Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)([OH:42])=[O:41]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:46]3[CH:47]=[CH:48][C:43]([C:40]([OH:42])=[O:41])=[CH:44][CH:45]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3ccc(C(=O)O)cc3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 4-carboxyphenylboronic acid replacing phenylboronic acid.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.[BH4-].[Na+]>O1CCCC1.C(O)C.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of 0.43 g of 11β-fluoro-3-hydroxy-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one in 4 ml of tetrahydrofuran, 2.3 ml of ethanol and 1 ml of water is mixed in portions at 0° C. with 111 mg of sodium borohydride, and it is stirred for 2 hours. Then, it is added to ice water, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/acetone. 0.32 g of 11β-fluoro-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol with [α]D22 =+16.2° (c=0.51% in methanol) is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:61][C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1>CN(C=O)C.O>[F:61][C:62]1[CH:70]=[CH:69][C:65]([C:66]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:67])=[CH:64][CH:63]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 66.7 %

Procedure:
DIPEA (46.5 mg, 0.36 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone-TFA salt (62 mg, 0.14 mmol) in DMF (0.5 mL). HOBT (19 mg, 0.14 mmol) and EDCI.HCl (28 mg, 0.14 mmol) were added at room temperature. After 2 minutes, 4-fluorobenzoic acid, (17 mg, 0.12 mmol) was added. The resulting mixture was stirred at room temperature for four hours. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford 35 mg (67% yield) of 4-fluoro-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 92.29%, HPLC Purity: 93.53%.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([OH:25])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:29]S(O)(=O)=O>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:29])([CH3:23])[CH3:24])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:26])=[CH:10][CH:11]=3)[N:6]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(O)ccc1O2

Procedure:
A vessel was charged with (S)-2′-amino-3-(3-hydroxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.679 g, 1.933 mmol) in methanol (23.51 mL, 580 mmol). methane sulfonic acid (0.627 mL, 9.66 mmol) was added, and the vial was sealed and placed in a 70° C. oil bath for 5 hours. The volatiles were evaporated, and the residue was loaded onto a silica gel cartridge in MeOH/DCM. The column was eluted onto an 80-g Redi-Sep column with 30-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM. This was not the best strategy as it clogged the column for a while. The fractions containing product were evaporated to give (S)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@@H:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3]1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:47])([F:46])[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:34][CH:33]=1.CN(P(N(C)C)(N(C)C)=O)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH2:11]([O:10][C:8]([N:6]1[C@@H:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:3][C:2](=[O:1])[C@H:7]1[CH2:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([F:46])([F:47])[C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])=[CH:36][CH:37]=1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)[C@@H](c2ccccc2)[C@@H](c2ccccc2)O1
Reactant: CC(C)(C)OC(=O)C(F)(F)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)C(F)(F)c1ccc(C[C@@H]2C(=O)O[C@H](c3ccccc3)[C@H](c3ccccc3)N2C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution at −78° C. of benzyl (2R, 3S)-(−)-6 oxo-2,3 diphenyl-4 morpholine carboxylate (10.5 g) and tert butyl 2-{4-(bromomethyl)phenyl}-2,2-difluoroacetate (6.2 g) and HMPA 55 mL in THF 550 ml. was added LiHMDS (28 mL, 1 M in THF) over a period of 1 hour 20 minutes. The reaction mixture was stirred further at −78° C. for 1 hour.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:4]=1[S:12]([NH2:15])(=[O:14])=[O:13]>[Pd].CO>[NH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:16])[CH3:1])[C:4]=1[S:12]([NH2:15])(=[O:13])=[O:14]
Reactant: CN(C)c1cccc([N+](=O)[O-])c1S(N)(=O)=O
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cccc(N)c1S(N)(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 2-dimethylamino-6-nitro-benzenesulfonamide (753 mg, 3.07 mmol), Pd (10%) on charcoal (100 mg) and methanol (25 ml) is hydrogenated at 25° C. for 2 h. Pd is removed by filtration, the solvent evaporated and the residue crystallized from TBME/cyclohexane to give 2-amino-6-dimethylamino-benzenesulfonamide as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[C:5]2[N:6]([C:10]([C:13]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([NH:21][C@H:22]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[CH3:23])[N:14]=3)=[CH:11][N:12]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[Na].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[OH:3][CH:1]([C:4]1[C:5]2[N:6]([C:10]([C:13]3[C:18]([C:19]#[N:20])=[CH:17][N:16]=[C:15]([NH:21][C@H:22]([C:24]4[CH:29]=[CH:28][C:27]([N:30]5[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]5)=[CH:26][CH:25]=4)[CH3:23])[N:14]=3)=[CH:11][N:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cccn2c(-c3nc(N[C@@H](C)c4ccc(N5CCNCC5)cc4)ncc3C#N)cnc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1cccn2c(-c3nc(N[C@@H](C)c4ccc(N5CCNCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
39 mg of the 4-(8-acetylimidazo[1,2-a]pyridin-3-yl)-2-{[(1S)-1-(4-piperazin-1-ylphenyl)ethyl]amino}pyrimidine-5-carbonitrile [156-3] was dissolved in a mixture solvent of 1 mL of tetrahydrofuran and 1 mL of methanol, then 2.8 mg of sodium boronhydride was added thereto, and stirred at room temperature for 15 minutes. Thereto, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with a mixture solvent of chloroform and methanol (chloroform:methanol=9:1). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insolubles were filtered, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative thin-layer chromatography, and 31.9 mg of 4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridin-3-yl]-2-{[(1S)-1-(4-piperazin-1-ylphenyl)ethyl]amino}pyrimidine-5-carbonitrile [156-4] was obtained as a two kinds of diastereomer mixture.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4].[CH3:24][NH:25][CH3:26]>C1COCC1>[CH3:24][N:25]([CH3:26])[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]([C:16]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[O:4]
Reactant: O=C(CBr)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 10 %

