Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:19]([OH:21])=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(OC(=O)C)(=O)C.C(=S)=S>[C:1]([NH:9][CH:10]1[CH2:11][CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]1=[O:21])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](CCc1ccccc1)C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CC(=O)OC(C)=O
Product: O=C(NC1CCc2ccccc2C1=O)c1ccccc1
Yield: 817.4 %

Procedure:
A solution of N-benzoyl homophenylalanine (4.4 g, 1.66 mmole) in acetic anhydride (60 ml) was heated on the steam bath for 1/2 hr. The solvent was removed in vacuo, the resulting oil was dissolved in CS2 and then added to a suspension of AlCl3 (6.2 g, 4.6 mmoles) in CS2 (60 ml). This mixture was heated at reflux for 1 hr, the solvent was removed in vacuo and ice was added to the residue. The reaction mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with brine, dried over Na2SO4 and evaporated to dryness to afford 3.6 g (88%) of product, m.p. 175° C. After recrystallization from toluene it had m.p. 175°-178° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([F:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][NH:30][CH3:31])=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][N:30]([CH3:31])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:22])=[CH:4][C:5]=4[F:21])[C:9](=[O:20])[N:10]3[CH3:19])=[CH:15][N:14]=2)=[CH:27][CH:26]=1
Reactant: Cn1c(=O)c(-c2cc(N)c(F)cc2F)cc2cnc(Cl)cc21
Reactant: CNCc1ccc(OC)cc1
Product: COc1ccc(CN(C)c2cc3c(cn2)cc(-c2cc(N)c(F)cc2F)c(=O)n3C)cc1
Temperature: 200 °C
Yield: 91 %

Procedure:
3-(5-Amino-2,4-difluorophenyl)-7-chloro-1-methyl-1,6-naphthyridin-2(1H)-one (2.4 g, 7.5 mmol) and 4-methoxy-N-methylbenzylamine (10 mL) were combined in a sealed vessel and heated to 200° C. overnight. The volatiles were removed in vacuo and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2,4-difluorophenyl)-1-methyl-1,6-naphthyridin-2(1H)-one (3 g, 91% yield), which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][C:23]1([CH:26]=[CH2:27])[CH2:25][O:24]1>>[OH:24][C:23]([CH3:25])([CH:26]=[CH2:27])[CH2:22][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: C=CC1(C)CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: C=CC(C)(O)CN1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 159 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-methyl-2-vinyloxirane and conditions outlined in procedure X. M.p.=74-77° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 5.9 (dd, 1H), 5.35 (d, 1H), 5.05 (d, 1H), 3.0-2.7 (m, 4H), 2.6 (m, 4H), 2.45 (d, 1H), 2.1 (t, 2H), 1.9-1.75 (m, 2H), 1.2 (s, 3H); LCMS: 386 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: CI
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
2-Chloro-9-cyclopentyl-5,7,8,9-tetrahydro-6H-pyrimido[4,5-b][1,4]diazepin-6-one (0.318 g, 0.0012 mol) and MeI (0.088 mL, 0.0014 mol, 1.18 eq) were added to DMF (5 mL) and the solution cooled to −10° C. NaH (0.03 g, 0.0013 mol, 1.07 eq) was added and the RM was stirred at 0° C. for 30 min and rt for 30 min. The solvent was evaporated under reduced pressure and the product extracted using EtOAc/H2O. The organic extracts were combined, washed with sat NaCl, dried (MgSO4) and evaporated under reduced pressure to give the product as a purple oily residue (0.25 g, 75%); 1H (DMSO-d6): δ 1.55 (4H, m, 2CH2), 1.7 (2H, m, CH2), 1.9 (2H, m, CH2), 2.63 (2H, t, J=5 Hz, CH2), 3.17 (3H, s, CH3), 3.65 (2H, t, J=5 Hz, CH2), 4.74 (1H, m, CH), 8.14 (1H, s, CH); MS+ve: 281.2; Rt=3.11 min (Analytical—1).
Reaction SMILES: [OH-].[Na+].NC(NCCOC1C=CC([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:29]([O:31]CC)=[O:30])[CH:17]=2)=CC=1)=O>C1COCC1.CO>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]2[CH:16]=[CH:17][C:18]([C:29]([OH:31])=[O:30])=[N:19]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCCNC(N)=O)cc2)n(-c2ccc(OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-n2ccc(C(=O)O)n2)cc1
Temperature: 25 °C
Yield: 175.6 %

