Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[N:21][OH:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:12][C@H:11]2[C@H:10]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)=[N:21][O:22]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H]2ON=C(c3ccc(Cl)cc3)[C@@H]2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To N-Boc pyrroline (480 mg; 2.83 mmol) and chloro oxime 2a (557 mg; 2.93 mmol) in ethyl acetate (15 mL), was added dropwise triethylamine (0.4 mL) in ethyl acetate (15 mL). The reaction mixture was stirred at room temperature for 24 hours. An additional portion of chloro oxime 2a (234 mg; 1.23 mmol) and triethylamine were added. After stirring overnight, the reaction mixture was poured into water (50 mL) and extracted. The organic layer was dried (MgSO4), filtered and evaporated. Chromatography with 30% ethyl acetate/hexanes yielded 3a as a white solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][C:23](=O)[N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O>[CH:1]1([C:7]2[C:8]3[CH:34]=[CH:33][C:32]([C:35]([O:37][CH3:38])=[O:36])=[CH:31][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCC(=O)N2CCCCC2)cccc1-3
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1c(OCCN2CCCCC2)cccc1-3
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (254 mg, 0.49 mmol) in tetrahydrofuran (1 ml) was added a solution (1 ml) of 1M BH3 THF complex in tetrahydrofuran, and the mixture was stirred at room temperature for 3 hr. 2N Hydrochloric acid (2 ml) was added to the reaction mixture, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and the reaction mixture was neutralized by adding 2N aqueous sodium hydroxide solution and saturated aqueous sodium hydrogen carbonate solution. Water was added, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried in vacuo to give methyl 12-cyclohexyl-4-[2-(piperidin-1-yl)ethoxy]-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (240 mg, yield 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH:22]([OH:39])[CH:23]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:35]([O:34][C:32]([NH:31][CH:23]([CH:22]([OH:39])[CH:21]([NH:20][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)CCCCCNC(=O)OCc1ccccc1

Procedure:
N-(6-(Benzyloxycarbonylamino)hexanoic acid was coupled to the resultant compound of Example 11 using the mixed anhydride procedure of Example 54A to give the desired compound after silica gel chromatography using 75% ethyl acetate in chloroform.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:15]([CH2:17][CH:18](OC)OC)[CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH:18]=[CH:17][N:15]([CH3:16])[C:13](=[O:14])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CN(C)C(=O)CNC(=O)OCc1ccccc1)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C=CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C

Procedure:
A solution of N2-benzyloxycarbonyl-N1-(2,2-dimethoxyethyl)-N1-methylglycinamide (1.9 Kg, 6.1 mol) and p-toluenesulfonic acid monohydrate (270 g) in toluene (29.4 L) was stirred at 80° C. for 4 hours. The resultant reaction mixture was cooled to room temperature, washed with water (4×2 L), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residual solid was subjected to column chromatography on silica gel eluting with heptane-ethyl acetate. Concentration of appropriate fractions provide the cyclization product as off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15](Cl)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[CH:20]1(B(O)O)[CH2:22][CH2:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(Cl)(Cl)Cl>O1CCOCC1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH:20]3[CH2:22][CH2:21]3)=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1cnn(-c2ncc(Cl)cc2C)c1C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnn(-c2ncc(C3CC3)cc2C)c1C
Yield: 75.5 %

Procedure:
A suspension of 1-(5-chloro-3-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (600 mg), cyclopropylboronic acid (369 mg), 1,1′-bis(di-tert-butylphosphino)ferrocene (51 mg), palladium acetate (24 mg) and tripotassium phosphate (1.83 g) in 1,4-dioxane (5 ml) was stirred under reflux for 6 hours. After completion of the reaction, the mixture was allowed to cool, and chloroform was added, filtered through Celite, and then the filtrate was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(5-cyclopropyl-3-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (462 mg) as a yellow solid. MS (ESI) m/z: 286 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:12](=[O:14])[C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:16][CH:15]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.4 %

Procedure:
4-Phenoxybenzoic acid (214 mg, 1.0 mmol), 1-hydroxybenzotriazole (203 mg, 1.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (290 mg, 1.5 mmol) and triethylamine (0.7 mL, 5 mmol) were dissolved in dichloromethane (15 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (190 mg, 1.0 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was concentrated and the residue was purified by column chromatography (silica gel, dichloromethane/methane=40:1) to give the product as a white solid (120 mg, 34%). LRMS (M+H+) m/z: calcd 348.15. found 348. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.28 (m, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.40 (t, J=7.2 Hz, 2H), 7.18 (t, J=7.5 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 5.84 (s, 1H), 4.27 (d, J=7.5 Hz, J=3.6, 2H), 2.15 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH:1]([C:14]([O:16][CH3:17])=[O:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:28])(=O)=O)=CC=1>O1CCCC1>[C:1]([C:14]([O:16][CH3:17])=[O:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[F:28]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82 %