Procedure:
Compound 531 (120 mg, 0.300 mmol) was dissolved in THF (2 mL), and a 2 mol/L solution of dimethylamine in THF (0.054 mL, 1.80 mmol) was added thereto, followed by stirring at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (chloroform), followed by reslurrying with a mixed solvent of 2-propanol and diethyl ether to afford the entitled Compound 533 (64.1 mg, 10%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:33]=[C:8]2[N:9]=[CH:10][C:11]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:21][CH:20]=3)=[C:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:7]2[N:6]=1)=[O:4].[Br:34]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:33]([Br:34])=[C:8]2[N:9]=[CH:10][C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][CH:24]=3)=[C:12]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ncc(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)n2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc2c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To an ice cold solution of 50 mg (0.113 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester in 2 mL of dichloromethane (DCM) was added a solution of 21 mg (0.118 mmol) of N-bromosuccinimide (NBS) in 1 mL of DCM and the resulting mixture was allowed to warm up to rt and stirred at rt overnight. The reaction mixture was concentrated to give a residue which was chromatographed on silica gel (5% ethyl acetate in dichloromethane) to afford 7 mg (11% yield) of 6-(4-benzyloxy-phenyl)-3-bromo-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as a colorless oil as indicated by 1H NMR (90% purity); LC-MS—calcd for C27H26BrN3O3 [M++H]+: 520.12, found: 520.0.
Reaction SMILES: C1(S([NH:10][C:11](N)=[O:12])(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1.[Cl:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28]>C(O)(=O)C>[Cl:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:11](=[O:12])[NH2:10]
Reactant: NC1CCCCC1Cl
Reactant: NC(=O)NS(=O)(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: NC(=O)NC1CCCCC1Cl

Procedure:
A mixture of 10.3 g of of N-[4-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-ethyl)-benzenesulfonyl-urea (melting point 171° -173°C), 300 ml of toluene, 30 ml of glycolmonomethyl-ether, 1.65 g of glacial acetic acid and 3.3 g of 2-chloro-cyclohexylamine are heated under reflux for 5 hours. Then the whole is concentrated in vacuo and the residue is treated with alcohol. The N-[4-(β<2-methoxy-5-chlorobenzamido> -ethyl)-benzenesulfonyl]-N'-(2-chlorocyclohexyl)-urea obtained as crude product melts at 194° -195°C after recrystallization from methanol/dimethylformamide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[CH:18]=[CH2:19]>C(OCC)C>[CH2:19]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)[CH:18]=[CH2:17]
Reactant: OCCc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=CCOc1ccc(CCO)cc1
Reaction time: 17 h
Yield: 60.5 %