Procedure:
1M NaOH (5 ml) was added to a solution of ethyl 5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.75 g) in THF (15 ml) and MeOH (10 ml). The reaction mixture was stirred at ambient temperature and concentrated in vacuo. The residue was dissolved in H2O and acidified by 1M HCl. white precipitates were collected and washed successively with H2O and IPE to give 5-(4–12-[(aminocarbonyl)amino]-ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (1.58 g) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:17]([S:16][CH3:15])=[CH:18][N+:19]([O-:21])=[O:20])[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1csc(CN(C)C)n1
Yield: 53.1 %

Procedure:
With 2 ml of acetonitrile were mixed 1 g of 2-{[2-(dimethylamino)methyl-4-thiazolyl]methylthio}ethylamine and 1.4 g of 1,1-bis(methylthio)-2-nitroethene, and the resulting mixture was subjected to reaction under reflux for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and 5 ml of ethanol was added to the resulting residue, after which the insolubles were removed by filtration. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography (Wako Silica Gel C-200, eluent; chloroform:ethanol=20:1 by volume) to obtain 0.8 g (yield 53%) of oily 1-{2-[[2-(dimethylamino)methyl-4-thiazolyl]methylthio]ethylamino}-1-methylthio-2-nitroethene.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:34]([NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:35])=[N:4][C:5]([CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][O:30][CH2:31][O:32]C)=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[N:6][C:7]=1[CH3:8].Cl.O1CCOC[CH2:45]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:31]([O:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH2:12][CH2:11][CH:10]([CH2:9][C:5]4[N:4]=[C:3]([C:34]([NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:35])[C:2]([OH:1])=[C:7]([CH3:8])[N:6]=4)[CH2:15][CH2:14]3)=[CH:17][CH:18]=2)=[CH:24][CH:25]=1)(=[O:32])[CH3:45]
Reactant: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Cc4ccc(COCOC)cc4)cc3)CC2)nc(C)c1O
Reactant: C1COCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)c1nc(CC2CCN(c3ccc(Cc4ccc(COC(C)=O)cc4)cc3)CC2)nc(C)c1O
Reaction time: 12 h
Yield: 68.4 %

Procedure:
Ethyl {[(5-hydroxy-2-{[1-(4-{4-[(methoxymethoxy)methyl]benzyl}phenyl)piperidin-4-yl]methyl}-6-methylpyrimidin-4-yl)carbonyl]amino}acetate (1.1 g, 1.9 mmol) was dissolved in ethyl acetate (14 mL), and a solution of hydrogen chloride in dioxane (4 M, 7 mL, 28 mmol) was added at room temperature, followed by stirring at the same temperature for 12 hours. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.60 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.74 g, 1.3 mmol) as a yellow oil (yield 69%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]([CH2:14][O:15][CH3:16])([CH3:13])[CH2:10][O:11][CH3:12])C.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(C)=O>[CH3:16][O:15][CH2:14][C:9]([CH2:10][O:11][CH3:12])([CH3:13])[C:8]([NH:7][CH2:6][CH2:5][CH:4]=[O:3])=[O:17]
Reactant: CCOC(CCNC(=O)C(C)(COC)COC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COCC(C)(COC)C(=O)NCCC=O
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a solution of 3 g of N-(3,3-diethoxy-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide in 71 mL of acetone was added 3.91 g of TsOH.H2O. The mixture was stirred over night at rt, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 100/0 to 0/100 as eluant to yield 2.19 g of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:13][C:14]3([OH:12])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(O)(Cn2nc(I)c3c(N)ncnc32)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A mixture of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.86 g, 0.0033 mol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.7 g, 0.0033 mol) and cesium carbonate (1.1 g, 0.0033 mol) in anhydrous N,N-dimethylformamide (30 mL) was stirred at 60° C. for 18 hours. The solvent was removed under reduced pressure. The residue was partitioned between water and dichloromethane (200 mL). The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with dichloromethane, and the solid was filtered to give tert-butyl 4-[(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl]-4-hydroxy-1-piperidinecarboxylate (0.66 g, 0.0014 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 8.7 min. MS: MH+ 475.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(c1)NC(=O)CC2
Temperature: 60 °C
Yield: 29.3 %

