Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[CH:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (7.43 mL, 0.105 mol) was added to oxalyl chloride (5.53 mL, 0.0654 mol) in methylene chloride (244.2 mL) at −78° C. After 10 min, tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (10.0 g, 0.0436 mol) in methylene chloride (488.4 mL) was added and the resultant mixture was stirred at −78° C. for 30 min. Triethylamine (30.4 mL, 0.218 mol) was then added and the mixture was stirred for 5 h with the temperature allowed to gradually warm up to room temperature. After being quenched with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried over MgSO4, evaporated to dryness and used directly in next step. LCMS (M+Na) 250.0.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:29][CH:30]5[CH2:35][NH:34][CH2:33][CH:31]5[N:32]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:29][CH:30]5[CH2:35][N:34]([C:36](=[O:38])[CH3:37])[CH2:33][CH:31]5[N:32]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CNCC6O5)cc34)cc2C)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(Oc6ccc(C)nc6)c(C)c5)c4c3)OC2C1

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazol-5-yl)-ethanone is prepared from N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride. MS APCI (+) m/z 510 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.28 (m, 2H), 7.00 (d, 1H), 5.28 (m, 1H), 4.89 (m, 1H), 4.15 (d, 0.5H), 4.03 (m, 1H), 3.84 (d, 0.5H), 3.75 (m, 1H), 3.47 (m, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.09 (d, 3H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]#[N:10])C.[H][H]>C(O)C.[Co]>[CH3:11][N:6]1[CH2:7][CH2:8][CH2:9][NH:10][C:4](=[O:3])[CH2:5]1
Reactant: [H][H]
Reactant: CCOC(=O)CN(C)CCC#N
Agent: [Co]
Solvent: CCO
Product: CN1CCCNC(=O)C1
Yield: 75.1 %

Procedure:
A solution of 750 g of N-methyl-N-(2-cyanoethyl)glycine ethyl ester (prepared from methylaminopropionitrile and ethyl chloroacetate) in 1 liter of ethanol is hydrogenated in the presence of 60 g of Raney cobalt in an autoclave at a temperature of from 80° to 90°C and under a pressure of 100 to 120 atms. of hydrogen. The calculated quantity of hydrogen has been absorbed after about 1 hour. The hydrogenated solution is filtered off from the catalyst. The solid residue left after the ethanol has been evaporated is freed from any greases adhering to it by means of a little ethyl acetate, and the white product, which does not show any tendency towards discoloration in air, is fractionated in a high vacuum with 5 g of sodium methoxide. 424 g of 1-N-methyl-hexahydro-1,4-diazepin-3-one melting at 91°C are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])[CH2:34][CH2:33]1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])[CH:9]=1)=[O:7].[OH-].[K+:54]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][C:27]=1[O:28][CH:29]([C:46]1[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=1)[CH2:30][CH2:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[O:44][CH3:45])[CH2:36][CH2:37]1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O-:22])=[O:21])[CH:9]=1)=[O:7].[K+:54]
Reactant: CCOC(=O)CCCn1cc(C(=O)c2ccc(OC(CCN3CCN(c4ccccc4OC)CC3)c3ccc(C)cc3)c(OC)c2)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)c2cn(CCCC(=O)[O-])c3ccccc23)ccc1OC(CCN1CCN(c2ccccc2OC)CC1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Ethyl 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl} indol-1-yl}butanoate (2.00 g) was dissolved in ethanol (20 ml). Potassium hydroxide (0.64 g) was added to the resultant solution and stirred overnight at room temperature. After removing the solvent, the residue was purified using an HP-20 column, obtaining 1.34 g of potassium 4-{3-{3-methoxy-4-{1-(4-methylphenyl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}indol-1-yl}butanoate as amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][N:19](C(OCC5C=CC=CC=5)=O)[CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.Br>O1CCOCC1.CC(O)=O.CCOCC>[F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:17]4([CH2:21][CH2:20][NH:19][CH2:18]4)[O:16][CH2:15][CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCOC21CCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCOC21CCNC1
Reaction time: 24 h

