Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[NH:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Na+].[Cl-].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:43][CH:44]1[CH2:46][CH2:45]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:43][CH:44]3[CH2:46][CH2:45]3)[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1

Procedure:
To a solution of the title compound of example 1, 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one (100 mg, 0.210 mmol) in DMF (2 ml) were added NaCl (8 mg), cesium carbonate (Cs2CO3, 103 mg, 0.315 mmol) and (bromomethyl)cyclopropane (0.041 ml, 0.420 mmol). The reaction mixture was stirred at ambient temperature for 15 hours. Additional 0.041 ml) of (bromomethyl)cyclopropane and 100 mg of Cs2CO were added. The reaction mixture was heated at 60° C. for 1 hour after which time it was partitioned between CHCl3 and water. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (3:97:0) as eluents to afford the title compound as a white solid (25 mg, 22% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:7]=1[NH2:26].Cl.[N:28]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:26][N:28]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cccc1OCCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCCl)cccc12
Temperature: 3 °C

Procedure:
A mixture of 2-(3-chloro-propoxy)-6-(naphthalene-1-sulfonylmethyl)-phenyl amine (1.66 g, 4.25 mmoles) in THF (7 mL), and 4M HCl (15 mL) was stirred in a round bottom flask, under nitrogen, at 3° C. A solution of sodium nitrite (0.3 g, 4.4 mmoles) in H2O (1 mL) was added dropwise. The reaction mixture was poured into a cold solution of saturated sodium bicarbonate (100 mL) and extracted with EtOAc. Compound was dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (1.6 g, 4 mmoles).
Reaction SMILES: O.O.[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[Na+].[Na+].[Na+].[OH:19][P:20]([O-:23])([O-:22])=[O:21].[Na+].[Na+].OP([O-])(O)=O.[Na+].[Cl-].[Na+]>O>[P:20]([O-:23])([O-:22])([O-:21])=[O:19].[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6]
Reactant: O=P([O-])([O-])O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])(O)O
Agent: [Cl-]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
The buffer concentrate is prepared by dissolving 0.484% by weight of sodium citrate dihydrate, 0.708% by weight of sodium phosphate dibasic, 0.088% by weight of sodium phosphate monobasic, monohydrate, and 1.486% by weight of sodium chloride in DI water. The pH is adjusted to about 7.2, if necessary.
Reaction SMILES: [C:1]([O:7][CH2:8]Br)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:10]([S:12]([C:14]1[S:15][C@@H:16]2[C@H:23]([C:24]([OH:27])([CH3:26])[CH3:25])[C:22](=[O:28])[N:17]2[C:18]=1[C:19]([O-:21])=[O:20])=[O:13])[CH3:11].[Li+]>CN(C=O)C.CCOC(C)=O>[CH2:10]([S:12]([C:14]1[S:15][C@@H:16]2[C@H:23]([C:24]([OH:27])([CH3:25])[CH3:26])[C:22](=[O:28])[N:17]2[C:18]=1[C:19]([O:21][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:20])=[O:13])[CH3:11]
Reactant: CCS(=O)C1=C(C(=O)[O-])N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Reactant: CC(C)(C)C(=O)OCBr
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)C1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)[C@@H](C(C)(C)O)[C@H]2S1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Pivaloyloxymethyl bromide (29.3 mg, 0.15 mmol) is added to a suspension of lithium (5R,6R)-2-ethylsulfinyl-6-(2-hydroxy-2-propyl)-pen-2-em-3-carboxylate (29.5 mg, 0.1 mmol) in anhydrous DMF (0.5 ml). The resulting mixture is stirred under a N2 atmosphere at room temperature for 4 hours. The mixture is diluted with EtOAc, washed repeatedly with water, dried with MgSO4, filtered, and evaporated under vacuum to afford a residue of the title compound. This material is purified by preparative TLC.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH3:26])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:27][C:28]([S:31]([NH2:33])=[O:32])([CH3:30])[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:33][S:31]([C:28]([CH3:30])([CH3:29])[CH3:27])=[O:32])[C:7]=2[N:8]=1
Reactant: CC(C)(C)S(N)=O
Reactant: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NS(=O)C(C)(C)C)c2n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 41.9 %

Procedure:
A mixture of 8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Example 94, 27 mg, 0.074 mmol), (±)-2-methyl-2-propanesulfinamide (12 mg, 0.099 mmol), palladium(II) acetate (1 mg, 4.44 μmol), cesium carbonate (48 mg, 0.147 mmol) and Xantphos (5 mg, 8.64 μmol) in 1,4-dioxane (0.7 mL) (degassed) was stirred at 100° C. for 18 hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0 to 90% EtOAc in cyclohexane to give the title compound (14 mg, 42%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])=[CH:5][CH2:6][CH3:7].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])=[CH:5][CH:6]([Br:10])[CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC=C(C)C(=O)OC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)=CC(C)Br
Yield: 82.5 %

