Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.Br[CH2:9][C:10]1[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=1[CH2:12][O:13][CH2:14][CH:15]([NH2:24])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]2[NH:24][CH2:9][C:10]3[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=3[CH2:12][O:13][CH2:14]2)=[CH:18][CH:19]=1
Reactant: NC(COCc1ccccc1CBr)Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Brc1ccc(CC2COCc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A mixture of compound 3k (1.6 g, 3.9 mmol) and K2CO3 (1.6 g, 12 mmol) in dry THF (30 mL) was stirred at rt overnight. LCMS indicated the total consumption of compound 3k. The reaction mixture was filtered and the filtrate was evaporated in vacuum to give 3l as a white solid (1.1 g, 86% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([CH3:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1N1CCCC1
Product: Cc1cc(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)c(NC(=O)OC(C)(C)C)cc1N1CCCC1

Procedure:
The title compound was prepared from (2-amino-4-methyl-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester acid tert-butyl ester (Example J39) (292 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (401 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (410 mg, 66%).
Reaction SMILES: [C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>>[C:4]([O:6][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])(=[O:5])[CH2:3][CH2:2][C:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)=[O:7]
Reactant: CCCCCCCCCCCCBr
Reactant: CN1C(C)(C)CC(OC(=O)CCC(=O)[O-])CC1(C)C
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCOC(=O)CCC(=O)OC1CC(C)(C)N(C)C(C)(C)C1

Procedure:
The product is prepared as described in Example 4b by reacting 27.1 g (0.1 mol) of mono(1,2,2,6,6-pentamethyl-4-piperidyl) succinate with 24.9 g (0.1 mol) of 1-bromododecane in the presence of 10.1 g (0.1 mol) of triethylamine. The product has a boiling point of 190° C./4 mbar.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[OH:55][C:48]1[C:47]([CH2:46][NH:45][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:13][CH:12]=2)=[C:52]([CH3:53])[CH:51]=[C:50]([CH3:54])[N:49]=1
Reactant: CC(C)(O)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)(C)O)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of 4-(2-hydroxypropan-2-yl)benzoic acid (0.09 g, 0.5 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=30:1) to give the pure product (0.11 g, 76%) as a white solid. LRMS (M+H+) m/z: calcd for 314.16. found 314. HPLC Purity (214 nm) 100%. 1H NMR (300 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.28-8.26 (m, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.7 Hz, 2H), 5.86 (s, 1H), 5.08 (s, 1H), 4.29 (d, J=4.8 Hz, 2H), 2.17 (s, 3H), 2.11 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[C:7]([O:6][C:4](=[O:5])[C@H:3]([NH:2][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CCOC(=O)CCCBr
Reactant: CC(C)(C)OC(=O)[C@H](N)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Temperature: 50 °C
Yield: 73.7 %

Procedure:
A mixture of (R)-tert-butyl 2-amino-2-phenylacetate hydrochloride (0.5 g, 2.051 mmol), ethyl 4-bromobutanoate (0.44 g, 2.26 mmol), and K2CO3 (1.13 g, 8.21 mmol) in CH3CN (10 mL) was heated to 50° C. for 40 hours. The mixture was diluted with EtOAc and then washed with H2O and brine. The organic was then dried (MgSO4), filtered and concentrated. Purification by chromatography (silica gel, 40% EtOAc in Hexanes) afforded 486 mg (74%) of the title compound. MS (ESI) m/z 322 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8]O)[O:4][C@H:3]1[N:10]1[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]1=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].CNC=O.C(Br)(Br)(Br)Br>CO>[N:39]([CH2:8][C@H:5]1[O:4][C@@H:3]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[C@@H:2]([F:1])[C@@H:6]1[OH:7])=[N+:40]=[N-:41]
Reactant: CCc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CNC=O
Solvent: CO
Product: CCc1cn([C@@H]2O[C@H](CN=[N+]=[N-])[C@@H](O)[C@@H]2F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.6 %

