.80-1.65 (m, 3H), 1.63-1.50 (m, 1H), 1.43 (s, 3H), 1.40-1.32 (m, 1H), 1.24-1.11 (m, 1H), 1.03-0.86 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:12]C(=O)C)([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Cl-].[Na+]>C(O)CO>[NH2:12][C:9]([CH3:11])([CH3:10])[CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: CC(=O)NC(C)(C)Cc1cccc(N)c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: CC(C)(N)Cc1cccc(N)c1
Temperature: 195 °C
Yield: 88 %

Procedure:
A solution of 1.7 g (8.3 mmol) of N-[2-(3-aminophenyl)-1,1-dimethyl-ethyl]-acetamide in 20 ml of ethylene glycol was treated with 3 g (75 mmol) of sodium hydroxide and the mixture heated at 195° C. for 20 hours. The mixture was cooled and added to 150 ml of 1M aqueous sodium hydroxide saturated with sodium chloride. The product was extracted with diethyl ether (3×100 ml). The combined organic phases were dried over magnesium sulfate, filtered and evaporated to give 1.2 g (88%) of 3-(2-amino-2-methyl-propyl)-aniline as a colorless oil. [Mass spectrum (ESI) M+CH3CN+ =206].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([CH:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[OH:20])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)c2ccc(Cl)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(4-Chloro-benzoyl)-azetidine-1-carboxylic acid tert-butyl ester (62.5 g, 210 mmol) in ethanol (1000 ml) cooled to 10° C. is treated with sodium borohydride (9.5 g, 250 mmol). The reaction mixture is allowed to warm to room temperature and stirred for 2 hours. The reaction mixture is added to water and the precipitate collected by filtration, and dried under vacuum to afford 3-[(4-Chloro-phenyl)-hydroxy-methyl]-azetidine-1-carboxylic acid tert-butyl ester. Mpt 123-125° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[CH:17][CH:18]=2)[C:13]1=[O:30].C(N(CC)CC)C.[CH3:38][N:39]([CH3:43])[CH2:40][C:41]#[CH:42].[Li+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:38][N:39]([CH3:43])[CH2:40][C:41]#[C:42][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][N:12]([C:3]3[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=3[CH3:1])[C:6]([O:8][CH3:9])=[O:7])[C:13]2=[O:30])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccc3ccc(OS(=O)(=O)C(F)(F)F)cc3c2=O)c1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(-n2ccc3ccc(C#CCN(C)C)cc3c2=O)c1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
A mixture of the methyl 4-methyl-3-[1-oxo-7-{[(trifluoromethyl)sulfonyl]oxy} isoquinolin-2(1H)-yl]benzoate (284 mg), PdCl2(PPh3)2 (13 mg), CuI (6 mg) and triethylamine (449 μl) were stirred in acetonitrile (4.2 ml) for 20 minutes. 1-Dimethylamino-2-propyne (69 μl) in acetonitrile (2.8 mL) was added dropwise and the reaction was stirred at 80° C. for 22 hours. LiCl (81 mg) was added and stirring continued at 80° C. for 1.5 hours. PdCl2(PPh3)2 (13 mg), CuI (6 mg) and 1-dimethylamino-2-propyne (69 μl) was added and stirring continued for a further 22 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water (×5), brine, dried (magnesium sulfate), and concentrated to an oil. Purification by column chromatography on a silica column eluting using a gradient of ethyl acetate to 10% methanol/ethyl acetate gave methyl 3-[7-[3-(dimethylamino)prop-1-yn-1-yl]-1-oxoisoquinolin-2(1H)-yl]-4-methylbenzoate as a light brown solid (126 mg); NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.27 (s, 6H), 3.52 (s, 2H), 3.86 (s, 3H), 6.79 (d, 1H), 7.43 (d, 1H), 7.60 (d, 1H), 7.79 (m, 2H), 7.87 (s, 1H), 7.99 (d, 1H), 8.23 (s, 1H); Mass Spectrum: M+H+ 375.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[NH:7][N:6]=[CH:5]2.P(Cl)(Cl)([Cl:15])=O.C(N(C(C)C)CC)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:15])=[N:7][N:6]=[CH:5]2
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nncc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-Bromo-2H-phthalazin-1-one (2.5 g), phosphorous oxychloride (11 mL) and diisopropyl ethyl amine (2 mL) was stirred at RT for 30 min then at 90° C. for 3 h. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate and washed with a saturated solution of NaHCO3, NH4Cl, and brine to afford the desired compound (2.0 g). TLC Rf 0.8 (EA/hexane 2/3).
Reaction SMILES: Br[C:2]1[N:19]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:18])([F:17])[CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:4]2[N:3]=1.C([N:22](S(F)(F)F)[CH2:23][CH3:24])C>C(Cl)(Cl)Cl>[F:17][C:10]([F:18])([CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:9]1[N:4]2[N:3]=[C:2]([NH:19][C:5]3[CH:24]=[C:23]4[C:8]([C:9]([CH3:10])=[N:4][NH:22]4)=[CH:7][CH:6]=3)[N:19]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: FC(F)(c1cccc2nc(Br)nn12)C1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2cc(Nc3nc4cccc(C(F)(F)C5CCOCC5)n4n3)ccc12
Temperature: 50 °C
Yield: 79 %

