Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1>O1CCCC1>[CH2:15]([O:14][C:12](=[O:13])[CH:11]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[CH3:16]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
Into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a suspension of NaH (74.0 g, 2.16 mol 1.05 equiv, 70%) in tetrahydrofuran (2000 mL) at 0° C., then ethyl 2-(diethoxyphosphoryl)acetate (514 g, 2.06 mol, 1.05 equiv, 98%) was added dropwise with stirring at 0° C. This was followed by the addition of a solution of tert-butyl 4-oxopiperidine-1-carboxylate (400 g, 1.97 mol, 1.00 equiv, 98%) in tetrahydrofuran (1200 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 60 min at room temperature, then quenched by the addition of 2000 mL of water. The resulting solution was extracted with 2×1000 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was washed with 1×1000 mL of hexane and dried to afford tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37].[S:38](N)([NH2:41])(=[O:40])=[O:39]>C(COC)OC>[NH2:41][S:38]([NH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([NH:28][O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:37])(=[O:40])=[O:39]
Reactant: NS(N)(=O)=O
Reactant: NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Solvent: COCCOC
Product: NS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
To a mixed liquid of 200 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 40 ml of dimethoxyethane was added 357 mg of sulfamide, followed by stirring at 80° C. for 2 days. The reaction solution was concentrated, added with chloroform, and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol), crystallized from ethyl acetate, and collected by filtration to obtain 62 mg of (3RS,4RS)-2-{(1SR,2SR)-2-[(aminosulfonyl)amino]cyclohexyl}-N-(benzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:24])(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:25][C:26](C)([O-:28])C.[K+].BrCCO>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][OH:28])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(O)cccc12
Reactant: CC(C)(C)[O-]
Agent: OCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1c(C(=O)C(C)C)cnc2c(OCCO)cccc12
Reaction time: 48 h
Yield: 39.6 %

Procedure:
To a solution of 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxyquinoline (5 g, 15.6 mmol) in dry tetrahydrofuran (250 ml) was added potassium t-butoxide (2.63 g, 23.4 mmol), followed by 2-bromoethanol (3.9 g, 31.2 mmol). The stirred mixture was heated under reflux for 16 hours, then a further quantity of potassium t-butoxide (2.63 g, 23.4 mmol) and 2-bromoethanol (3.9 g, 31.2 mmol) added, and heating continued for 2 days. The solvent was evaporated, and the residue treated with aqueous sodium bicarbonate and extracted into dichloromethane. The extracts were dried and evaporated to an oil, which was purified by flash chromatography (silica gel, dichloromethane/methanol) and recrystallisation from 40-60 petroleum ether to yield 3-isobutyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)-quinoline (2.25 g), m.p. 154°-156°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.C([O:30][CH2:31][C:32](Cl)=[O:33])(=O)C.CCN(C(C)C)C(C)C.[OH-].[Na+]>[Cl-].[Na+].O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][N:18]([C:31](=[O:30])[CH2:32][OH:33])[CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CO)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
To a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo-[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 6 mg, 0.017 mmol) was added 2-chloro-2-oxoethyl acetate (3.5 mg, 0.025 mmol), followed by DIEA (8.9 μL, 0.051 mmol). The reaction was stirred at ambient temperature overnight, then concentrated, and MeOH (0.2 mL) was added followed by sodium hydroxide (6.8 mg, 0.085 mmol). After stirring at ambient temperature for 5 hours, the reaction was diluted with brine and extracted with several portions of DCM in a phase separator tube. The combined organic extracts were concentrated and purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/H2O, to provide the title product (3.6 mg, 52% yield). MS (apci) m/z=412.5 (M+H).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(F)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.3 g--see Preparation 3), 4-fluorophenethyl bromide (0.22 g), anhydrous potassium carbonate (0.4 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was concentrated in vacuo and the residue partitioned between dichloromethane (20 ml) and 10% aqueous potassium carbonate (20 ml). The layers were separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.259 g.
Reaction SMILES: O=[C:2]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6]CC)=O.[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=2[CH3:32])=[C:19]([NH2:33])[NH:18][N:17]=1>C(O)(=O)C>[CH3:15][C:16]1[C:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[C:23]=2[CH3:32])=[C:19]2[NH:33][C:2]([CH:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[CH:3][C:4](=[O:6])[N:18]2[N:17]=1
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: Cc1n[nH]c(N)c1Cc1cccc(C(F)(F)F)c1C
Solvent: CC(=O)O
Product: Cc1nn2c(=O)cc(C3CCOCC3)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 140 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (0.78 mg, 3.90 mmol) in acetic acid was added 3-methyl-4-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-5-amine (1.0 g, 3.71 mmol) in microwave reaction vessel. It was sealed and heated with microwave reactor at 140° C. for 40 minutes. The reaction mixture was cooled, diluted with acetic acid (5 mL) and stood for overnight. Precipitate was observed, filtered. Solid was washed with acetic acid (2 mL) and cooled methanol (2 mL). Solid was dried. The titled compound was obtained and used in next step. (1.02 g, 68%) LC/MS: MS (ES+) m/e 406 (MH+).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:25])[CH2:16][C:17](=O)[CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:13].[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[N+:27]=[N-:28].O>CN(C=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[C:17]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:25])[N:28]=[N:27]1
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Reactant: [N-]=[N+]=Nc1ccccc1F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CCOCC1
Reaction time: 0.25 h