Procedure:
A mixture of 0.4 g of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil, 0.44 g of triphenylphosphine, 0.48 g of sodium azide and 6 ml of dry methylformamide was stirred at room temperature under nitrogen while 0.48 g of carbon tetrabromide was added portionwise. The mixture was stirred at room temperature under nitrogen for 20 hours. 3 ml of methanol were added, the mixture was stirred for 0.5 hour and then evaporated. The residue was stirred for 0.5 hour with 8 ml of 0.5M sodium hydroxide solution. The resulting suspension was filtered and the insoluble triphenylphosphine oxide was washed with water. The filtrate was acidified to pH 5 by the addition of hydrochloric acid and then extracted three times with 20 ml of ethyl acetate. The extracts were dried over magnesium sulfate, filtered and evaporated. The residual solid was washed on to a filter. with 10 ml of diethyl ether/petroleum ether (1:1) and then dried in vacuo to give 0.4 g of 1 -(5-azido-2,5-dideoxy-2-fluoro-β-D-arabinofuranosyl)-5-ethyluracil as a white solid of melting point 185°-188° C.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3([CH2:28]OS(C)(=O)=O)[CH2:27][CH2:26]3)[O:16][N:15]=2)=[CH:10][CH:9]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[C:17]([C:25]3([CH2:28][S:2][CH3:1])[CH2:26][CH2:27]3)[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: COCOc1ccc(-c2noc(C3(COS(C)(=O)=O)CC3)c2-c2ccccc2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1ccc(-c2noc(C3(CSC)CC3)c2-c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
To a mixture consisting of sodium thiomethoxide (0.33 g) in N,N-dimethylformamide (3 mL) is added a mixture consisting of methanesulfonic acid 1-[3-(4-methoxymethoxy-phenyl)-4-phenyl-isoxazol-5-yl]-cyclopropylmethyl ester (synthetic intermediate prepared in Example 11, Step iv, 1 g) in N,N-dimethylformamide at 0° C. The mixture is stirred at 80° C. for four hours and is cooled to room temperature. The mixture is then diluted with ethyl acetate (50 mL) and is sequentially washed with 1 N hydrochloric acid solution (3×15 mL), water (15 mL), and brine solution (15 mL.) The mixture is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford the synthetic intermediate 3-(4-methoxymethoxy-phenyl)-5-(1-methylsulfanylmethyl-cyclopropyl)-4-phenyl-isoxazole (0.89 g.)
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH2:18])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1.CN(C)C1C=CC=CC=1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>C1COCC1>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH:18][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)C1(Oc2cc(N)c(F)cc2Cl)CC1
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cc(OC2(C(=O)OCC)CC2)c(Cl)cc1F

Procedure:
The obtained ethyl 1-(2-chloro-4-fluoro-5-amino-phenoxy)cyclopropanecarboxylate (1 equivalent) and dimethylaniline (1 equivalent) are added to THF and ethyl chloroformate (1 equivalent) is gradually added in drops thereto. After completion of addition, to the reaction solution is added aqueous diluted hydrochloric acid and the mixture is extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 1-(2-chloro-4-fluoro-5-ethoxycarbonylaminophenoxy)cyclo-propanecarboxylate.
Reaction SMILES: [NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH2:9][SH:10])=[O:6].Cl.[N:22]([O-])=[O:23].[Na+]>O>[NH2:1][C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][CH2:4][C:5]([NH:7][C@H:8]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])[CH2:9][S:10][N:22]=[O:23])=[O:6]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N[C@@H](CCC(=O)N[C@@H](CSN=O)C(=O)NCC(=O)O)C(=O)O
Reaction time: 1 h

