Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:48]([C:50]1[N:51]=[C:52]([C:63]([O-])=[O:64])[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=1)#[N:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:63]([C:52]2[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=[C:50]([C:48]#[N:49])[N:51]=2)=[O:64])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN1C(=O)CC(c2ccc(N)c(C3=CCCCC3)c2)CC1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1=O
Yield: 26.6 %

Procedure:
A solution of 266 mg (0.891 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 623 mg (1.34 mmol) of PyBroP, 300 mg (0.981 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 466 μL (2.67 mmol) of DIEA at RT for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromagography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 130 mg (27%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H37N5O4Si, 548.3 (M+H). found 547.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](F)[N:11]=2)=[O:9])=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1.[C:18]([N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:17])=[CH:6][C:7]=1[C:8]([C:10]1[N:11]=[C:12]([N:28]2[CH2:29][CH2:30][CH2:31][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH2:27]2)[CH:13]=[CH:14][CH:15]=1)=[O:9]
Reactant: Nc1ncc(Br)cc1C(=O)c1cccc(F)n1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCCN(c2cccc(C(=O)c3cc(Br)cnc3N)n2)CC1
Temperature: 95 °C
Yield: 59 %

Procedure:
A mixture of (2-amino-5-bromopyridin-3-yl)(6-fluoropyridin-2-yl)methanone (190 mg, 0.64 mmol), 1-Boc-homopiperazine (0.14 ml, 0.70 mmol) and potassium carbonate (310 mg, 2.24 mmol) in dimethylfonmamide (4 ml) was heated at 95° C. for 48 hours. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was slurried in EtOAc and K2CO3 was filtered off. The mother liquors were concentrated in vacuo. The resulting residue was purified on silica gel by flash column chromatography (ISCO Companion|, 12 g column, 0-20% EtOAc/Petrol) to give the title compound as a yellow solid (180 mg, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.Cl[C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[C:24]([NH2:29])[N:23]=1>C(O)CCCC>[Cl:28][C:27]1[C:22]([NH:19][CH2:18][C:17]2[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:20])=[N:23][C:24]([NH2:29])=[N:25][CH:26]=1
Reactant: Nc1ncc(Cl)c(Cl)n1
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3Cl)nc12
Solvent: CCCCCO
Product: Cc1cccc2cc(CNc3nc(N)ncc3Cl)c(-c3ccccc3Cl)nc12

Procedure:
A mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)methanamine (0.050 g, 0.18 mmol), and 4,5-dichloro-2-aminopyrimidine (0.029 g, 0.18 mmol, 1 eq) were stirred in 1-pentanol (0.9 mL) at 80° C. for 4 days. After purification, 5-chloro-N4-((2-(2-chlorophenyl)-8-methylquinolin-3-yl)methyl)pyrimidine-2,4-diamine [PI3Kδ IC50=165 nM] was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.18 (1H, s), 7.86 (1H, d, J=7.8 Hz), 7.72 (1H, s), 7.45-7.64 (7H, m), 7.28 (1H, t, J=5.9 Hz), 6.02 (2H, s), 4.46 (2H, d, J=18.8 Hz), 2.65 (3H, s) Mass Spectrum (ESI) m/e=410.0 and 412.1 (M+1)
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:10](=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:22])[CH:8]=2)[N:3]1[CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[CH2:53](Br)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.O>CN(C)C=O>[CH2:53]([O:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([O:33][CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29][CH2:28]1)[C:2](=[O:1])[N:11]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]2=[O:21])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: CCOC(=O)CCCCn1c(=O)c2cc(O)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCCCn1c(=O)c2cc(OCc3ccccc3)ccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 30.6 %

Procedure:
To a suspension of ethyl 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.34 g, 2.13 mmol) obtained in Example 105 and potassium carbonate (354 mg, 2.56 mmol) in N,N-dimethylformamide (50.0 ml), benzyl bromide (305 ml, 2.56 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 18.5 hours. The reaction mixture was combined with water and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO4) the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1, v/v) to give the ethyl ester of the title compound (450 mg, 29%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[N:15][N:14](C3CCCCO3)[C:13](=[O:23])[CH:12]=2)=[N:7][CH:8]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:16]=[N:15][NH:14][C:13](=[O:23])[CH:12]=2)=[N:7][CH:8]=1
Reactant: COc1ccc(COc2cnn(C3CCCCO3)c(=O)c2)nc1
Agent: Cl
Solvent: CO
Product: COc1ccc(COc2cn[nH]c(=O)c2)nc1