Procedure:
A solution of 2-methylpent-2-enoic acid methyl ester (1.20 g, 9.37 mmol) and N-bromosuccinimide (1.83 g, 10.2 mmol) in dry carbon tetrachloride (15 mL) irradiated with a 250 W sunlamp so as to achieve a state of reflux for 2.5 hours. After cooling, the succinimide was filtered off, the carbon tetrachloride was evaporated, and the product was distilled over a short path under reduced pressure to give the title compound (1.60 g, 82%) as a colourless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1.N12CCCN=C1CCCCC2>C1COCC1>[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:9][CH:8]=1
Reactant: c1nc[nH]n1
Reactant: Fc1ccc(CBr)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Fc1ccc(Cn2cncn2)cc1
Yield: 68 %

Procedure:
To a stirred solution of 1,2,4-triazole (0.803 g, 11.6 mmol) in THF (100 mL) at 0° C. was added 4-fluorobenzyl bromide (2.0 g, 10.6 mmol), then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 12.7 mmol) and the mixture was slowly warmed to room temperature. The solution was concentrated in vacuo, then purified by column chromatography (SiO2, MeOH/EtOAc, 5:95) to yield a white solid in 68% yield.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(=S)=S.C(Cl)(Cl)Cl>[C:19]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[OH:14])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: S=C=S
Product: CC(=O)c1cc(C(C)(C)C)cc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
A vigorously stirred solution of 5-tert-butyl-salicyclic acid (3.88 g) in carbon disulphide (80 ml) was treated portionwise with anhydrous aluminium chloride (8.8 g). The mixture was brought cautiously to the reflux temperature and treated with acetyl chloride (3.45 g) dropwise during 15 minutes. The mixture was heated at reflux with vigorous stirring for 20 hours and then the mixture was added to a mixture of chloroform (80 ml), ice (100 g) and concentrated hydrochloric acid (20 ml), and stirred for a further one hour. The organic layer was then separated, washed with water (3 × 20 ml), and dried over anhydrous sodium sulphate, and the solvent was removed in vacuo. The resulting solid was recrystallized from ethyl acetate, to give 3-acetyl-5-tert-butylsalicylic acid (2.3 g), m.p. 159°-161° C.
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[CH:7]1)[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:27](=[O:29])[N:10]2[CH2:11][C@H:6]1[CH:7]=[C:8]([CH2:15][CH3:16])[C@H:9]2[C:12]([NH2:14])=[O:13])[CH:2]=[CH2:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCONC1C=C(CC)[C@H](C(N)=O)NC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C=C(CC)[C@H]2C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 255.3 %