Procedure:
N-(N-L-γ-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolved in deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperature and then the reaction mixture was cooled to 0° C. With rapid stirring, a solution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) was added and stirring with cooling of the reaction mixture was continued for approximately 1 hour after which time the pink precipitate which formed was collected by vacuum filtration. The filter cake was resuspended in chilled 40% acetone-water (600 ml) and collected by vacumm filtration. The filter cake was washed with acetone (2×200 ml) and ether (100 ml) and then dried under high vacuum at room temperature in the dark to afford the title compound as a pink powder. 1H NMR (D2O) δ: 1.98 (m, 2H), 2.32 (t,2H), 3.67 (t, 1H), 3.82 (s 2H), 3.86 (dd, 1H), 3.98 (dd, 1H), 4.53 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[CH:11]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]=[C:9]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc2c(cc1F)C(=O)CCC2
Reactant: C1COCCN1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1F)C(N1CCOCC1)=CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
To a mixture of methyl 3fluoro-5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (0.155 g, 0.698 mmol) and morpholine (0.304 mL, 3.49 mmol) in toluene (5.0 mL) at 0° C. was added titanium(IV) chloride (1M in toluene) (0.384 mL, 0.384 mmol) dropwise. The ice-bath was removed, and the orange, heterogeneous reaction mixture was stirred at room temperature for 16 hours. The heterogeneous, orange reaction mixture was filtered under reduced pressure through a pad of Celite which was then rinsed with toluene (3×10 mL). The pale yellow filtrate was concentrated under reduced pressure to give methyl 3fluoro-5-morpholino-7,8-dihydronaphthalene-2-carboxylate (0.122 g, 0.419 mmol, 60.0% yield). The product had an LC/MS M+1=292.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(O)=[O:2].C[CH2:21][N:22]=C=NCCCN(C)C.Cl.CN1CCOCC1.CN>C(Cl)Cl>[CH3:21][NH:22][C:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C(O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CNC(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Reaction time: 72 h
Yield: 48.2 %

Procedure:
A mixture of 4-(3-carboxyphenoxy)-1-nitrobenzene (3.72 g, 14.4 mmol), EDCI.HCl (3.63, 18.6 mmol), N-methylmorpholine (1.6 mL, 14.5 mmol) and methylamine (2.0 M in THF; 8 mL, 16 mmol) in CH2Cl2 (45 mL) was stirred at room temp. for 3 d, then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and the resulting mixture was extracted with a 1M HCl solution (50 mL). The aqueous layer was back-extracted with EtOAc (2×50 mL). The combined organic phases were washed with a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure to give 4-(3-(N-methylcarbamoyl)phenoxy)-1-nitrobenzene as an oil (1.89 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])[C:8]([CH2:22][NH2:23])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:34]1[N:42]=[CH:41][N:40]=[C:39]2[C:35]=1[NH:36][CH:37]=[N:38]2>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:19])[F:20])[C:8]([CH2:22][NH:23][C:34]1[N:42]=[CH:41][N:40]=[C:39]3[C:35]=1[N:36]=[CH:37][NH:38]3)=[CH:7]2
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure H using (8-methyl-2-(2-(trifluoromethyl)-phenyl)quinolin-3-yl)methanamine (0.1 g, 0.316 mmol, 1 eq) in EtOH (2 mL) was treated with iPr2NEt (0.07 mL, 0.4 mmol, 1.2 eq) followed by 6-chloropurine (0.049 g, 0.317 mmol, 1 eq). After purification, N-((8-methyl-2-(2-(trifluoro-methyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine as yellow syrup. The yellow syrup was triturated with CH2Cl2 and filtered to provide N-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-9H-purin-6-amine [PI3Kδ IC50=91 nM] as yellow syrup. 1H NMR (DMSO-d6) δ ppm 12.93 (1 H, s), 7.98-8.31 (4 H, m), 7.90 (1 H, d, J=7.8 Hz), 7.74-7.82 (2 H, m), 7.69 (2 H, t, J=6.5 Hz), 7.59 (1 H, d, J=7.0 Hz), 7.42-7.52 (1 H, m), 4.42-4.77 (2 H, m), 2.62 (3 H, s). Mass Spectrum (ESI) m/e=435.1 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:27]=4[CH3:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: Cc1ccc(C)c(C(=O)O)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(C)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,5-dimethylbenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5]>C(O)C.CO.[Pd]>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1cccc(C)c1C(=O)NCc1ccc(-c2cc[nH]c(=O)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1cccc(C)c1C(=O)NCc1ccc(C2CCNC(=O)C2)cc1