Procedure:
A solution of 5-(5-methoxy-pyridin-2-ylmethoxy)-2-(tetrahydro-pyran-2-yl)-2H-pyridazin-3-one (500 mg, 1.58 mmol) in a mixture of MeOH (5 mL) and concentrated aqueous HCl (0.65 mL) is heated at reflux for 2 h. Most of the volatiles are removed under reduced pressure and water is added. The formed precipitate is filtered off and dried.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@@H:15](OS(C(F)(F)F)(=O)=O)[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]>CN(C)C=O.C(OCC)C>[CH2:5]([O:7][C:8]([C@:10]1([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[C@H:15]([N:1]=[N+:2]=[N-:3])[CH2:14][C@@H:13]2[C@H:11]1[C@@:12]2([F:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:9])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@H](OS(=O)(=O)C(F)(F)F)[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](N=[N+]=[N-])[C@@](NC(=O)OC(C)(C)C)(C(=O)OCC)[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
313 mg of sodium azide was added to 1.63 g of (1R,2R,3S,5R,6R)-2-t-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester dissolved in 16.3 mL of N,N-dimethylformamide, and the mixture was stirred for 1 hour at room temperature, and then for 20 hours at 35° C. 104 mg of sodium azide was further added thereto, and the mixture was stirred for 18 hours at 35° C. After being diluted with 50 mL of diethyl ether, the mixture was washed twice with water and then with a saturated aqueous solution of sodium chloride. The organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:1), thereby yielding 775 mg of (1R,2R,3R,5R,6R)-3-azido-2-t-butoxycarbonylamino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][C:18]#[N:19])[CH3:13].O>O1CCCC1>[CH2:21]([O:20][CH:15]([O:14][CH2:12][CH3:13])[CH2:16][CH:17]([C:5](=[O:6])[C:4]([F:11])([F:10])[F:3])[C:18]#[N:19])[CH3:22]
Reactant: CCOC(CCC#N)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC
Yield: 32.3 %

Procedure:
To a 40°-45° C. stirring suspension of hexanewashed sodium hydride (5.5 g of a 60% dispersion, 0.14 mol) in 200 mL of dried tetrahydrofuran is added dropwise a solution of ethyl trifluoroacetate (15 g, 0.11 mol) and 3-cyanopropionaldehyde diethyl acetal (17 g, 0.11 mol) in 100 mL of dry tetrahydrofuran. The previously gray suspension slowly turns light brown in color. The reaction mixture is stirred at 50°-55° C. overnight before being quenched by slow addition of 2-propanol (15 mL). Rotary evaporation of the volatiles yields a dark oil, to which is added 150 mL of pH 7 water. Unreacted starting materials are conveniently removed by washing the aqueous layer with diethyl ether (3×30 mL). The basic aqueous phase is then acidified with 12 N hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed once with saturated sodium bicarbonate (40 mL) and once with brine (15 mL) before being dried over magnesium sulfate. Rotary evaporation yields a reddish oil which is flash chromatographed over silica gel using 4:1 hexane-ethyl acetate as eluent to provide the desired product (9 g, 32%) as a yellow oil.
Reaction SMILES: C([O:5][C:6]([C:8]([CH3:26])=[CH:9][C:10]1[C:11](=[O:25])[C:12]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:12]2[C:11](=[O:25])[C:10](/[CH:9]=[C:8](\[CH3:26])/[C:6]([OH:7])=[O:5])=[C:16]([O:17][CH3:18])[C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1
Reactant: COc1c(C=C(C)C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(/C=C(\C)C(=O)O)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 25.1 %

