Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c2cc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 36.7 %

Procedure:
To 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (89 mg, 0.3 mmol) in DMF (3 mL) was added 4-tert-butylphenyl isocyanate (54 μL, 0.3 mmol) and the solution stirred at 50° C. for 4 h. The reaction was allowed to cool to room temperature, diluted with H2O, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated in vacuo, and purified by column chromatography (25-100% EtOAc/hexanes) to give 1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (54 mg, 0.11 mmol, 38%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 7.60 (s, 1H), 7.56 (s, 1H), 7.40-7.21 (m, 7H), 6.91 (d, 1H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 473 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C:36]1([F:41])[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C:36]([F:41])([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: FC1(F)CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(F)(F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3,3-difluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.61 (s, 1H), 4.01 (m, 2H), 3.80 (m, 2H), 3.45 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 460 [M+H]
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]([N:12]3[CH:16]=[CH:15]N=C3)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:19](N)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>>[Cl:1][C:2]1[CH:18]=[N:17][C:5]2[NH:6][C:7]([NH:12][CH2:16][CH2:15][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:8][S:9](=[O:10])(=[O:11])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCN
Reactant: O=S1(=O)N=C(n2ccnc2)Nc2ncc(Cl)cc21
Product: CCCCCCCCNC1=NS(=O)(=O)c2cc(Cl)cnc2N1

Procedure:
m.p. 170°-175° C.; from 7-chloro-3-(imidazol-1-yl)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1,1-dioxide and octylamine. (Compound 14).
Reaction SMILES: [Cl:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH3:14])=[CH:9][CH:8]=2)[C:5]([S:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21].I([O-])(=O)(=O)=[O:25].[Na+].O>CO>[Cl:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH3:14])=[CH:11][CH:12]=2)[C:5]([S:15]([CH:16]([CH3:17])[CH3:18])=[O:25])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)C(=O)c1nc(SC(C)C)n(-c2ccc(CC)cc2)c1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=C(C)C(=O)c1nc(S(=O)C(C)C)n(-c2ccc(CC)cc2)c1Cl
Yield: 41.4 %

Procedure:
A mixture of 3.0 g (8.6 mmol) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylthio)-imidazol-4-yl]-2-methyl-2-propen-1-one and 2.3 g (11 mmol) of sodium metaperiodate was heated at 50° C. for 3 hours in 30 ml of 90% aqueous methanol. The mixture was cooled and poured into water. Extraction with dichloromethane yielded an oil which was purified by flash chromatography on silica (20% ethyl acetate in petroleum ether) to obtain 1.3 g (41%) of [5-chloro-1-(4-ethylphenyl)-2-(prop-2-ylsulfinyl)-imidazol-4-yl]-2-methyl-2-propen-1-one as cream-colored crystals melting at 83°-4° C.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][C:8](=O)[CH2:7][N:6]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:23][NH:24][CH3:25].[C:35]1([CH3:47])[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1>>[CH2:11]([N:6]1[CH2:7][C@@H:8]([N:24]([CH2:23][C:22]2[CH:21]=[C:20]([C:19]([F:33])([F:34])[F:18])[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=2)[CH3:25])[CH2:9][C@H:5]1[C:3]([N:44]1[CH2:45][CH2:46][N:41]([C:37]2[CH:36]=[C:35]([CH3:47])[CH:40]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1)=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C1CC(=O)CN1Cc1ccccc1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cccc(N2CCNCC2)c1
Product: Cc1cccc(N2CCN(C(=O)[C@@H]3C[C@H](N(C)Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CN3Cc3ccccc3)CC2)c1
Yield: 13.4 %

Procedure:
As described for Example 56b and 56d, 1-benzyl-4-oxo-pyrrolidine-2-carboxylic acid methyl ester (100 mg, 0.428 mmol) was converted, using (3,5-bis-trifluoromethyl-benzyl)-methyl-amine instead of 3,5-bis-trifluoromethyl-benzylamine, and using 1-m-tolyl-piperzine instead of 1-(3-trifluoromethyl-phenyl)-piperazine, to the title compound (12.1 mg, 13.4%) as light yellow oil. MS m/e=619.4[M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29]C)=[O:28])=[C:22]([F:31])[CH:21]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CO.[OH-].[Li+].Cl>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:31])[CH:21]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl [4-(2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetate (1.50 g, 3.25 mmol) in 21 ml of tetrahydrofuran was added 14 ml of methanol and 14 ml of water. Lithium hydroxide (0.401 g, 16.7 mmol) was added to the reaction mixture, and the reaction mixture was stirred at RT overnight. 1 M hydrochloric acid was added to adjust the pH to 4. The volatiles were removed under reduced pressure, and the remaining aqueous solution was extracted with dichloromethane (3×20 ml). The organic fractions were combined, dried over magnesium sulphate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Biotage 100 g) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 434.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[N:3][CH:2]=1.[OH-].[Li+]>CO.O1CCCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH3:9])=[N:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(C)Oc2ccncn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(Oc1ccncn1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
To a solution of methyl 4-(1-(pyrimidin-4-yloxy)ethyl)benzoate (0.26 g, 1 mmol) in methanol (5 mL) and tetrahydrofuran (15 mL) was added lithium hydroxide (120 mg, 5 mmol) in water (5 mL), then stirred at room temperature for 5 hours. The reaction mixture was concentrated, the residue was acidified with 6 N hydrochloric acid, by filtration the solid was collected to give-4-(1-(pyrimidin-4-yloxy)ethyl)benzoic acid (0.19 g, 78% yield). LRMS (M+H+) m/z: calcd for 244.08. found 244.
Reaction SMILES: C([CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(O)=O.[C:9]([O-:12])(=[O:11])[CH3:10].[Na+].C(OO)(=O)C>[Ru](I)I.C1C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[C:9]([O:12][CH:4]1[NH:7][C:6](=[O:8])[CH2:5]1)(=[O:11])[CH3:10]
Reactant: O=C1CC(C(=O)O)N1
Reactant: CC(=O)[O-]
Agent: I[Ru]I
Agent: CC(=O)OO
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC1CC(=O)N1
Yield: 34.9 %