Procedure:
To a solution of 2,6-dimethyl-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide (see compound 5 of example 3B) in ethanol/methanol (5:1), 10% Pd/C was added and the mixture was hydrogenated (1 atm) at 23° C. for 12 hours. The catalyst was filtered through celite pad and washed with methanol. Filtrate and washings were combined and the solvent was then concentrated and chromatographed (SiO2, 3-15% EtOAc/MeOH) to provide the title compound. MS found for C21H24N2O2 as (M+H)+ 337.1 1H NMR (400 MHz, dmso-d6): δ: 8.76 (t, J=5.6 Hz, 1H); 7.52 (brs, 1H), 7.27-7.14 (m, 4H); 7.13-6.99 (m, 3H); 4.40 (d, J=6.4 Hz, 2H); 3.23-3.16 (m, 2H); 3003-2.98 (m, 1H); 2.35-2.21 (m 2H); 2.17 (s, 6H); 1.88-1.78 (m, 2H).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C:11]1([CH3:21])[CH2:16][CH:15]([NH:17][CH3:18])[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C(C)=CC=CC=1>[Cl:3][C:2]1[N:1]=[C:8]([N:17]([CH3:18])[CH:15]2[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12][C:11]([CH3:21])([CH3:10])[CH2:16]2)[N:7]=[C:5]([N:17]([CH:15]2[CH2:14][C:13]([CH3:20])([CH3:19])[NH:12][C:11]([CH3:21])([CH3:10])[CH2:16]2)[CH3:18])[N:4]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(c1nc(Cl)nc(N(C)C2CC(C)(C)NC(C)(C)C2)n1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
18.4 g of cyanuric chloride and 34.0 g of 2,2,6,6-tetramethyl-4-(methylamino)piperidine were dissolved in 250 ml of xylene, and the solution was stirred at a temperature of 90°-110° C. for 3 hours. 30 ml of a saturated aqueous solution of potassium carbonate were then added and the resulting mixture was heated under reflux for 5 hours. At the end of this time, the reaction mixture was poured into water and extracted with benzene. The extract was dried over anhydrous potassium carbonate and then the benzene was distilled off. The residue was recrystallized from ethyl acetate, giving the title compound in the form of crystals melting at 179°-180° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38](=[O:37])[CH2:39][OH:40])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CO)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (100 mg, 0.207 mmol) produced in Example C52(v) in pyridine (2.0 mL) was added acetoxyacetyl chloride (48.9 μL, 0.455 mmol), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2.0 mL), sodium carbonate (100 mg, 0.943 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (10 mL). The obtained suspension was washed with 5% aqueous ammonium chloride solution (10 mL), 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/hexane to give the title compound (63.0 mg, 56%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccc(C(C)C)cc2)c1Br
Yield: 77 %

Procedure:
4-iso-Pro pyl-N-(4-bromo-3-methyl-5-isoxazolyl) benzenesulfonamide was prepared in the same manner as described in Example 30 from 5-amino-4-bromo-3-methylisoxazole and 4-iso-propylbenzenesulfonyl chloride in 77% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 130-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15](C=O)=[C:11]2[O:12][C:13]=1[CH3:14].C1C=C(Cl)C=C(C(OO)=[O:29])C=1.C([O-])([O-])=O.[K+].[K+].CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([OH:29])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1O
Temperature: 0 °C

Procedure:
3-(2,4-Dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carbaldehyde (750 mg, 2.426 mmol) and m-CPBA (897 mg, 3.64 mmol) are stirred in DCM (10.5 ml) at RT for 3 hours, whereupon the reaction mixture is diluted with DCM (120 ml). The organic phase is washed with sat. NaHCO3 (70 ml) and the phases separated via a phase separator. Back extraction of the aqueous phase with DCM (50 ml) is carried out and the combined organic phases are concentrated in vacuo. The resultant yellow gum is dissolved in MeOH (16.80 ml) and K2CO3 (1676 mg, 12.13 mmol) is added. The reaction is stirred at RT for 30 mins before the MeOH is removed in vacuo. The resulting solid is diluted with water (˜100 ml) and the product is extracted into EtOAc (2×100 ml). The combined organic extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is isolated as a light orange solid which is dissolved DCM (15 ml), cooled to 0° C. and the resultant solid collected by filtration to afford the title compound as a pale yellow solid. MS: m/z 297.15 [M+H]+.