Procedure:
4-[2-(Tert-butoxycarbonyl)propenyl]-8-chloro-3-methyoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.35 g) in methylene chloride (7 mL) was treated with trifluoroacetic acid. The solution was stirred under argon at room temperature for 40 minutes and then it was concentrated to a white solid. The solid was dissolved in hot methanol (30 mL). The solution was filtered and concentrated to 7 mL volume as a solid formed. The solid was filtered off, washed with cold methanol, and air-dried to give a white solid (0.0748 g); mp=277.4°-278.6° C. (dec); 1H NMR (d6 -DMSO) 7.17 (s,1) for olefin proton; MS: m/z=304, 322 (base peak)(M+1). Analysis for C15H12ClNO5 : Calculated: C, 56.00; H. 3.76; N. 4.35; Found: C, 55.86; H. 3.82; N, 4.32.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH3:30])[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18]OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[I-].[Na+].[O:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.Cl>CC(C)=O.C(#N)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:28][O:29][CH3:30])[C:8]([NH:10][C@@H:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[O:24])=[C:15]([CH2:18][N+:42]4[CH:41]=[CH:40][C:39]([C:35]5[O:34][CH:38]=[CH:37][N:36]=5)=[CH:44][CH:43]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: c1cc(-c2ncco2)ccn1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(-c4ncco4)cc3)CS[C@H]12)c1csc(N)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
0.75 g of sodium 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-carboxylate (hereinafter referred to Compound 1), 2.25 g of sodium iodide and 0.51 g of 4-(oxazol-2-yl)-pyridine were added to a mixture of 0.4 ml of 4 N hydrochloric acid and 1.2 ml of acetonitrile, followed by stirring at 80° C. for 1 hour. After allowing the mixture to cool, the reaction mixture was poured into acetone, and the precipitate formed was separated by filtration and washed with acetone. The resulting crude powder was dissolved in water, and the solution was subjected to column chromatography of Diaion HP-20 (trade name of Mitsubishi Chemical Industries, Ltd.). The column was developed with a mixture of water-tetrahydrofuran (93:7 by volume). The eluate was further subjected to reversed phase high performance liquid chromatography (column packing: Develosil, trade name of Nomura Chemical Co., Ltd.) and developed with a mixture of water-acetonitrile (89:11 by volume) to obtain the titled compound. Melting point: 160°-170° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([CH2:20][CH2:19][N:18]([CH3:31])[CH3:17])(=[O:23])=[O:22])=[CH:29][CH:28]=1
Reactant: CN(C)CCS(=O)(=O)c1ccc(N)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCS(=O)(=O)c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 37.7 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.17 g, 0.61 mmol) and 4-(2-dimethylamino-ethanesulfonyl)-phenylamine (0.14 g, 0.61 mmol) were stirred in N,N-dimethylformamide (3 mL) and triethylamine (0.16 mL) at 60-70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-{[(4-{[2-(dimethylamino)ethyl]sulfonyl}-phenyl)amino]methylene}isoquinoline-1,3(2H,4H)-dione (0.11 g, 36%) as a golden powder.
Reaction SMILES: [CH3:1][C:2]1([C:10]([O-])=O)[CH2:6][CH2:5][C:4](C)([CH3:7])[C:3]1=[O:9].[K+].Cl>CO.O>[CH3:1][C:2]1([CH3:10])[CH2:6][CH2:5][CH:4]([CH3:7])[C:3]1=[O:9]
Reactant: CC1(C)CCC(C)(C(=O)[O-])C1=O
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1CCC(C)(C)C1=O

Procedure:
A solution of the product of Example 8c in methanol and water (7.4 g, ˜35.7 mmol) was acidified with concentrated hydrochloric acid to pH=1 and then heated to reflux for 1 hour. The reaction mixture was cooled and then diluted with water (70 mL) and the organics were extracted with diethyl ether (80 mL×4). The combined organic phase was washed with brine (160 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a light yellow liquid contaminated with some solvent (4.93 g, Purity: ˜85%). 1H NMR (400 MHz, CDCl3) δ 2.26-2.09 (m, 2H), 1.85-1.79 (m, 1H), 1.72-1.64 (m, 1H), 1.54-1.45 (m, 1H), 1.12 (d, J=6.8 Hz, 3H), 1.08 (s, 3H), 0.98 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18](Cl)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>ClCCl>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Solvent: ClCCl
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21
Yield: 84.6 %

Procedure:
Following the procedure of Example X-2, the reaction of 3-benzyloxy-7-chloro-1-ethyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example N-2, 200 mg, 0.572 mmol) with 4-methylpiperazine (0.152 mL, 1.37 mmol) in dichloromethane (3 mL) afforded 200 mg of the title compound as a solid, mp 178-179° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1>>[CH3:20][C:21]1[C:25]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1ccc(OCc2cccc(C(=O)O)c2)cc1