Procedure:
To a stirred solution of Example 36 (0.388 g, 0.763 mmol) in 1,4-dioxane (5 mL) was added 33 wt % HBr in AcOH (1 mL) at room temperature. After 24 h, the resulting white slurry was diluted with Et2O (50 mL), filtered and dried to afford desired product as 1:1:1 product:HBr:dioxane adduct 0.3521 g, 85%). 1H NMR (500 MHz, DMSO-d6) δ: 12.30 (1H, s), 9.48 (1H, t, J=6.4 Hz), 9.17 (1H, s), 7.39-7.36 (2H, m), 7.20-7.15 (2H, m), 4.57-4.48 (2H, m), 4.08-4.04 (2H, m), 3.94-3.84 (2H, m), 3.75-3.69 (1H, m), 3.60-3.49 (6H, m), 3.47-3.31 (4H, m), 2.69-2.62 (1H, m), 2.44-2.38 (1H, m). HRMS (M+H) calcd for C18H20N4O4F: 375.1469; found: 375.1466.
Reaction SMILES: C(N[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:17][CH3:18])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)CC.CC1C=CC(C(O)C(OC(=O)C)=O)=CC=1>CC(C)=O>[CH3:18][O:17][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[O:15][CH3:16])[CH2:13][CH2:14][CH2:5][CH2:6]2
Reactant: CCCNC1CCc2cc(OC)c(OC)cc2C1
Agent: CC(=O)OC(=O)C(O)c1ccc(C)cc1
Solvent: CC(C)=O
Product: COc1cc2c(cc1OC)CCCC2
Reaction time: 0.5 h
Yield: 74 %

Procedure:
2-(N-propyl)amino-6,7-dimethoxy tetraline (3.69 g; 0.0147 moles) (prepared as indicated in step (a) of Example 2 was dissolved in 43 cc of acetone. To the resulting solution the acid chloride of p-methyl-O-acetyl-mandelic acid (1.45 g; 0.007 moles) was added. The solution was kept at room temperature for 30 minutes and subsequently filtered and concentrated under vacuum. The residue was taken up with methylene chloride and washed with 5% HCl, 5% NaHCO3 and H2O to neutrality. The organic phase was dried over anhydrous Na2SO4 and brought to dryness. 2.4 g of 2-[(N-propyl, N-p-methyl-O-acetyl mandelyl)amino]-6,7-dimethoxy tetraline were obtained. To the amide thus obtained (2.4 g; 0.0058 moles) BH3 in THF (17.4 cc; 0.017 moles) was added at 0° C. The solution was kept at the reflux temperature for three hours. Subsequently, 16 cc of 6N HCl were added at 0° C., the solution was kept at the reflux temperature for 30 minutes and then concentrated under vacuum in order to remove the THF. The acid solution was alkalinized with 4N NaOH and extracted with chlorophorm. The organic phase was washed with H2O to neutrality and concentrated under vacuum. The solid which formed was taken up with ethyl acetate and upon addition of gaseous HCl 1.4 grams of a white solid product were obtained (yield 74%). ##STR28##
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:26](OC)(OC)OC>CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]=[CH:26]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: Nc1ccccc1NCCCC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CCC(CCCn3cnc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 160 mg of N-(3-(1-benzyl-piperidin-4-yl)-propyl)-benzene-1,2-diamine (from Step E) in 4.3 mL of trimethyl orthoformate was added 0. 16 mL concentrated HCl. After stirring at 80° C. for 16 hr, the reaction was diluted with EtOAc and washed with sat'd NaHCO3 solution. Aqueous phase was extracted with 2×20 mL EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated to give 198 mg of oil, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][CH:7]=[N:8][OH:9])([CH3:4])[CH3:3].ClN1C(=O)CCC1=O.[C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])(=O)[CH:19]([CH3:21])[CH3:20].C[O-].[Na+].CO>CN(C)C=O.O1CCCC1.CCOCC>[CH3:1][C:2]([O:5][CH2:6][C:7]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:18]([CH:19]([CH3:21])[CH3:20])[O:9][N:8]=1)([CH3:4])[CH3:3]
Reactant: COC(=O)CC(=O)C(C)C
Reactant: CC(C)(C)OCC=NO
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1c(COC(C)(C)C)noc1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of (1,1-dimethylethyl)oxyethanal oxime (8.59 g, 65.5 mmol) in N,N-dimethylformamide (50 mL) was added N-chlorosuccinimide (8.45 g, 65.5 mmol). The solution was stirred for approximately 1 hour. The solution was poured into ether and washed twice with water. The organic layer containing the crude imidoyl chloride was then washed with brine, was dried over magnesium sulfate and concentrated. Then to a solution of methyl isobutyrylacetate (8.86 mL, 78.6 mmol) in tetrahydrofuran (40 mL) at 0° C. was added a 0.5 M solution of sodium methoxide in methanol (157 mL, 78.6 mmol). After stirring for approximately 5 minutes the above imidoyl chloride was added in tetrahydrofuran (30 mL). A solid was observed to precipitate. After the addition was complete the mixture was allowed to stir and warm to ambient temperature overnight. Then the solution was poured into ether and washed with water containing sodium chloride, dried over magnesium sulfate and concentrated to afford methyl 3-{[(1,1-dimethylethyl)oxy]methyl}-5-(1-methylethyl)-4-isoxazolecarboxylate (10.6 g, 63%). 1H-NMR (400 MHz, DMSO-d6) δ 4.52 (s, 2H), 3.77 (s, 3H), 3.67 (septet, J=7 Hz, 1H), 1.25 (d, J=7 Hz, 6H), 1.18 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=O)[O:24]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1.[H-].[NH2:33][NH2:34].O>O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([NH:33][NH2:34])=[O:24])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: NN
Reactant: COc1ccc(N2CCN(c3ccc(NC(=O)Oc4ccccc4)cc3F)CC2)cc1
Agent: [H-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(c3ccc(NC(=O)NN)cc3F)CC2)cc1
Yield: 79.5 %