Procedure:
2-(4-Hydroxyphenyl)ethanol (100 g), anhydrous potassium carbonate (100 g) and allyl bromide (98 g) were refluxed with stirring for 17 hours. The mixture was cooled, filtered (washing through with acetone) and evaporated under reduced pressure to give an oily residue. This residue was dissolved in diethyl ether, washed with aqueous sodium hydroxide, washed with saturated brine, dried (MgSO4) and evaporated in vacuo to afford an oil. This was chromatographed on a silica gel column using dichloromethane to afford 2-(4-allyloxyphenyl)ethanol (78 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH:10]=[C:11]([CH3:13])[NH2:12])=[CH:5][CH:4]=1.CN(C)C=O.[C:20](OC)(=[O:23])[C:21]#[CH:22]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:10]2[CH:22]=[CH:21][C:20](=[O:23])[NH:12][C:11]=2[CH3:13])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C=C(C)N)cc1
Reactant: C#CC(=O)OC
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: COc1ccc(C(=O)c2ccc(=O)[nH]c2C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 93 g of 3-(4-methoxyphenyl)-1-methyl-3-oxo-1-propenamine and 200 ml of dimethylformamide was added 46 ml of methyl propiolate over a 30 minute period and the reaction mixture was stirred at ambient temperature for 3 hours and then gently refluxed for 24 hours. The reaction mixture was allowed to cool, treated with 200 ml of isopropyl alcohol and the solid filtered. The solid was washed with isopropyl alcohol and dried at 90°-95° C. to yield, as white shiny crystals, 75.8 g of 5-(4-methoxybenzoyl)-6-methyl-2(1H)-pyridinone, m.p. 228°-230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)O)c2)=C(C)C1=O
Reactant: CC(C)N
Product: COC1=C(OC)C(=O)C(Cc2cccc(C=CC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 34.4 %

Procedure:
3-[3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (55 mg, 0.16 mmol) obtained in Example 36 and isopropylamine (0.016 ml, 0.18 mmol) were used, and a method similar to that described in Example 24 was employed to obtain the title compound (21 mg, 0.055 mmol, yield 34%).
Reaction SMILES: [C:1](O)(C(F)(F)F)=O.C(Cl)Cl.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:26][C:25]3[C:24](=[O:27])[N:23]([C:28]4[CH:44]=[CH:43][C:31]([O:32][CH2:33][CH2:34][NH:35][C:36](=O)[O:37]C(C)(C)C)=[C:30]([O:45][CH3:46])[CH:29]=4)[CH:22]=[N:21][C:20]=3[CH:19]=2)=[CH:14][CH:13]=1.CC(OC(C)=O)=O.CCN(CC)CC>C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:26][C:25]3[C:24](=[O:27])[N:23]([C:28]4[CH:44]=[CH:43][C:31]([O:32][CH2:33][CH2:34][NH:35][C:36](=[O:37])[CH3:1])=[C:30]([O:45][CH3:46])[CH:29]=4)[CH:22]=[N:21][C:20]=3[CH:19]=2)=[CH:16][CH:17]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCNC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OCCNC(C)=O
Reaction time: 2.5 h

Procedure:
A 10% TFA/CH2Cl2 solution (0.5 mL) containing tert-butyl 2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-ethylcarbamate (15 mg, 0.03 mmol) (Example 3) was stirred for 2.5 hr whereupon the volatiles were removed under vacuum. To the residue containing 3-(4-(2-aminoethoxy)-3-methoxyphenyl)-6-(4-chlorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one was sequentially added CH2Cl2 (0.25 mL), Ac2O (20 mg, 0.2 mmol) and Et3N (74 mg, 0.7 mmol). After standing overnight, the reaction was diluted with aq Na2CO3 and extracted 4× with CH2Cl2. The combined organic layers were washed with brine and dried over Na2SO4. After removal of the solvent the residue was chromatographed on silica gel using 5-10% MeOH/EtOAc to elute the desired acetamide (12 mg). 1H NMR (CDCl3) δ 2.03 (s, 3H), 3.72 (m, 2H), 3.91 (s, 3H), 4.16 (t, 2H, J=4.8 Hz), 6.13 (m, 1H), 6.94 (dd, 1H, J=8.4 Hz, J=2.2 Hz), 6.98 (d, 1H, J=2.2 Hz), 7.02 (d, 1H, J=8.4 Hz), 7.45 (d, 2H, JAB=8.7 Hz), 7.54 (s, 1H), 7.66 (d, 2H, JAB=8.7 Hz), 8.14 (s, 1H); HPLC (Method #1): 3.67 min; LCMS m/z: 498 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[OH:21][C:22]1[CH:31]=[C:30]2[C:25]([CH2:26][CH:27]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][O:29]2)=[CH:24][CH:23]=1>O>[C:35]([O:34][C:32]([CH:27]1[CH2:26][C:25]2[C:30](=[CH:31][C:22]([O:21][CH2:2][C:3]3[N:4]=[C:5]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[O:6][C:7]=3[CH3:8])=[CH:23][CH:24]=2)[O:29][CH2:28]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)C1COc2cc(O)ccc2C1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(c1)OCC(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.2 %