Procedure:
A solution of 7-hydroxy-3,4-dihydro-1H-quinolin-2-one (310 mg, 1.90 mmol) and 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (666 mg, 2.28 mmol) in DMF (3.0 mL) is treated with Cs2CO3 (1.25 g, 3.80 mmol). The resulting suspension is heated at 60° C. for 5 hours and then quenched with water dropwise. The mixture is extracted with EtOAc (40 mL×3) and the combined organics are dried (Na2SO4), concentrated to a suspension. It is then filtered and the solid is rinsed with EtOAc (2 mL) and dried under vacuum to obtain pure product (233 mg, 29%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2]1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C>ClCCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([CH:21]3[CH2:20][CH2:19][C:18]([N:17]([CH3:31])[CH3:16])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22]3)[CH2:2]2)=[CH:8]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-piperidine-3-yl-1H-indole (233 mg, 1.16 mmole) and 4-dimethylamino-4-phenylcyclohexanone (253 mg, 1.16 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1.16 mmole) and sodium triacetoxy boron hydride (350 mg, 1.63 mmole) were added to this mixture. The mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (20 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The non-polar diastereoisomer was obtained as a colourless oil in a yield of 208 mg (45%) and the polar diastereoisomer was obtained as a colourless oil in a yield of 50 mg (11%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:25][CH2:24][CH:21]2[CH2:22][CH2:23][N:18]([C:16](=[O:17])[C:15]3[CH:26]=[CH:27][CH:28]=[C:13]([CH3:12])[CH:14]=3)[CH2:19][CH2:20]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)N2CCC(CO)CC2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
53.3 g (0.28 mol) of 4-methylbenzenesulphonyl chloride in 60 ml of pyridine are added to a solution of 52 g (0.22 mol) of 1-(3-methylbenzoyl)-4-piperidinemethanol in 100 ml of pyridine. The mixture is stirred at 20° C. for 4 h, and then poured into ice. The phase is extracted with dichloromethane, and the organic phase washed with 5N aqueous hydrochloric acid solution and dried over magnesium sulphate. The solvents are evaporated off under reduced pressure and 70 g of white solid are obtained.
Reaction SMILES: C(N(CC)CC)C.[C:8]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:21][C@@H:22]([CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]>C(Cl)Cl>[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:21][C@@H:22]([CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C@H:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:24])=[O:20])([OH:19])=[O:18]
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reactant: O=C1CCCCCCCCC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)CCCCCCCCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 5 h
Yield: 30.4 %