Procedure:
To a solution containing 5 (0.3 g, 0.7 mmol) and hydrazine monohydride (0.19 mL, 3.7 mmol) in 1,4-dioxane. The reaction mixture was stirred and heated to reflux for 4 h. After cooling to room temperature water was added and the mixture was stirred for 30 min. The precipitated solid was filtered and the solid was washed with acetonitrile and then dried under vacuum to obtain the hydrazinecarboxamide intermediate 6 (0.2 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[F:16][C:17]1[CH:41]=[CH:40][C:20]([CH2:21][O:22][C:23]2[C:24](B(O)O)=[CH:25][C:26]3[C:27]([CH3:36])([CH3:35])[CH2:28][CH2:29][C:30]([CH3:34])([CH3:33])[C:31]=3[CH:32]=2)=[CH:19][CH:18]=1>>[OH:8][C:7]1[CH:2]=[CH:3][C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:5][C:6]=1[C:24]1[C:23]([O:22][CH2:21][C:20]2[CH:40]=[CH:41][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:32][C:31]2[C:30]([CH3:34])([CH3:33])[CH2:29][CH2:28][C:27]([CH3:36])([CH3:35])[C:26]=2[CH:25]=1
Reactant: CC1(C)CCC(C)(C)c2cc(B(O)O)c(OCc3ccc(F)cc3)cc21
Reactant: CCOC(=O)C=Cc1ccc(O)c(Br)c1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(C=CC(=O)O)ccc3O)c(OCc3ccc(F)cc3)cc21
Yield: 47 %