Procedure:
To a stirred solution of 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole (103.5 mg, 0.5 mmol) and potassium carbonate (138.4 mg, 1 mmol), tert-butyl 7-hydroxychromane-3-carboxylate (125 mg, 0.5 mmol) was added and the reaction mixture was stirred at room temperature for 48 hrs. Water (50 ml) was added and the precipitated product was extracted with 25 ml of diethyl ether. Ether layer was washed with water (25 ml) twice and dried. On evaporation of solvent, the product was obtained as pale yellow gum (150 mg, 36%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]2[C:8](=[N:13][OH:14])[CH2:7][CH:6]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[CH2:5][C:4]=2[N:3]=1.[CH3:20][N:21]([CH3:45])[CH2:22][CH2:23]ON=C1CC(C2C=CC(F)=CC=2)CC2N=C(N)N=C(C)C1=2>>[CH3:20][N:21]([CH3:45])[CH2:22][CH2:23][O:14][N:13]=[C:8]1[CH2:7][CH:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[CH2:5][C:4]2[N:3]=[C:2]([NH2:1])[N:11]=[C:10]([CH3:12])[C:9]1=2
Reactant: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccc(F)cc1)C2
Reactant: Cc1nc(N)nc2c1C(=NO)CC(c1ccco1)C2
Product: Cc1nc(N)nc2c1C(=NOCCN(C)C)CC(c1ccco1)C2

Procedure:
The title compound was prepared from 2-amino-7-furan-2-yl-4-methyl-7,8-dihydro-6H-quinazolin-5-one oxime (compound 33), following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one O-(2-dimethylamino-ethyl)-oxime (example 3/a stage 5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[O:14]=[C:11]1[NH:12][N:13]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:15](=[O:17])[CH3:16])[CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:10]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(-c2ccc(=O)[nH]n2)c1
Product: CC(=O)Nc1cccc(-c2ccc(=O)[nH]n2)c1

Procedure:
A mixture of 37 g of 6-(3-aminophenyl)-3(2H)-pyridazinone and 500 ml of acetic anhydride was heated at 85°-90° C. for 8 hours. The solvent was removed in vacuo and the residue dissolved in 500 ml of methanol. To this solution was added portionwise 40 g of potassium hydroxide. The solution was refluxed for 3 hours and the solvent removed in vacuo. The residue was dissolved in water and the solution neutralized with hydrochloric acid. The resulting solid was collected and recrystallized from dichloromethane-methanol, giving 10.8 g of the desired compound as crystals, mp 250°-252° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>CN(C=O)C.CCOC(C)=O>[CH:15]([N:4]1[C:3](=[O:18])[C:2]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])([CH3:17])[CH3:16]
Reactant: N#Cc1cccc(CCN)c1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NCCc2cccc(C#N)c2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 8.7 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (150 mg, 0.525 mmol) was dissolved in dry DMF (1 mL) under nitrogen atmosphere. 3-(2-Aminoethyl)benzonitrile (78 mg, 0.530 mmol) was added followed by TEA (53 mg, 0.525 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (18 mg, 56.3%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 2.60 (t, 2H), 3.17 (q, 2H), 4.37-4.46 (m, 1H), 5.49 (bs, 1H), 6.88 (s, 1H), 7.02 (d, 1H), 7.30-7.34 (m, 1H), 7.47-7.57 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 20.38, 35.75, 44.70, 47.90, 107.72, 113.00, 118.70, 125.17, 129.19, 129.67, 130.36, 130.77, 131.95, 132.20, 133.23, 135.11, 139.03, 158.60; Mass Spectrum: M+H+ 396.1.