Procedure:
DBU (1.32 ml; 8.82 mmol; 1.10 eq.) was dissolved in DMF (16.5 ml) and put under nitrogen atmosphere. 3-Oxo-3-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester (Pharmacore, 1.767 g; 8.82 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.1 g; 8.02 mmol; 1 eq.) in DMF (15 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 2 hours. Water (40 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×40 mL). Combined organic layers were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 320.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31]C1C=CC=CC=1C[Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: Fc1ccccc1C[Mg]Cl
Product: OC(Cc1ccccc1F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-fluoro-benzylmagnesium chloride (available from Rieke Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=392.1.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:20][CH:19]=3)=[C:15]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH:38]([CH3:40])[CH3:39])[S:14][C:13]=2[CH:41]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([O:17][C:18]3[CH:19]=[CH:20][C:21](/[CH:24]=[CH:25]/[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:23]=3)=[C:15]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH:38]([CH3:40])[CH3:39])[S:14][C:13]=2[CH:41]=1
Reactant: CC(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O[Si](C)(C)C(C)(C)C)ccc23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3C(C)C)sc3cc(O)ccc23)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48.3 %

Procedure:
To a solution of (E)-isopropyl 3-(4-((6-((tert-butyldimethylsilyl)oxy)-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (35 mg, 0.060 mmol) in THF (2.0 mL) at 0° C. was added tetra-n-butylammonium fluoride (1.0 M in THF, 0.089 mL, 0.089 mmol) dropwise, the reaction immediately turned bright yellow in color. Stirring was continued at 0° C. for 45 min after which the reaction was warmed to room temperature for 15 min and then quenched by addition of st. aq. NaHCO3. The aqueous layer was extracted with EtOAc (4×) and the combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting crude material was purified by column chromatography (SiO2, 0-20% EtOAc/Heptane) to afford (E)-isopropyl 3-(4-((6-hydroxy-2-(2-isopropylphenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylate (14.0 mg, 0.029 mmol, 49% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.55 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.8 Hz, 2H), 7.37-7.20 (m, 5H), 7.11 (td, J=7.6, 1.5 Hz, 1H), 6.89-6.81 (m, 3H), 6.32 (d, J=16.0 Hz, 11H), 5.05 (p, J=6.2 Hz, 1H), 3.23 (p, J=6.9 Hz, 1H), 1.28 (d, J=6.2 Hz, 6H), 1.16 (d, J=6.8 Hz, 6H). HRMS (m/z, MH+): 473.1774.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:9][CH:10]([CH2:29][OH:30])[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)(Cl)Cl>[OH:9][CH:10]([CH2:29][OH:30])[CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Reactant: CCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)CCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
Hexanoyl chloride (2.65g, 19.7 mmoles) was added dropwise to a reactor containing N-(2,3-dihydroxypropyl)-hexadecylamine (2.65g, 19.7 mmoles)in 8 mL of chloroform. The reaction was stirred for 16 hours at room temperature. When the reaction was completed, the mixture was concentrated, ethanol and water was added, and the pH of the reaction was adjusted to 14. This mixture was extracted with chloroform, and organic layer was collected and concentrated. The crude sample was purified on silica column chromatography to give 1.56 g of product.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(N(C(C)C)CC)(C)C.[CH:19]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][N:34]=[C:33]3[SH:41])=[CH:24][CH:23]=2)[CH2:21][CH2:20]1>CN(C=O)C>[CH:19]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([N:32]3[C:36]([C:37]([F:38])([F:40])[F:39])=[N:35][N:34]=[C:33]3[S:41][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: FC(F)(F)c1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Sc1nnc(C(F)(F)F)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 60 °C
Yield: 37.3 %