Procedure:
2-Bromo-5-(difluoro(tetrahydro-2H-pyran-4-yl)methyl)-[1,2,4]triazolo[1,5-a]pyridine. (Diethylamino)sulfur trifluoride (4.26 mL, 32.2 mmol) was added to a stirred solution of (2-bromo-[1,2,4]triazolo[1,5-c]pyridin-5-yl)(tetrahydro-2H-pyran-4-yl)methanone (2 g, 6.45 mmol) in chloroform (40 mL) in a high pressure flask under nitrogen. The flask was sealed and heated at 50° C. for 16 h. The reaction was quenched with methanol (1 mL). The resulting mixture was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate. The organics were washed with brine and then dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was purified using flash chromatography (5-50% ethyl acetate in hexane), to give the desired product (1.7 g, 5.12 mmol, 79% yield) as a light yellow solid. MS (ESI) m/z 334.2 [M+2]+.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[C:13]([O:15][C:16](=[O:17])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH:32]([OH:35])([CH3:34])[CH3:33]>>[CH2:1]([N:8]1[C@H:12]([C:13]([O:35][CH:32]([CH3:34])[CH3:33])=[O:14])[C@H:11]([C:16]([OH:15])=[O:17])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)O
Reactant: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Solvent: c1ccccc1
Product: CC(C)OC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid anhydride (16.8 g), benzene (230 ml) and isopropanol (5.50 g) was refluxed for 10 hours. A part (about 150 ml) of the reaction mixture was concentrated under reduced pressure. The residue was stirred with n-hexane (30 ml) at room temperature for 5 hours. Crystals produced were filtered and dried to yield racemic cis-1,3-dibenzyl-5-isopropoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (9.61 g). M.P., 108°-109° C.
Reaction SMILES: [F:1]/[CH:2]=[C:3](\[CH2:13]O)/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.CS(Cl)(=O)=O.[Br-:27].[Li+]>CC(C)=O>[Br:27][CH2:13]/[C:3](=[CH:2]\[F:1])/[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)NC/C(=C/F)CO
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC/C(=C/F)CBr
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a stirring solution of (Z)-tert-butyl 3-fluoro-2-(hydroxymethyl)-allylcarbamate (0.50 g, 2.44 mmol) in acetone (15 mL) at 0° C. under N2 was added sequentially triethylamine (0.51 mL, 3.65 mmol) and methanesulfonyl chloride (0.23 mL, 2.92 mmol). The resulting mixture was stirred at this temperature for 30 min. The reaction mixture was filtered to remove the precipitated salts and the filter cake was washed with further acetone (10 mL). The filtrate was charged with lithium bromide (1.06 g, 12.18 mmol) and the resulting suspension was stirred at room temperature for 1 h. The reaction mixture was partitioned between water (25 mL) and ethyl acetate (25 mL) and the aqueous layer was extracted with further ethyl acetate (25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo to give (Z)-tert-butyl 2-(bromomethyl)-3-fluoroallylcarbamate as a pale yellow oil (0.63 g, 96%). 1H-NMR (300 MHz; CDCl3) δ ppm: 1.47 (9H, s), 3.80 (2H, br s), 4.09 (2H, d, J 2.6 Hz), 4.75 (1H, br s), 6.65 (1H, d, J 81.9 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:15])=O)=[CH:8][CH:7]=[CH:6]2)[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[O:20][CH2:21][C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23].C([O-])(=O)C>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][CH:30]=1)[O:20][CH2:21][C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])=[O:15])=[CH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2c(C(=O)O)cccc2c1
Reactant: CC(C)OC(=O)COc1cccc(N)c1
Agent: CC(=O)[O-]
Product: CCc1ccc2c(C(=O)Nc3cccc(OCC(=O)OC(C)C)c3)cccc2c1

Procedure:
In accordance with the procedure of Example 1, step 5, 6-ethyl-1-naphthoic acid (51 mg, 0.25 mmol) and isopropyl 2-(3-aminophenoxy)acetate (64 mg, 0.31 mmol) were converted into 34 mg (34%) of isopropyl 243-(6-ethyl-1-naphthamido)phenoxy)acetate.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[H-].[Na+].Cl[CH2:15][C:16]1[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:15][C:16]2[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])=[N:18][C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])[N:3]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C

Procedure:
Prepared according to Procedure I. A solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (400 mg, 1.5 mmol) in DMF (5 mL) at 0° C. was treated with NaH (60%, 67.4 mg, 1.1 eq) for 30 min before addition of a solution of 3-(chloromethyl)-8-methyl-2-o-tolylquinoline (435 mg, 1 eq) in DMF (2 mL). The mixture was stirred at room temperature over night. The reaction mixture was partitioned between DCM (50 mL) and water (50 mL). The insoluble was filtered and washed with DCM and water. The organic layer from the filtrate was separated, dried over Na2SO4, concentrated and purified by column chromatography on silica gel (eluent: DCM/MeOH, 25/1) to provide a white solid [PI3Kδ IC50=6 nM]. 1H-NMR (DMSO-d6) δ 7.96 (s, 1H), 7.85 (s, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.44 (d, J=7.0 Hz, 1H), 7.31 (t, J=7.1 Hz, 1H), 6.94-6.99 (m, 4H), 5.26 (s, 2H), 2.45 (s, 3H), 1.79 (s, 3H). Mass Spectrum (ESI) m/e=507 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O-:20])=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.O.[NH4+:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([NH2:22])=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3c(C(=O)[O-])cccc3o2)cc1
Reactant: [NH4+]
Solvent: O
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1
Yield: 45 %

Procedure:
Methyl 2-(4-methoxyphenylbenzo[d]oxazole-4-carboxylate (68 mg, 0.24 mmol) in ammonium water (10 mL) was stirred at 30° C. overnight, then filtered, and the cake was washed with water, dried in vacuum to obtain 2-(4-methoxyphenylbenzo[d]oxazole-4-carboxamide (29 mg, yield 45%). 1H-NMR (400 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.17-7.19 (d, J=8 Hz, 1H), 7.49 (dd, 1H), 7.94-7.97 (m, 3H), 8.25-8.26 (d, J=8 Hz, 2H), 8.49 (brs, 1H); LC-MS (ESI) m/z 269 [M+1]−.