Procedure:
1.15 g (10 mmol) of 4-carboxyazetidine-2-one (MW 115) was added with 0.905 g (11 mmol) of anhydrous sodium acetate, 3.2 g of acetic acid, 2.8 g of ethyl acetate and 0.433 g (1 mmol) of benzene ruthenium diiodide, cooled to 10°-15° C., then added dropwise 8.25 g of acetic acid solution containing 22% peracetic acid over one hour while stirring. A further 15 hour stirring was carried out at the same temperature, the solvent was distilled off under reduced pressure, followed by purification by silica gel column chromatography (hexane/ethyl acetate=1/1 by volume) to obtain 0.45 g of 4-acetoxyazetidine-2-one (yield: 35%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]2[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:40]3[CH:39]=[N:38][N:37]([CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH:41]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
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: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and the mixture was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After reaction completion, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 3 the title compound (0.08 g, 66%). LCMS: 547.35 (M+1)+; HPLC % 97.60 (@254 nm) (Rt; 4.071; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.; 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.17 (s, 1H), 8.05 (t, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 5.85 (s, 1H), 4.26 (d, 2H, J=4 Hz), 4.0 (d, 2H, J=6.4 Hz), 3.49-3.53 (m, 6H), 2.72 (t, 2H), 2.40 (bs, 6H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.6.1-1.70 (m, 4H), 1.42-1.50 (m, 4H).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.[N:21]1([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O.C(O)C>[O:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][C@H:2]([OH:1])[CH2:3][N:24]2[CH2:25][CH2:26][N:21]([C:27]3[N:28]=[CH:29][CH:30]=[CH:31][N:32]=3)[CH2:22][CH2:23]2)=[N:13]1
Reactant: c1cc(OC[C@H]2CO2)cc(-c2noc3ncccc23)c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1cccc(-c2noc3ncccc23)c1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-3-(3-oxiranylmethoxy-phenyl)-isoxazolo[5,4-b]pyridine in dimethylformamide and ethanol and 2-piperazin-1-yl-pyrimidine in ethanol essentially as described above in Example 102. Purity by LC/MS=100%, [M+H]+=433.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[O:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[K+].[K+].[NH3:25]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:9])[NH:25][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=c1occ(-c2ccncc2)c2ccccc12
Reactant: N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]cc(-c2ccncc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(Pyridin-4-yl)isocoumarin (4.9 g) was suspended in ethanol and 28% aqueous ammonia, and the mixture was heated under reflux for 1 hr. Concentrated hydrochloric acid was added to acidify the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. After the completion of the reaction, aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with a mixed solvent (chloroform:methanol=10:1). The organic layer was dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was collected by filtration to give 4-(pyridin-4-yl)-2H-isoquinolin-1-one (2.9 g).
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5](CC)(CC)[C:6]#[N:7].[C:14]([O:18][C:19](=[O:28])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=O)([CH3:17])([CH3:16])[CH3:15].O>COCCOC>[C:14]([O:18][C:19](=[O:28])[NH:20][CH:21]([CH2:5][C:6]#[N:7])[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26])([CH3:17])([CH3:16])[CH3:15]
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=CCCCC(CC#N)NC(=O)OC(C)(C)C
Temperature: 20 °C