Procedure:
Methylene chloride (10 ml), triethylamine (190 μl, 1.37 mmol) and sebacic anhydride (292.4 mg, 1.59 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (316.2 mg, 1.34 mmol), followed by stirring for 5 hours. Then, the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:methanol=20:1 and chloroform:methanol=9:1) to obtain the title compound (171.1 mg, yield 30.4%) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:3]=1.[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(Cl)Cl>[F:8][C:7]1[C:2]([N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)=[N:3][C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:5][CH:6]=1
Reactant: CN1CCNCC1
Reactant: Fc1ccc(Cc2ncc(F)c(Cl)n2)cc1
Solvent: ClCCl
Product: CN1CCN(c2nc(Cc3ccc(F)cc3)ncc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A mixture of 0.48 g (2 mmol) of 4-chloro-5-fluoro-2-(4-fluorobenzyl)-pyrimidine from Step 2 and 1.53 mL (14 mmol) of 4-methylpiperazine in 10 mL of methylene chloride was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in methylene chloride. The resultant solution was washed with 4×30 mL of water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 0.59 g (95% yield) of the title compound as an oil; 1H NMR (CDCl3) d 2.32 (s, 3H), 2.47 (t, 4H), 3.78 (t, 4H), 3.99 (s, 2H), 6.97 (m, 2H), 7.29 (m, 2H), 7.97 (d, 1H). The product was carded on to the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([O:10][CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])([CH3:12])[CH3:11])=[O:30])=[CH:27][CH:26]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Reaction time: 4 h
Yield: 34 %

Procedure:
To a solution of tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (0.95 g, 5.0 mmol) and diisopropylethylamine (0.87 mL, 5.0 mmol) in DCM (25 mL) was added 4-methoxybenzoyl chloride (0.69 mL, 5.0 mmol) at room temperature and the mixture was stirred for 4 h. The reaction mixture was partitioned between DCM and 50% brine solution. The organic layer was separated, dried with Na2SO4, filtered and concentrated. The residue was dissolved in ethyl acetate and washed with 0.5 M hydrochloric acid. The organic layer was separated, dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate in heptane (0-25%) to give the title compound (0.55 g, 34%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.09-7.90 (m, 2 H), 7.04-6.81 (m, 2 H), 4.65 (br s, 1 H), 4.35 (s, 2H), 3.88 (s, 3 H), 1.44 (s, 9 H), 1.40 (s, 6 H). m/z (APCI+) for C17H25NO5 224.1 (M-tBuCO2—+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:21]I>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: CI
Product: CN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1

Procedure:
The same procedure was followed as in Example 11 using the compound (10) synthesized in Example 3 and methyl iodide to produce the above.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14].[Br:16][CH2:17][CH2:18]O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:18][CH2:17][Br:16])=[CH:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1cc(O)c2ccccc2c1O
Reactant: OCCBr
Product: O=C(O)c1cc(OCCBr)c2ccccc2c1O
Temperature: 90 °C
Yield: 50 %

Procedure:
60 g (0.3 mol) of 1,4-dihydroxy-2-naphthoic acid was added to 150 ml of 2-bromoethanol and, under heating at 90° C. with stirring, hydrogen chloride gas was bubbled into the mixture during a reaction period of 2 hours. The mixture was cooled to from 10° to 20° C. and the crystals precipitated were collected by filtration to obtain 47.4 g (50% yield) of 1-hydroxy-4-(β-bromoethoxy)-2-naphthoic acid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([NH:17][C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:16])[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:49]N(C)C=O.CI>O>[C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:13]=[C:14]([CH:44]=[CH:45][CH:46]=2)[C:15]([N:17]([C:18]2[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][S:34]([C:37]3[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[CH:28]=[CH:27][C:19]=2[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:49])=[O:16])[S:8][CH:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1NC(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)COc1ccc(CCCS(=O)(=O)c2ccc(Cl)cc2)cc1N(C)C(=O)c1cccc(OCc2nc(C(C)(C)C)cs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Under ice-cooling, ethyl 2-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (266 mg, 0.39 mmol) was added to a mixture of 60% sodium hydride (19 mg, 0.48 mmol) and dimethylformamide (2 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was again cooled with ice, methyl iodide (29 μl, 0.47 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the product formed was extracted with toluene. The extract was washed with water and brine in that order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (eluent=chloroform:methanol=50:1) to give ethyl 2-[N-[3-[(4-tert-butyl-2-thiazolyl)methoxy]benzoyl]-N-methylamino]-4-[3-(4-chlorophenylsulfonyl)propyl]phenoxyacetate (213 mg, 0.31 mmol, 78%).