Procedure:
4.8 milliliters KN(SiCH3)2 were dropped into 5 milliliters (C6H5)2CHCOOCH3 in tetrahydrofuran at -78° C. and the resulting yellow suspension was stirred for 45 minutes. 1.2 molar equivalents N-fluorobenzenesulfonimide prepared according to Example 1 above in 4 milliliters tetrahydrofuran were dropped into the mixture and stirring continued at -78° C. for 1 hour. The mixture was allowed to warm up to room temperature, quenched with ammonium chloride, and acidified with 0.1N hydrogen chloride. Extraction with dichloromethane, drying, and evaporation were followed by purification on a silica gel column. White crystalline (C6H5)2CFCOOCH3 was obtained in 82% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[C:2]([C:28]5[CH:29]=[N:24][CH:25]=[N:26][CH:27]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cncnc3)ccc1OCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 20.9 %

Procedure:
A mixture of 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.5 mmol), pyrimidin-5-ylboronic acid (200 mg, 0.75 mmol), Cs2CO3 (490 mg, 1.5 mmol) was stirred in dioxane and water (5:1, 3.0 mL) followed by the addition of Pd(dppf)Cl2 (30 mg). The reaction mixture was bubbled with N2 gas for 10 min, the reaction tube was sealed, and the contents were stirred at 130° C. under microwave irradiation for 30 min. The mixture was filtered through celite and the filtrate was concentrated and purified with prep-HPLC to give 557 (39 mg, 13%). 1H-NMR (CDCl3, 400 MHz): δ 9.23 (s, 1H), 9.01 (s, 2H), 8.78 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.53-7.53 (d, J=2.4 Hz 1H), 7.52-7.51 (d, J=2.4 Hz 1H), 5.90-5.83 (m, 1H), 4.58-4.56 (m, 2H), 4.53-4.51. MS (ESI) m/z 374.17 [M+H+]
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].[O-]CC.[Na+].O>C(O)C>[N+:8]([CH2:11][C:4]1([OH:7])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)([O-:10])=[O:9]
Reactant: O=C1CCOCC1
Reactant: C[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])CC1(O)CCOCC1
Yield: 33.7 %

Procedure:
A solution of tetrahydro-4H-pyran-4-one (45.0 g, 449 mmol) and nitromethane (36.5 mL, 674 mmol) in ethanol (27 mL) was treated with a solution of sodium ethoxide in ethanol (2.67 M, 8.40 mL, 22.5 mmol) using the method described in Part A of Example 9. The reaction mixture was transferred to a reparatory funnel and water (450 mL) was added. The mixture was extracted with ethyl acetate (3×900 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to a light brown oil. Ethyl acetate/hexanes was added and pale brown crystals formed that were isolated by filtration and dried to provide 4-(nitromethyl)tetrahydro-2H-pyran-4-ol (24.4 g, 34%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][CH2:16][N:17]1[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]1=[S:24].[I:25]I>C1COCC1.[Cl-].[NH4+]>[I:25][C:22]1[N:17]([CH2:16][CH2:15][O:14][CH3:13])[C:18](=[S:24])[NH:19][C:20](=[O:23])[CH:21]=1
Reactant: II
Reactant: COCCn1ccc(=O)[nH]c1=S
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCCn1c(I)cc(=O)[nH]c1=S
Temperature: -20 °C
Reaction time: 20 h
Yield: 108 %