Procedure:
To a solution of (R)-5-(allyloxyamino)-3-ethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 214, 0.35 g, 1.55 mmol) and diisopropylethyl amine (1.082 mL, 6.21 mmol) in acetonitrile (110 mL) at 0° C. was added triphosgene (0.157 g, 0.53 mmol) as a solution in acetonitrile (4 mL). The triphosgene solution was added at a rate of 4 mL/hour. Once addition was complete the reaction was stirred at 0° C. for ˜1 hour. The reaction mixture was diluted with ethyl acetate, then washed with saturated sodium bicarbonate and brine. The aqueous washes were extracted once with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-100% ethyl acetate/hexanes) afforded the title compound (0.340 g, 87%) as a colorless oil.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9](O)=O)=[CH:3][CH:2]=1.BrC1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:21][CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>CN1C(=O)CCC1>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([C:7]#[C:8][C:9]2[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:21][CH:20]=2)=[CH:3][CH:2]=1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1
Reactant: CC(=O)NC(C)Cc1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CN1CCCC1=O
Product: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(-c3ccccc3)cc2)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To 0.22 g (1.00 mmol) biphenyl-4-yl-propynoic acid (I28) and 0.26 g (1.00 mmol) N-[2-(4-bromo-phenyl)-1-methyl-ethyl]-acetamide (I44.1) in 3.00 mL NMP are added 0.06 g (0.10 mmol) 1,1′-bis(diphenylphosphonino)ferrocene, 1.68 g (6.00 mmol) TBAF*H2O and 0.05 g (0.05 mmol) tris(dibenzylidenacetone)dipalladium(0). The reaction mixture is stirred at 90° C. for 3 h. The mixture is allowed to cool to r.t. and poured onto saturated aq NH4Cl solution. The precipitate is filtered, washed with water and purified by column chromatographie (silica gel; DCM/MeOH 9/1). The resulting product is triturated with isopropanol and dried at 60° C. in vacuo.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:31]([CH:32]=1)[CH2:30][C:8]1([CH2:13][CH2:12][N:11]([C:14](=[O:29])[CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[O:7]2)([O-:3])=[O:2].FC(F)(F)C(O)=O.[NH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>C(Cl)Cl.O.CN(C=O)C>[F:48][C:47]([F:49])([F:50])[C:44]1[CH:43]=[CH:42][C:41]([NH:40][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][C:8]4([O:7][C:6]5=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:32][N:31]5[CH2:30]4)[CH2:13][CH2:12]3)=[O:29])[CH2:21][CH2:20]2)=[O:23])=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCN(C(=O)Nc2ccc(C(F)(F)F)cc2)CC1)N1CCC2(CC1)Cn1cc([N+](=O)[O-])nc1O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
Tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate prepared in Example 653 (300 mg, 0.67 mmol) was dissolved in methylene chloride (5 ml). To the solution, trifluoroacetic acid (10 ml) was added followed by stirring at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the solution, methylene chloride (1 ml) and triethylamine (1 ml) were added followed by stirring at room temperature for 5 minutes. The solution was concentrated under reduced pressure, and the residue was dissolved in DMF (10 ml). To the solution, a mixture of 4-aminobenzotrifluoride (0.17 ml, 1.33 mmol) and 1,1′-carbonyldiimidazole (220 mg, 1.33 mmol) and DMF (5 ml) stirred at room temperature for 3 hours was added followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and crystallized from methylene chloride-isopropyl ether to afford 4-[(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazole-2,4′-piperidin]-1′-yl)-2-oxoethyl]piperazine-1-carboxylic acid (4-trifluoromethylphenyl)amide (213 mg, yield 59%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH3:21])[CH:19]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=1.O.[OH-].[Na+].Cl>C1COCC1.CO.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:3]=[C:4]([C:15]2[CH:16]=[N:17][N:18]([CH:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=3)[CH3:21])[CH:19]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(C(C)n2cc(-c3cc(C)cc(Nc4ncccn4)c3)cn2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncccn2)cc(-c2cnn(C(C)c3ccc(C(=O)O)cc3)c2)c1
Temperature: 50 °C

Procedure:
A solution of methyl 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoate (125 mg, 0.302 mmol) in THF (5.0 mL), methanol (1.0 mL), and water (1.0 mL) was diluted with sodium hydroxide (1.0 M in water, 1.0 mL, 1.0 mmol). The reaction mixture was stirred and heated to 50° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with hydrochloric acid (1.0 M in water, 1.0 mL, 1.0 mmol) while stirring. The resulting suspension was diluted with ethyl acetate (100 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford 4-(1-(4-(3-methyl-5-(pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)ethyl)benzoic acid. The material was used without purification in the subsequent step. MS ESI calcd. for C23H22N5O2 [M+H]+ 400. found 400.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][C:17](C)=[CH:18][CH3:19])(=[O:14])[C:11]([CH3:13])=[CH2:12].O1CCOC[CH2:22]1>N(C(C)(C)C#N)=NC(C)(C)C#N.C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:15][CH2:16][CH:17]=[C:18]([CH3:19])[CH3:22])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: C=C(C)C(=O)OCC(C)=CC
Reactant: C1COCCO1
Agent: C=Cc1ccc(O)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1C
Product: C=C(C)C(=O)OCC=C(C)C
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A 1-liter flask was charged with 72.1 g (0.60 mol) of 4-hydroxystyrene, 49.2 g (0.60 mol) of 2-methyl-2-butenyl methacrylate, 1.5 g (0.009 mol) of azobisisobutyronitrile and 300 ml of dioxane, and the mixture was stirred for 20 hours at 20° C. in a nitrogen gas stream. The resultant reaction mixture was poured into 5 liters of xylene, and precipitate formed was collected by filtration. The resultant solids were dissolved in 300 ml of acetone, and the solution was poured into 4 liters of n-hexane to collect precipitate formed by filtration (reprecipitation process). This reprecipitation process was repeated 3 times, and the resultant precipitate was then dried to obtain 103.5 g of a 4-hydroxystyrene/3-methyl-2-butenyl methacrylate copolymer. The GPC analysis of the copolymer thus obtained revealed that its Mw was 8,800. Besides, the 1H-NMR spectrum analysis of the polymer revealed that the copolymerization ratio of 4-hydroxystyrene to 3-methyl-2-butenyl methacrylate was 53/47.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.O1CCCC1.[CH2:24]([CH:27]1[CH2:32][CH2:31][CH:30](O)[CH2:29][CH2:28]1)[CH2:25][CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[CH3:18][C@@:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH:30]4[CH2:31][CH2:32][CH:27]([CH2:24][CH2:25][CH3:26])[CH2:28][CH2:29]4)[CH:3]=3)[CH:8]=2)[CH2:16][O:15][C:14](=[O:17])[NH:13]1
Reactant: CCCC1CCC(O)CC1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
(R)-4-(6-Hydroxynaphthalen-2-yl)-4-methyl-oxazolidin-2-one (Example 4, 0.301 g, 0.00124 mol) was dissolved in tetrahydrofuran (5.00 mL, 0.0616 mol). 4-Propylcyclohexanol (0.211 g, 0.00148 mol) and triphenylphosphine polymer-bound (1.07 g, 0.00198 mol) were added and the mixture was stirred at room temperature. Diisopropyl azodicarboxylate (0.390 mL, 0.00198 mol) was then added and the mixture was stirred for 2 days at room temperature. The mixture was filtered through CELITE™, concentrated and purified by flash chromatography (0-30% EtOAc in methylene chloride) to give 0.4942 g of the title product (109% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:9]([C:15]2[N:19]([CH2:20][CH3:21])[N:18]=[N:17][N:16]=2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:9]([C:15]2[N:19]([CH2:20][CH3:21])[N:18]=[N:17][N:16]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCn1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.75 h
Yield: 101.1 %