Procedure:
Ethyl 2-bromo-2-methylpropanoate (89 μL, 0.596 mmol) and diisopropylethylamine (0.31 mL, 1.789 mmol) were added to a solution of 4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazole-3-thiol (0.2 g, 0.596 mmol) in DMF (1.2 mL) and the mixture heated at 60° C. for 20 hours. The mixture was concentrated, acidified with HCl (1M aqueous, 2 mL) and extracted with ethyl acetate (3×3 mL). The combined organic extracts were dried over sodium sulfate, concentrated and purified by column chromatography (0-25% EtOAc/hexanes) to provide ethyl 2-(4-(4-cyclopropylnaphthalen-1-yl)-5-(trifluoromethyl)-4H-1,2,4-triazol-3-ylthio)-2-methylpropanoate as a clear oil (0.1 g, 37%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15](=[O:17])[NH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27](O)=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32].C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[Cl:21][C:22]1[C:27]([O:19][C:18](=[O:20])[C@H:12]([CH2:13][CH2:14][C:15](=[O:17])[NH2:16])[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[C:26]([Cl:29])[C:25]([Cl:30])=[C:24]([Cl:31])[C:23]=1[Cl:32]
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CC(C)=O
Product: NC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
To a solution of 0.700 g. of N-benzyloxycarbonyl-L-glutamine, 0.665 g. of pentachlorophenol and 0.55 g. of 2,2'-dipyridyl disulfide in 20 ml. of dry acetone is added an acetone solution of 0.655 g. of triphenyl phosphine with stirring at 0°C. The produced precipitates are recovered by filtration and washed successively with a 3 % sodium bicarbonate solution, water and ether and recrystallized from a mixture of dimethylformamide and methanol to give 0.952 g. of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[S:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.[C:36]1([CH3:45])[C:37]([N:42]=[C:43]=[O:44])=[CH:38][CH:39]=[CH:40][CH:41]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[N:17]=[C:18]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:43]([NH:42][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[CH3:45])=[O:44])=[CH:26][CH:27]=2)[S:19][CH:20]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)c1ccc(OCc2csc(Cc3ccc(N)cc3)n2)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2csc(Cc3ccc(NC(=O)Nc4ccccc4C)cc3)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94 %