Procedure:
To a stirring solution of diisopropylamine (8.3 mL, 59.10 mmol) in THF (50 mL) was added n-butyl lithium (2N in hexanes, 30.0 mL, 60.0 mmol) dropwise at −78° C. under argon. The reaction mixture was slowly warmed to −20° C. and then cooled to −78° C. A solution of 1-(2-methoxyethyl)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (5.0 g, 26.85 mmol) in THF (50 mL) was added dropwise at −78° C. The reaction mixture was slowly warmed to −10° C. over 1 hour and then cooled to −78° C. A solution of iodine (15.0 g, 59.07 mmol) in THF (50 mL) was added at −78° C. and the reaction mixture was stirred at room temperature for 20 hours. Reaction was diluted with saturated aqueous ammonium chloride (200 mL) and the organic solvents were removed under reduced pressure. The aqueous residue was acidified to pH 4 with 1N aqueous HCl and extracted with CH2Cl2 (3×300 mL, 1×200 mL). The combined organic layers were washed with 10% aqueous sodium thiosulfate solution (400 mL), brine (300 mL), dried over MgSO4 and concentrated in vacuo. The resulting residue was stirred in CH2Cl2 at room temperature and solids were collected by filtration to give the title compound (9.05 g, 54%) as a pale brown solid. The filtrate was concentrated and purified by flash chromatography (0-25% CH2Cl2/EtOAc) to afford a second batch of the title compound (3.10 g, 18%) as a cream colored solid (72% combined yield).
Reaction SMILES: C([Li])CCC.[Br-].[CH2:7]([O:9][C:10]1[CH:35]=[CH:34][C:13]([CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][CH:11]=1)[CH3:8].[CH2:36]([Si:41]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:46][CH2:45][CH:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH2:37][CH2:38][CH2:39][CH3:40]>CCCCCC.O.O1CCCC1>[CH2:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:47][CH:44]2[CH2:43][CH2:42][Si:41]([CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH2:46][CH2:45]2)=[CH:34][CH:35]=1)[CH3:8]
Reactant: CCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=O)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(OCC)cc2)CC1
Reaction time: 2 h
Yield: 96.9 %

Procedure:
65 ml of an n-hexane solution of 1.60 moles of n-butyl lithium was added to a mixture of 48.0 g of p-ethoxybenzyltriphenylphosphonium bromide and 200 ml of tetrahydrofuran to obtain a ylide solution. 27.4 g of 4-n-pentyl-4-phenyl-4-silacyclohexane carbaldehyde was dropped in the solution. After agitation at room temperature for 2 hours, the resultant solution was charged into iced water and extracted with ethyl acetate. The extract was subjected to ordinary washing and concentrating operations to obtain a residue, to which n-hexane was added. The resultant crystals of triphenylphosphine oxide were removed by filtration and the flitrate was concentrated. The resultant residue was purified through silica gel column chromatography to obtain 38.0 g (yield: 97%) of 4-(2-(4-ethoxyphenyl)ethenyl)-1-n-pentyl-1-phenyl-1-silacyclohexane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1.[NH2:20][NH2:21]>C1COCC1>[NH:20]([C:2]1[N:7]=[C:6]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][N:3]=1)[NH2:21]
Reactant: NN
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NN)nc1C(F)(F)C(F)(F)F
Yield: 95 %