Procedure:
To a solution of ethyl 3,3-bis(4-fluorophenyl)-2-(1-ethyl-1H-tetrazol-5-yl)-2-propenoate (1.0 g, 2.6 mmoles) at -78° in CH2Cl2 was rapidly added 7.8 mL (7.8 mmoles) of diisobutylaluminum hydride solution (1.0 Molar in methylene chloride). After stirring for 45 minutes, the mixture was quenched with 1N HCl solution. The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residual oil was triturated with hexane to give 0.9 g (100%) of the title compound; m.p.=103°-111° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([N:14]3[CH:23]([CH3:24])[CH2:22][C:21]4[C:16](=[CH:17][C:18]([C:25]5[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=5)=[CH:19][CH:20]=4)[CH2:15]3)[N:11]=[C:10]([NH2:31])[N:9]=2)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[N:41]([CH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1)=[C:42]=[O:43]>CN(C)C=O.CO>[NH2:31][C:10]1[N:11]=[C:12]([N:14]2[CH:23]([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][C:18]([C:25]4[CH2:26][CH2:27][N:28]([C:42]([NH:41][CH:44]5[CH2:48][CH2:47][CH2:46][CH2:45]5)=[O:43])[CH2:29][CH:30]=4)=[CH:19][CH:20]=3)[CH2:15]2)[CH:13]=[C:8]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[N:9]=1
Reactant: CC1Cc2ccc(C3=CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: O=C=NC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC1Cc2ccc(C3=CCN(C(=O)NC4CCCC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Methylpiperazin-1-yl)-6-[3-methyl-7-(1,2,3,6-tetrahydropyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (21.0 mg) HCl salt in N,N-dimethylformamide (1.0 mL) was treated with N,N-diisopropylethylamine (0.070 mL, 0.40 mmol). To the solution was added isocyanatocyclopentane (11.1 mg, 0.100 mmol). The mixture was stirred at r.t. for 2 h. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=531.2.
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:16])[CH:11]2[NH2:15])[C:8]=1[C:17]([O-:19])=[O:18])(=[O:4])[CH3:3].Cl[CH2:21][O:22][C:23](=[O:36])[C@H:24]([CH:33]([CH3:35])[CH3:34])[NH:25]C(OC(C)(C)C)=O>CN(C)C=O.C(OCC)(=O)C>[NH2:25][CH:24]([CH:33]([CH3:35])[CH3:34])[C:23]([O:22][CH2:21][O:18][C:17]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH2:15])[C:10]2=[O:16])=[O:19])=[O:36]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(N)C2SC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(N)C(C)C)N2C(=O)C(N)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, which is prepared by the general procedure described in W. German Offen. 2,236,620, are mixed in 100 ml of dimethyl formamide and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water with aqueous bicarbonate and again with water. The organic layer is dried over magnesium sulfate, filtered, and evaporated to dryness to give 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0 oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the amine protecting group is removed by standard procedures to give the title product.