Procedure:
3-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenoxymethyl]-benzoic acid was prepared using general procedure 1 from 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and 3,5-dimethylisoxazole-4-boronic acid (ASDI Incorporated, Newark, Del.). Mass spectrum MH+=324.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([OH:13])[C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[C-:14]#[N:15].[Na+].O>CS(C)=O>[C:14]([CH2:2][C:3]1[N:4]=[C:5]([OH:13])[C:6]2[S:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1)#[N:15]
Reactant: Oc1nc(CCl)nc2c1SCCC2
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1nc(O)c2c(n1)CCCS2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Product from Example 3, step A, (1.8 g, 0.01 mol) was dissolved in 10 ml of DMSO and sodium cyanide (1.0 g) was added. The reaction mixture was stirred at 25° C. for 3.5 hours and then poured into water (150 ml). The solution was extracted with ethyl acetate, the ethyl acetate was dried and then evaporated to give the title compound as an oil that was used directly in Step B hereof.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[CH:35][N:36]([CH2:38][CH2:39][C:40]([NH2:42])=[O:41])[CH:37]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:33]3[N:34]=[CH:35][N:36]([CH2:38][CH2:39][C:40]([NH2:42])=[O:41])[CH:37]=3)[CH:30]=[C:31]([CH3:32])[C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(-c3cn(CCC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c(C)cc(-c3cn(CCC(N)=O)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethyl-4-methyl-6-(1-(2-aminocarbonylethyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=O)=[CH:12][C:11]=1[CH3:19]>>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][C:11]=1[CH3:19]
Reactant: Nc1ccccc1O
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1cc(-c2nc3ccccc3o2)ccc1Br
Temperature: 200 °C
Reaction time: 8 h

Procedure:
Polyphosphoric acid (100 mL) was added to a beaker containing 2-aminophenol (17.7 g, 162 mmol) and 4-bromo-3-methylbenzoic acid (13.6 g, 64 mmol). The mixture was heated at 200° C. for 1 h, then poured into ice water (1 L) and allowed to stand overnight. The mixture was filtered and dried to afford 2-(4-bromo-3-methyl(phenyl))-benzoxazole as a colorless solid. A solution of 2-(4-bromo-3-methyl(phenyl))-benzoxazole (670 mg, 2.3 mmol), 2-(tributylstannyl)pyridine (850 mg, 2.3 mmol), Pd(Ph3P)4 (270 mg, 0.23 mmol) and DMF (23 mL) was degassed with bubbling argon for 15 min. The reaction mixture was heated at 100° C. for 8 h. The reaction was cooled to rt, and KF (500 mg) and H2O (250 mL) were added. The mixture was extracted with MTBE (3×50 mL), and the combined organic extracts were washed with water (2×20 mL), brine (1×20 mL), dried (MgSO4), and concentrated to afford an oil. Purification of the oil by flash chromatography on silica gel (EtOAc:hexanes 1:2) afforded the desired 2-(3-methyl-4-pyridin-2-ylphenyl)-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.91 (d, 1H), 8.52 (t, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 7.97 (br t, 1H), 7.89 (d, 1H), 7.70–7.72 (m, 1H), 7.61 (d, 1H), 7.51–7.54 (m, 1H), 7.30–7.33 (m, 2H), 2.45 (s, 3H), MS (ESI) 287 (M+H)+.
Reaction SMILES: [CH:1]1([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:18])(=O)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(OCC)C>[Cl:18][CH:8]([C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of ethyl 3-cyclohexyl-3-oxopropanoate (1.0 g, 5.0 mmol) in diethyl ether (15 mL) was added sulfuryl chloride (750 mg, 5.5 mmol) at 0° C., and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (150 mL) were added to the reaction solution, and the mixture was stirred for 30 min. The organic layer was washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (870 mg, 60%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.Cl.[CH3:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]1.CCN(CC)CC>CCO>[Br:1][C:2]1[C:3]([O:9][CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[N:4][C:5]([NH:29][C@H:26]2[CH2:27][CH2:28][C@@H:23]([CH3:22])[CH2:24][CH2:25]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2nc(Cl)ncc2Br)C1
Reactant: C[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(Oc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3-(5-bromo-2-chloropyrimidin-4-yloxy)azetidine-1-carboxylate (6 g, 16.4 mmol), cis-4-methylcyclohexanamine hydrochloride (2.4 5g, 16.4 mmol) and Et3N (7 mL, 49.2 mmol) in EtOH (20 mL) was executed in microwave reactor at 130° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography (silica gel, eluted by 10 to 20% ethyl acetate in DCM) to give the titled compound (6.5 g, 90% yield). MS (ESI) m/z: Calc. 440.1 (M+). Found: 442.1 (M++2).