Procedure:
The title compound was prepared as described in Example 18, but employing a solution of ethyl 2-chloro-4-pentafluoroethylpyrimidine-5-carboxylate (0.30 g, 0.99 mmol) and hydrazine (0.16 g, 5.0 mmol) in THF (20 mL) resulting in a 95% yield (0.28 g); 1HNMR (CDCl3) δ 8.86 (bs, 1H), 7.12 (bs, 1H), 4.37 (q, 2H), 1.72 (bs, 2H), 1.38 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1)=[O:8]
Reactant: ClCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1cscn1
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of Example 18A (2.65 g, 9.4 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.247 g, 10.3 mmol). The reaction mixture was stirred for 30 min. and then treated with commercially available 4-(chloromethyl)thiazole (1.25 g, 9.4 mmol). The resulting mixture was stirred at room temperature for 18 h, poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The organics were washed with water, brine (2×100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by using an Analogix® Intelliflash280 ™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound (2.56 g, 72% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.28 (s, 3 H), 3.77 (s, 3 H), 5.50 (s, 2 H), 7.10 (d, J=8.7 Hz, 1H), 7.31 (d, J=1.6 Hz, 1 H), 7.38-7.52 (m, 2 H), 7.63 (dd, J=14.5, 2.6 Hz, 1 H), 9.09 (d, J=2.0 Hz, 1 H). MS (DCI) m/z 398 (M+H)+; MS (DCI) m/z 380 (M+H)+. Anal. Calculated for C16H14ClN3O2S2: C, 50.59; H, 3.71; N, 11.06. Found: C, 50.57; H, 3.02; N, 11.03.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[C:1]([O:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7]([Cl:24])=[O:8])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Oc1cc(F)ccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(F)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-acetoxy-4-fluorobenzoic acid (852 mg, 4.9 mmol) in dry dichloromethane (40 mL) under dry nitrogen were added sequentially dry DMF (8 drops), dry pyridine (0.5 mL) and oxalyl chloride (0.5 mL). After stirring 1.5 h at room temperature, the reaction mixture was evaporated to dryness to afford 2-acetoxy-4-fluoro-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=O)[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].Cl.[NH2:30][OH:31]>CO.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:22][CH:23]2[CH2:27][CH2:26][C:25](=[N:30][OH:31])[CH2:24]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C(CC2CCC(=O)C2)C(=O)Nc2cnccn2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCC(=NO)C2)C(=O)Nc2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 54.3 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-oxo-cyclopentyl)-N-pyrazin-2-yl-propionamide (prepared as in Example 45, 121.9 mg, 0.29 mmol) and hydroxylamine hydrochloride (30.4 mg, 0.43 mmol) in methanol (0.85 mL) and pyridine (0.85 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to 25° C. and was then concentrated in vacuo. The resulting residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 80-100% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(3-hydroxyimino-cyclopentyl)-N-pyrazin-2-yl-propionamide (68.8 mg, 55%) as a white solid: mp 205-207° C.; (ES)+-HRMS m/e calcd for C19H21ClN4O4S (M+H)+ 437.1045. found 437.1048.
Reaction SMILES: [NH2:1][C@H:2]([C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:24])[C:22]=1[NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.[C:32]([O:36][C:37]([NH:39][CH2:40][CH2:41][C:42](ON1C(=O)CCC1=O)=[O:43])=[O:38])([CH3:35])([CH3:34])[CH3:33]>C(Cl)(Cl)Cl>[NH2:23][C:22]1[N:21]([CH3:24])[N:20]=[CH:19][C:18]=1[NH:17][C:15](=[O:16])[C@@H:2]([NH:1][C:42](=[O:43])[CH2:41][CH2:40][NH:39][C:37]([O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:38])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)NCCC(=O)ON1C(=O)CCC1=O
Reactant: Cn1ncc(NC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cn1ncc(NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CCNC(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.3 %

Procedure:
To a solution of tert-butyl (5S)-5-amino-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-6-oxohexylcarbamate (1.60 g) and triethylamine (0.47 g) in chloroform (100 ml) was added N-[3-(tert-butoxycarbonylamino)propionyloxy]succinimide (1.34 g). The mixture was stirred at room temperature for 15 hours. The mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a crude product of tert-butyl (5S)-6-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-5-{[3-(tert-butoxycarbonylamino)propionyl]amino}-6-oxohexylcarbamate (2.09 g) as an oil. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH2:19])[CH3:18])=[CH:7]2.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>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]=[CH:14][S:15][CH:16]=1)[C:8]([C@@H:17]([NH:19][C:21]1[N:29]=[CH:28][N:27]=[C:26]3[C:22]=1[N:23]=[CH:24][NH:25]3)[CH3:18])=[CH:7]2
Reactant: C[C@H](N)c1cc2cccc(Cl)c2nc1-c1cscn1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2nc1-c1cscn1

Procedure:
Prepared according to Procedure H using (1S)-1-(8-chloro-2-(thiazol-4-yl)-quinolin-3-yl)ethanamine (0.045 g, 0.155 mmol), 6-chloropurine (0.029 g, 0.19 mmol, 1.2 eq) and DIEA (0.33 mmol, 2.0 eq) in n-butanol (3 mL). N-((S)-1-(8-chloro-2-(thiazol-4-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine [PI3Kδ IC50=16 nM] was obtained after purification as a white solid. 1H-NMR (MeOD) δ ppm 9.22 (s, 1H), 8.63 (s, 1H), 8.44-8.46 (m, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.88-7.93 (m, 2H), 7.56 (t, 1H), 1.77 (d, 3H), Mass Spectrum (ESI) m/e=408 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)=O.[C:23]1([SH:33])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:23]1([S:33][CH2:6][CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCOS(C)(=O)=O
Reactant: Sc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCSc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 10A (42 mg), naphthalene thiol (45 mg), and potassium carbonate (36 mg) in acetonitrile (2 mL) was heated at 80° C. for 3 days. The reaction mixture was poured into water, extracted with dichloromethane and purified by flash chromatography on silica gel with 0-20% ethyl acetate in hexanes.