Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[C:13](O)=[N:14][C:15]([CH3:18])=[N:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:13]1[C:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:11])=[O:10])=[CH:17][N:16]=[C:15]([CH3:18])[N:14]=1
Reactant: COc1ccc(S(=O)(=O)c2cnc(C)nc2O)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(S(=O)(=O)c2cnc(C)nc2Cl)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidin-4-ol (200 mg, 0.714 mmol) in phosphorus oxychloride (4 mL) was refluxed under N2 for 2 h and then cooled to room temperature. Solvents were removed in vacuo, and the residue was poured into ice water with stirring. The mixture was neutralized with saturated sodium bicarbonate to pH˜7 and extracted with methylene chloride (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (1:1 ethyl acetate/hexanes) to provide 4-chloro-5-(4-methoxy-benzenesulfonyl)-2-methyl-pyrimidine (177 mg, 83%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.32 (s, 1H), 7.93 (d, J=7.2 Hz, 2H), 7.01 (d, J=7.2 Hz, 2H), 3.89 (s, 3H), 2.77 (s, 3H); ESI MS m/z 299 [(M+H)+, calcd for C12H12ClN2O3S, 299.0].
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23][CH:24]([C:28](O)=[O:29])[C:25](O)=[O:26])[CH2:15][CH3:16]>>[OH:29][C:28]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:25](=[O:26])[C:24]=1[S:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:14][CH2:15][CH3:16]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: CCCc1ccccc1SC(C(=O)O)C(=O)O
Product: CCCc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.990 mL, 4.83 mmol) and diethyl ester of [(2-propylphenyl)thio]propanedioic acid (1.00 g, 3.22 mmol). m.p. 158-160° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.972 (t, 3H), 1.64 (m, 2H), 2.71 (t, 2H), 6.87 (s, 1H), 6.92 (m, 1H), 7.06 (m, 2H), 7.16 (m, 1H), 7.55 (m, 3H), 7.85 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].C(Cl)Cl>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:6]1[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cn(CCCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
5-methyl-2,4(1H,3H)-pyrimidinedione (commercially available, 0.55 g, 3.97 mmol) was dissolved in dry DMF (15 mL). K2CO3 (0.548 g, 3.97 mmol) was added and the mixture stirred at room temperature for 1 hour. 1-bromo-5-chloropentane (0.526 ml, 3.97 mmol) was then added and the suspension was stirred at room temperature for 4 h. The volume of solvent was reduced, then DCM was added and the organic layer was washed with water, the organic phase was evaporated and the crude purified by FC (DCM/MeOH 98/2-95/5) to afford 0.1 g of the title compound (y=11%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 665.33 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]([Cl:23])(=O)(=[O:21])[OH:20]>C(Cl)(Cl)Cl>[O:18]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:19]([Cl:23])(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (330 mg) obtained in Example 24-1 was dissolved in chloroform and then added with chlorosulfuric acid (manufactured by Kishida Chemical Co., Ltd.) (0.177 ml) under ice-cooling. The solution was stirred at room temperature for 2 days, and then concentrated and dried. The resultant was gradually added with phosphorus pentachloride (300 mg) and then heated to 80° C., followed by stirring for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][C:61]1[CH:66]=[CH:65][C:64]([CH2:67][NH2:68])=[CH:63][CH:62]=1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][CH2:67][C:64]3[CH:65]=[CH:66][C:61]([CH3:60])=[CH:62][CH:63]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 1-(4-methylphenyl)methanamine (63.8 mg, 0.526 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)=[CH:4][C:3]=1[O:15][CH:16]([C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1[Cl:26])[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:46]1([CH2:52][CH2:53]O)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.CCOC(/N=N/C(OCC)=O)=O>>[Cl:26][C:19]1[C:20]([F:25])=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[CH:16]([O:15][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:53][CH2:52][N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:12][CH:13]=2)[CH:6]=[N:7][C:2]=1[NH2:1])[CH3:17]
Reactant: CC(Oc1cc(-c2ccc(O)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(Oc1cc(-c2ccc(OCCN3CCOCC3)nc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h
Yield: 52.2 %