Procedure:
To a solution of ethyl 3-methoxy-4-[2-(4-aminobenzyl)-4-thiazolyl]methoxybenzoate (87.8 mg, 0.220 mmol) in THF (2.0 mL) was added triethylamine (30.5 ul, 0.220 mmol) and o-tolyl isocyanate (30 μl), and the reaction mixture was stirred at room temp for 21 hr. The reaction mixture was poured into ice-water and the resulting precipitates filtered off. The filtrate was extracted with CHCl3, washed with H2O, and brine. The extract was dried over Na2SO4. The solvent was removed under a reduced pressure to afford 110.4 mg (94%) ethyl 3-methoxy-4-[2-[4-[N′-(2-methylphenyl)ureido]benzyl]-4-thiazolyl]methoxybenzoate as a pale yellow crystalline powder. 1H-NMR (400 MHz, CDCl3) δ1.38 (t, J=7.3 Hz, 3H), 2.28 (s, 3H), 3.92 (s, 3H), 4.28 (s, 2H), 4.35 (q, J=7.3 Hz, 2H), 5.29 (s, 2H), 6.20 (s, 1H), 6.47 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 7.20 (s, 1H), 7.24 (s, 2H), 7.27 (s, 2H), 7.33 (d, J=8.3 Hz, 2H), 7.49 (d, J=7.3 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 7.63 (dd, J=2.0, 8.3 Hz, 1H); MS (FAB) m/z 532 M++1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[S:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:15]1[CH:14]=[CH:13][N:12]2[C:7]([S:6][CH2:5][CH2:4][CH2:3][CH2:2][N:18]3[C:19](=[O:21])[CH2:20][S:16][C:17]3=[O:22])=[CH:8][CH:9]=[CH:10][C:11]=12
Reactant: O=C1CSC(=O)N1
Reactant: ClCCCCSc1cccc2nccn12
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 8.35 g (35.4 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 4.15 g (35.4 mmol) of thiazolidine-2,4-dione in 200 ml of N,N-dimethylformamide, 5.30 ml (35.4 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate). The resulting crude crystal was purified by recrystallization (solvent: chloroform/diethyl ether) to yield 10.01 g (88.0%, light orange crystal) of the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][C:6]1[C:10]2[C:11](=[O:25])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[CH2:5][C:6]1[C:10]2[C:11](=[O:25])[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1
Reactant: COc1ccccc1Cc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=c1c2c(Cc3ccccc3O)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 64.7 %

Procedure:
To a solution of 3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (50 mg, 0.13 mmol, prepared in Example 22) in acetic acid (1 ml) was added 47% hydrogen bromide (0.5 ml), and the mixture was heated under reflux. After additional 47% hydrogen bromide (1 ml) and acetic acid (1 ml) was added, the mixture was heated under reflux for 2 days, then admixed with water, filtered to give precipitates which were dried to afford 3-(2-hydroxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (31 mg, 64%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH:7]=O)[CH:2]=[CH2:3].[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1.O.C(Cl)Cl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH:7]=[N:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Cl)cc1C=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOc1ccc(Cl)cc1C=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-allyloxy-5-chloro-benzaldehyde (8.55 g, 43.48 mmol, 1.0 eq.) and 2-methyl-2-propanesulfinamide (6.86 g, 56.64 mmol, 1.3 eq.) in THF (200 mL), titanium (IV) ethoxide (52.3 mL, 49.84 mmol, 1.1 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with water (1000 mL) and DCM (300 mL).The reaction mixture was filtered. The layers were separated. The aq. phase was extracted with DCM (2×200 mL). The comb. org. phases were washed with water (1×250 mL), sat. aq. NaCl soln. (1×150 mL), dried over MgSO4, and concentrated in vacuo. The residue was used without further purification.
Reaction SMILES: [CH2:1](OCC)[CH3:2].[C:6]([C:10]1[CH2:14][CH2:13][C:12](=O)[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl>O>[CH2:1]([C:13]1[CH2:12][CH:11]=[C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])[CH:14]=1)[CH3:2]
Reactant: CC(C)(C)C1=CC(=O)CC1
Reactant: CCOCC
Agent: Cl
Solvent: O
Product: CCC1=CC(C(C)(C)C)=CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78 %

Procedure:
A 300 ml three neck flask equipped with a magnetic stirrer and a three-way cock was charged with 200 ml of diethyl ether and 52 ml (154 mmol) of a diethyl ether solution of 3.0-Methylmagnesium bromide under nitrogen atmosphere. 3-tert-Butylcyclopentenone 17.8 g (129 mmol) was added dropwise in one hour on an ice and water bath. The solution was stirred at room temperature for 20 hours, and then the reaction solution was poured into 100 ml of 2N hydrochloric acid. The organic layer was separated, and the aqueous layer was extracted twice with 50 ml of ether. The organic layers thus obtained were combined and washed twice with a saturated sodium hydrogen carbonate aqueous solution, twice with water and twice with a saturated salt solution. The organic layer was dried on magnesium sulfate, and the solvent was removed by distillation. Then, the residue was purified by column chromatography to obtain 20.2 g (GC purity: 75%) of a pale yellow transparent liquid. The yield was 78%. The product was identified by means of a 1H-NMR spectrum. The measurement results thereof are shown below.