Procedure:
Sodium hydride (50% suspension in oil, 1.2 g, 0.025 mol) is placed in 100 ml of dry 1.2-dimethoxyethane. The slurry is cooled to 20° C. and diethylcyanomethyl phosphonate (4.43 g, 0.025 mol) is added dropwise with stirring. After the addition, the solution is stirred at room temperature for 1 hour until gas evolution has ceased. To the yellow solution, maintained below 25° C., is added dropwise t-butyl(5-formylpentyl)carbamate (5.38 g, 0.025 mol). The solution is stirred at room temperature for 1 hour and refluxed for 0.5 hour. A large excess of water is added and the product t-butyl-(7-cyanohepten-6-yl)carbamate (3.63 g, 61%) is extracted with ether.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[OH:29]
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Reactant: c1cscn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(O)c2nccs2)c1
Reaction time: 2 h
Yield: 52 %

Procedure:
Thiazole (30 μl) was dissolved in tetrahydrofuran (1 ml) to prepare a solution which was cooled under an argon atmosphere to −78° C. n-Butyllithium (1.56 M hexane solution) (260 μl) was added to the cooled solution, and the mixture was stirred for 2 hr. A solution (2 ml) of 2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-benzaldehyde (compound 26) (138 mg) in tetrahydrofuran was then added to the reaction solution, and the mixture was stirred at −78° C. for one hr. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give [2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanol (90 mg, yield 52%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([CH:30]([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]5[CH:6]=[N:7][NH:8][C:9]5=4)[N:1]=3)=[CH:25][C:24]([CH:30]([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(C(F)F)nn1-c1ncccc1Cl
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 540 mg (2.82 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 20 mL of anhydrous acetonitrile is added 771 mg (2.82 mmol) of 2-(3-chloro-pyridin-2-yl)-5-difluoromethyl-2H-pyrazole-3-carboxylic acid followed by 1.02 mL (12.7 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 766 μL (9.9 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 50° C. for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. The pale yellowish product obtained is engaged in the next step; LC/MS:429/431 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[NH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:20])[CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[F:20][C:4]1[CH:3]=[C:2](/[N:1]=[CH:29]/[C:27]2[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)c(F)c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Yield: 81 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 0.28 g, 1 mml) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9e, 324 mg, 81%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([OH:16])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:34](I)[CH2:35][CH2:36][CH3:37].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:17][CH3:18])=[C:11]([O:16][CH2:34][CH2:35][CH2:36][CH3:37])[CH:12]=2)[CH:7]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C=Cc2cc(O)c(OC)cc2C1Cc1cccc(OC)c1
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)N(C(=O)OCC)C=C2
Temperature: 85 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (840 mg, 2.28 mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassium carbonate (1.89 g, 13.6 mmol) and butyl iodide (0.78 mL, 6.83 mmol) dropwise. The reaction mixture was heated with stirring at 85° C. for 18 hrs. The solvent was evaporated and the residue was diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 20% ethyl acetate/hexane) afforded 6-Butoxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (560 mg, 56% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].[Br:13]N1C(=O)CCC1=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([Br:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)ccc1N
Yield: 37.5 %

Procedure:
A solution of 2.00 g (12.04 mmol) 3-Amino-pyridine-2-carboxylic acid ethyl ester and 2.57 g (14.44 mmol, 1.2 equiv.) of N-Bromosuccinimide in 80 ml of acetonitrile was stirred for 2 h at room temperature. Silicagel (5 g) was added to the reaction mixture Which was evaporated to dryness. The residue was loaded onto a Flash chromatography column (SiO2, 50 g) and eluted with heptane/ethyl acetate 3:1. One obtains 1.11 g (4.51 mmol, 37%) of the title compound as a white cristalline solid, MS (ISP): m/e=245.1, 247.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18](O)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][C:24]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([O:34][CH3:35])[C:24]=4[O:23][CH3:22])[CH2:29]3)=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 10 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 29 (10% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.71 and 2.98 (2t, 2H), 3.49 and 4.03 (2t, 2H), 3.68-3.81 (4s, 6H), 4.42 and 4.93 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.81 and 7.08 (2d, 1H), 7.63-7.67 (m, 2H), 7.71-7.81 (m, 1H), 7.89-8.00 (2d, 1H), 8.08-8.16 (m, 2H), 8.50-8.57 (m, 2H); MS (ESI) m/z 460 ([M+H]+).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1.[Cl:23][CH2:24][CH2:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27]1>>[ClH:23].[CH2:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][N:26]1[CH2:25][CH2:24][N:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9]1
Reactant: O=S(=O)(c1ccc(O)cc1)C1CCNC1
Reactant: ClCCN1Cc2ccccc2C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=S(=O)(c1ccc(O)cc1)C1CCN(CCN2Cc3ccccc3C2)C1

Procedure:
The title compound, MS: m/e=373.3 (M+H+) was prepared from (RS)-4-(pyrrolidine-3-sulfonyl)-phenol trifluoroacetic acid salt and 2-(2-chloro-ethyl)-2,3-dihydro-1H-isoindole. 2-(2-Chloro-ethyl)-2,3-dihydro-1H-isoindole is a known compound and has been prepared as described in the following reference: G. Shoeb; J. Pharm. Sci.; 51; 1962; 469-471.