Procedure:
To a mixture of 6′-amino-5′-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-[3,3′]bipyridinyl-6-ol (78 mg, 0.20 mmol), triphenyphosphine (63 mg, 0.24 mmol) and 2-morpholin-4-yl-ethanol (0.026 mL, 0.22 mmol) was added DEAD (0.034 mL, 0.22 mmol). After stirring overnight more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After several hours, more alcohol (0.026 mL, 0.22 mmol) was added. After several more hours, more PPh3 (63 mg, 0.24 mmol) and more DEAD (0.034 mL, 0.22 mmol) were added. After stirring overnight, the mixture was partitioned between dichloromethane and half-saturated brine. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of dichloromethane, methanol to afford 5-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-6′-(2-morpholin-4-yl-ethoxy)-[3,3′]bipyridinyl-6-ylamine (53 mg, 53%).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.O>C1(C)C(C)=CC=CC=1>[CH3:14][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[N:9]=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:16]([F:15])([F:25])[F:26])[CH:18]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CN(C)CCCOc1ccccc1N
Solvent: Cc1ccccc1C
Solvent: O
Product: CN(C)CCCOc1ccccc1N=Cc1cccc(C(F)(F)F)c1
Yield: 52.6 %

Procedure:
A solution of 19.4g of 2-(3-dimethylaminopropoxy)aniline and 17.4g of m-trifluoromethylbenzaldehyde in 100ml of xylene is refluxed for about 6 hours. The water formed in the reaction is collected in a Dean-Stark tube. The solvent is removed under reduced pressure and the residue fractionated to yield 18.4g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm. of Hg.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.[CH3:22]O>>[CH3:5][N:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:16][CH:17]=2)[CH2:10][CH2:11]1
Reactant: CO
Reactant: CN1CCN(c2ccc(CC(=O)O)cc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(N2CCN(C)CC2)cc1

Procedure:
Thionyl chloride (0.32 g, 2.77 mmol) was added dropwise to a suspension of 2-(4-(4-methylpiperazin-1-yl)phenyl)acetic acid (2.60 g, 11.1 mmol) in MeOH (30 ml) at 0° C. and refluxed for 5 h. The reaction mixture was concentrated and the residue was dissolved in water, made alkaline with saturated sodium bicarbonate solution up to pH-8 and extracted with DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to get the crude compound. The crude was purified by column chromatography over neutral alumina using 4% MeOH in DCM as eluent to afford 250 mg of methyl 2-(4-(4-methylpiperazin-1-yl)phenyl)acetate as brown color solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([C:18]3[CH2:22][C:21]([C:27]4[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=4)([C:23]([F:26])([F:25])[F:24])[O:20][N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:21]2([C:23]([F:25])([F:24])[F:26])[O:20][N:19]=[C:18]([C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][CH:9]=[C:8]4[C:6]([OH:7])=[O:5])[CH2:22]2)[CH:32]=[C:31]([Cl:33])[CH:30]=1
Reactant: CC(C)(C)OC(=O)c1cccc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a stirred solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid tert-butyl ester (Example 9.5) (1.0 g) in dichloromethane (2 ml) was added trifluoroacetic acid (2 ml) and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was concentrated to give a solid which was washed with cyclohexane to give 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylic acid (0.76 g). 1H-NMR (DMSO, 400 MHz): 8.95 (m, 2H), 8.20 (d, 1H), 7.90 (d, 1H), 7.65-7.80 (m, 5H), 4.50 (q, 2H).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[CH:31]=[CH:30][C:29]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][N:22]3[C:23](=[O:27])[C:24]=2[CH2:25][CH3:26])[CH:14]=[CH:15][CH:16]=1>CN(C)C=O>[CH3:9][O:10][C:11]1[CH:12]=[C:13](/[CH:17]=[CH:18]/[C:19]2[N:20]=[C:21]3[CH:31]=[CH:30][C:29]4([CH2:2][CH:28]4[N:22]3[C:23](=[O:27])[C:24]=2[CH2:25][CH3:26])[C:32]([O:34][CH3:35])=[O:33])[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1c(/C=C/c2cccc(OC)c2)nc2ccc(C(=O)OC)cn2c1=O
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(/C=C/c2cccc(OC)c2)nc2n(c1=O)C1CC1(C(=O)OC)C=C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trimethyl-sulphoxonium iodide (1 g) was reacted with 50% sodium hydride (0.22 g) in dimethylformamide (30 ml) under stirring at room temperature for 30 minutes, then a solution of 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester, m.p. 177°-179° C., (1.27 g) in dimethylformamide (20 ml) was added. The mixture was allowed to react under stirring at room temperature for 2 hours, then it was diluted with ice water and the precipitate was filtered, so obtaining 1.19 g of 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, methyl ester (m.p. 184°-188° C.), which was treated with 0.5% KOH in 95% ethanol solution (40 ml) at reflux temperature for 15 minutes. After cooling the reaction mixture was diluted with water and acidified with acetic acid and the precipitate was filtered: crystallization from CH 2 Cl2 /methanol gave 2-trans-[2-(3-methoxy-phenyl)-ethenyl]-3-ethyl-6,7-methylen-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (0.65 g), m.p. 184°-188° C. NMR (CF3COOD) δ: 1.22(d.d) (one of 6,7-methylen protons), 1.36(t) (--CH2 --CH3), 2,96(m)(--CH2CH3 and 6,7-methylen proton), 4.12(s) (OCH3), 5.50(d.d) (c-6 proton), 7.03(d) (c-9 proton), 7.36(d) (Hβ -vinyl proton), 7.68(d) (Hα -vinyl proton), 7.18-7.70(m) (4-phenyl protons), 8.26(d) (c-8 proton), JHαHβ =16 Hz.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[C:22]([Cl:30])[N:21]=1>CN(C)C=O>[ClH:30].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:22]1[N:21]=[C:20]([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=1
Reactant: Clc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc2c(c(N3CCc4ccccc4C3)n1)CCCC2
Product: Cl
Yield: 28.2 %