Procedure:
In a manner similar of Example 1(c), by reaction of 1.0 g (3.7 mmol) of ethyl 3-(3-bromo-4-hydroxyphenyl)acrylate obtained in Example 34(d) with 1.97 g (5.5 mmol) of 3-(4-fluorobenzyloxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylboronic acid obtained above, 825 mg (44%) of the expected compound were obtained in the form of a white solid having a melting point of 123°-125° C.
Reaction SMILES: [S:1]1[CH2:6][S:5][CH2:4][S:3][CH2:2]1.[Li].[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1>O1CCCC1>[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([OH:14])[CH:2]2[S:3][CH2:4][S:5][CH2:6][S:1]2)=[CH:11][CH:10]=1
Reactant: C1SCSCS1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Li]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1SCSCS1
Temperature: -60 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 2.6 g of 1,3,5-trithiane, and 12 ml of 1.6M n-bytyl lithium was added dropwise under an argon atmosphere at a temperature of about -20° C. After completion of the dropwise addition, the resulting mixture was stirred for 2 hours. Next, the reaction mixture was cooled to about -60° C., and then a solution of 4.4 g of 4,4'-difluorobenzophenone dissolved in 100 ml of tetrahydrofuran was dropped thereinto. After completion of the dropping, the reaction temperature was slowly raised to 0° C. After stirring at 0° C. for another 1 hour, the reaction mixture thus obtained was poured into ice water and the resulting mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product thus obtained was recrystallized from ether-hexane to give 5.58 g of the desired compound.
Reaction SMILES: [CH3:1]I.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=[S:20])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O.CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([S:20][CH3:1])[O:13][C:14]=2[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:6][CH:5]=1
Reactant: O=C(O)CCc1oc(=S)[nH]c1-c1ccc(Cl)cc1
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Methyl iodide (0.34 ml) was dropwise added to a mixture of 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (1.42 g), an aqueous solution of 2 N sodium hydroxide (5.5 ml) and N,N-dimethylformamide (15 ml), with cooling with ice. After the reaction mixture was stirred for 30 minutes, water was added to the resulting reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated w ere collected by filtration to obtain 4-(4-chlorophenyl)-2-methylthio-5-oxazolepropionic acid (1.45 g, 97%). This was recrystallized from ethanol to give colorless needles. mp 183-184° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH:6]([CH2:11][N:12]3[C:17]4=[N:18][C:19]([C:23]5[CH:28]=[CH:27][N:26]=[CH:25][N:24]=5)=[CH:20][C:21](=[O:22])[N:16]4[CH2:15][C:14]([CH3:30])([CH3:29])[CH2:13]3)[CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:14]1([CH3:30])[CH2:15][N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][N:24]=3)[N:18]=[C:17]2[N:12]([CH2:11][CH:6]2[CH2:5][C:4]3[N:3]=[C:2]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:10]=[CH:9][C:8]=3[CH2:7]2)[CH2:13]1
Reactant: CC1(C)CN(CC2Cc3ccc(Cl)nc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC1(C)CN(CC2Cc3ccc(-c4ccccc4)nc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 140 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
A solution of 0.22 g (0.52 mmol) of (+/−)9-(2-chloro-6,7-dihydro-5H-[1]pyrindin-6-ylmethyl)-7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one in 3 ml of anhydrous toluene and 0.5 ml of ethanol was treated with 0.625 ml (2M solution in water) of sodium carbonate, 36 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium and 0.095 g (0.780 mmol) of phenyl-boronic acid. After being stirred for 24 h at 140° C., water was added, the mixture was extracted with dichloromethane. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol/ammonia in the proportions 99/1/0.1 to give 0.133 g of pure product obtained in the form of free base. Mp: 209-211° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:23]=[CH:22][O:21][CH:20]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]1>>[O:21]1[CH:22]=[CH:23][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:25]4[CH2:30][CH2:29][CH:28]([NH:31][C:32](=[O:34])[CH3:33])[CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:24])[CH:13]=2)=[CH:20]1
Reactant: O=c1cc(OCc2ccoc2)ccn1CCc1ccc(CBr)cc1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccoc4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(Furan-3-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 5.1c from 150 mg (85% purity, 0.33 mmol) 1-[2-(4-bromomethylphenyl)-ethyl]-4-(furan-3-ylmethoxy)-1H-pyridin-2-one (example 5.1b) and 187 mg (1.31 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:8]=[C:9]([S:13]([N:16]2[C:20](=[O:21])[CH2:19][N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]2=[O:28])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)=[O:6])C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)=O.O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:5]([C:7]1[CH:8]=[C:9]([S:13]([N:16]2[C:20](=[O:21])[CH2:19][N:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:17]2=[O:28])(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1)([OH:6])=[O:4]
Reactant: C=CCOC(=O)c1cccc(S(=O)(=O)N2C(=O)CN(c3ccccc3)C2=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(S(=O)(=O)N2C(=O)CN(c3ccccc3)C2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
In 10 ml of a 10% solution of formic acid in tetrahydrofuran (THF), were dissolved 400 mg (1.00 mmol) of 3-(3-allyloxycarbonylbenzenesulfonyl)-1-phenyl-imidazolidin-2,4-dione obtained in Example 33. The resultant solution wad deaerated under reduced pressure. To the solution, 50 mg of tetrakis(triphenylphosphine)palladium and 50 mg of triphenylphosphine were added, followed by stirring at room temperature for 2 hours under shielding from the light. After completion of the reaction, the liquid reaction mixture was concentrated under reduced pressure, and crude crystals obtained as residue were collected by filtration, washed with ethyl acetate and then dried, thereby obtaining 350 mg (yield: 97.0%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:21]3[CH:20]=[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:24]=[CH:23][CH:22]=3)=[O:31])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(-c2ccccc2)c1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(-c4ccccc4)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-biphenyl-3-yl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.08 min; [M+H]+=453.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:27])=[C:15]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23]C(=O)C)[CH2:19]3)[CH:16]=2)[C:11](=[O:28])[C:10]([C:29]([OH:31])=[O:30])=[CH:9]1.C(O)C.[ClH:35]>O>[ClH:35].[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:27])=[C:15]([N:18]3[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19]3)[CH:16]=2)[C:11](=[O:28])[C:10]([C:29]([OH:31])=[O:30])=[CH:9]1
Reactant: CC(=O)NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccncc2F)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3-c2ccncc2F)C1

Procedure:
0.5 g of 1-(3-fluoro-4-pyridyl)-6-fluoro-7-(3-acetamido-1-pyrrolidyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is added to 15 ml of ethanol, 10 ml of water and 5 ml of conc. hydrochloric acid. The reaction mixture is refluxed for 18 hours, cooled and concentrated under a reduced pressure to remove the solvent completely.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][N:13]=[C:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15]1>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][N:13]=[C:14]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: ON=C1CC(c2ccccc2)Oc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)ON=C2CC(c3ccccc3)Oc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of p-toluenesulfonyl chloride (83 g) in 125 ml pyridine was added dropwise at 5°-10° to 2,3-dihydro-4-(hydroxyimino)-2-phenyl-4H-1-benzopyran (52 g) in 230 ml pyridine. The reaction mixture was then stirred for 20 hours at room temperature, poured into ice-water to separate out the title compound, which was filtered, washed several times with water, then once with ether, and finally dried in air. Yield: 85.5 g; m.p. 141°-143°.