Procedure:
After 4-fluoro-2-methylaniline(0.75 ml, 6.6 mmol) was added to a mixture solution of 4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-2-chloro-5,6,7,8-tetrahydroquinazoline(0.90 g, 3.0 mmol) and dimethylformamide(5 ml), 0.36 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: Br[C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)[S:5][CH:6]=1.[C:25]([Cu])#[N:26].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C>[C:25]([C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[C:4]([NH:7][C:8](=[O:20])[CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][CH:14]=[N:15]3)[S:5][CH:6]=1)#[N:26]
Reactant: COC(=O)c1c(Br)csc1NC(=O)Cc1cccc2ncccc12
Reactant: N#C[Cu]
Agent: CN[C@@H]1CCCC[C@H]1NC
Solvent: CN(C)C=O
Product: COC(=O)c1c(C#N)csc1NC(=O)Cc1cccc2ncccc12
Temperature: 150 °C

Procedure:
A 20 mL microwave vessel was charged with methyl 4-bromo-2-(2-(quinolin-5-yl)acetamido)thiophene-3-carboxylate (560 mg, 1.38 mmol), CuCN (540 mg, 6 mmol), DMF (8 mL), and (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (300 uL). The reaction mixture was flushed with nitrogen and sealed under a teflon cap before being heated to 150° C. using microwave radiation for 0.5 h. The reaction mixture was concentrated under reduced pressure to give an oil that was partitioned between an organic layer of 10% iPrOH/chloroform and an aqueous layer saturated with sodium bicarbonate. The heterogeneous organic layer was filtered and concentrated under reduced pressure to give a green oil. The crude product was purified by column chromatography with 60-70% ethyl acetate/hexanes. Yield: 40 mg (8%). Method [1]: rt=1.401 min; MH+ 352.0.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(N)=[O:23].O.CCOC(C)=O>O1CCOCC1>[OH:23][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: NC=O
Reactant: O=C(CCl)c1c[nH]c2cc(OCc3ccccc3)ccc12
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CO)c1c[nH]c2cc(OCc3ccccc3)ccc12
Temperature: 110 °C
Reaction time: 10 h
Yield: 82 %

Procedure:
A solution of 11 in dioxane was added to formamide-water (10:1). The mixture was stirred at 110° C. for 10 hrs., then worked up and purified as described above to yield 82% of 13 as colorless prisms with mp 194°-195° C. (EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[O:18][C:19]=1[CH3:20])[CH:6]=[CH:7][CH:8]=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][CH2:8][CH:30]2[S:26][C:27](=[O:32])[NH:28][C:29]2=[O:31])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[O:18][C:19]=1[CH3:20]
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=C1CSC(=O)N1
Product: COc1cc(CCCC2SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 9 %

Procedure:
According to the same manner as that described in Example 13, 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]cinnamaldehyde was condensed with 2,4-thiazolidinedione, and the resulting product was subjected to catalytic hydrogenation to give 5-[3-[3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]propyl]-2,4-thiazolidinedione (yield: 9%). This product was recrystallized from chloroform-diethyl ether. Colorless prisms, mp: 109-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:21]O.[OH-].[Na+]>O1CCOCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=3)[O:18][N:21]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(CC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Brc1ccc(-c2cc(-c3ccc(Br)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
In a 250 ml round bottom flask, 4 g (10.4 mmol) of [2] was dissolved in 100 ml dry dioxane and heated to reflux, then 3.0 g (43.2 mmol) hydroxylamine hydrogen chloride in 10 ml water and 5 ml (25 mmol) 5 N NaOH was then dropped into the refluxing mixture. After 12 hours, the reaction mixture was cooled down to room temperature, and the solvent was removed in vacuo. The product was recrystallized from ethanol. Characterization. Yield: 3.41 g (85%). M.P. 218.5-219.5° C. 1H NMR (300 MHz, CDCl3, 20° C., δ): 7.78 (d, 2H, ArH), 7.74 (d, 2H, Ar′H), 7.66 (d, 2H, ArH), 7.62 (d, 2H, Ar′H), 6.82 (s, 1H, isoxazole proton). EI-MS: 379 (M+), 224, 183, 155.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9][C@H:8]2[NH:16][C:17](=[O:19])[CH3:18])[C:3]1=[O:20].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][N:13]([CH3:15])[C@H:10]1[CH2:9][C@@H:8]([NH:16][C:17](=[O:19])[CH3:18])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[C:3]2=[O:20])[CH2:12][CH2:11]1
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C[C@H](N(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.5 %

Procedure:
To a solution of N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(dimethylamino)cyclohexyl)acetamide (40 mg, 0.14 mmol) in isopropanol (6 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (39 mg, 0.17 mmol) and triethylamine (0.02 mL, 0.14 mmol). The mixture was stirred at RT for 16 h and concentrated in vacuo to a crude oil, which was purified by semi-preparative reverse phase HPLC (gradient elution, water/methanol/TFA) to give the title compound (70 mg, 71% yield). LC/MS found [M+H]+=479. 1H-NMR (400 MHz, CD3OD), δ ppm: 8.87 (s, 1H), 8.72 (s, 1H), 8.22 (m, 1H), 7.87 (m, 1H), 5.49 (m, 1H), 4.23 (m, 1H), 4.2 (m, 1H), 4.12 (m, 1H), 3.75 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 2.82 (s, 6H), 2.51 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 2.14-1.86 (m, 5H), 1.84 (s, 3H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:55][CH2:56][CH2:57][N:58]1[CH2:62][CH2:61][CH2:60][C:59]1=[O:63]>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:55][CH2:56][CH2:57][N:58]4[CH2:62][CH2:61][CH2:60][C:59]4=[O:63])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: O=C1CCCN1CCCO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCCC1=O
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 141.3 %

Procedure:
Diethyl azodicarboxylate (261 mg, 1.5 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (393 mg, 1.5 mmol) and 1-(3-hydroxypropyl)-2-pyrrolidinone (107 mg, 0.75 mmol) in methylene chloride (5 ml) under nitrogen. The mixture was stirred for 20 minutes at ambient temperature and then purified by pouring directly onto a column of silica eluting with methylene chloride/ethyl acetate/methanol (60/35/5 followed by 60/30/10). The purified product was triturated with ether and collected by filtration. The solid was dissolved in ethyl acetate and treated with 3M hydrogen chloride in ethyl acetate (0.4 ml). The precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxopyrrolidin-1-yl)propoxy)quinazoline hydrochloride (170 mg, 70%).