Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][N:12]3[CH2:17][CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:14][CH2:13]3)[CH2:6]2)[O:4]CC1>CC(C)=O.Cl>[C:18]1([C:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH:7]3[CH2:8][CH2:9][CH2:10][C:5](=[O:4])[CH2:6]3)[CH2:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1=C(c2ccccc2)CCN(CC2CCCC3(C2)OCCO3)C1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCCC(CN2CC=C(c3ccccc3)CC2)C1
Yield: 88.7 %

Procedure:
A solution of 1-(1,4-dioxaspiro[4.5]dec-7ylmethyl)-1,2,3,6-tetrahydro-4-phenylpyridine (Step C) (90.4 g) in 500 mL of acetone and 500 mL of 10% aqueous hydrochloric acid solution is refluxed, under nitrogen, for 3 hours. The solvent is evaporated in vacuo and partitioned into ethyl acetate/dilute ammonium hydroxide solution. The organic extract is dried over magnesium sulfate and concentrated, leaving the title compound (68.9 g) as a light pink solid; mp 56°-59° C. Mass spectrum (MS) electron ionization (EI) 269 (m, 41%), 172 (100%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:38]=[CH:37][C:22]([CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[OH-].[Na+].C(O)C.Cl>O>[CH:1]([C:4]1[N:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:23][O:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[CH:37][CH:38]=2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccc3)c3nc(C(C)C)cs3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1csc(N(CCc2ccccc2)Cc2ccc(COc3ccc(CCC(=O)O)cc3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A mixture of methyl 3-{4-[(4-{[(4-isopropyl-1,3-thiazol-2-yl)(2-phenylethyl)amino]methyl}benzyl)oxy]phenyl}propanoate (350 mg), 2N aqueous sodium hydroxide solution (2 mL) and ethanol (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was diluted with water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated to give the title compound (210 mg, yield 62%) as colorless crystals.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][C@@H:24]1[C@@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:29]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:28]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:27][CH:25]1[OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:56]([O:62][CH2:63][C:64]([Cl:67])([Cl:66])[Cl:65])(=[O:61])[CH2:57][C:58](O)=[O:59].N1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:58]([O:26][CH:25]1[O:27][C@H:28]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[C@@H:29]([O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C@H:30]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@H:24]1[O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:59])[CH2:57][C:56]([O:62][CH2:63][C:64]([Cl:66])([Cl:65])[Cl:67])=[O:61]
Reactant: O=C(O)CC(=O)OCC(Cl)(Cl)Cl
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CC(=O)OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)OCC(Cl)(Cl)Cl
Reaction time: 1 h
Yield: 87.1 %

Procedure:
Dicyclohexylcarbodiimide (305 mg, 1.47 mmol) was added to a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (810 mg, 1.5 mmol), 2,2,2-trichloroethyl hydrogen malonate (330 mg, 1.4 mmol) and pyridine (196 mg, 2.48 mmol) in dry methylene chloride (6 mL). A white precipitate appeared almost immediately and a slight temperature increase was noticed. The mixture was stirred further for one hour, then diluted with ether (10 mL) and filtered. The solid was washed with ether (2×5 mL) and the filtrates were evaporated under reduced pressure in the presence of silica (2 g). Chromatography over silica gel (60-200 mesh, 40 g, elution with ether-hexanes, 1:1.5) afforded 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl 2,2,2-trichloroethyl malonate 2 (929 mg, 1.22 mmol, 87%) as a viscous colorless syrup; NMR (CDCl3, 90 MHz): δ7.37+7.32 (aromatic protons), 6.43 (d, J=2 Hz, H-1, α-anomer), 5.71 (d, J=7 Hz, H-1, β-anomer), 4.92-4.42 (m, benzylic protons) with a high singlet at 4.78 (OCH2Cl3), 3.87-3.40 (m, sugar skeleton and malonyl protons); aromatic ratio, α:β=1.7 IR (CCl4): 3090, 3075, 3024, 2925, 2875, 1770 (s), 1755 (s), 1100 (s) cm-1.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.B1C2CCCC1CCC2.[OH-:30].[Na+].OO>C1COCC1>[F:1][C:2]1[CH:18]=[C:17]([CH2:19][CH2:20][OH:30])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[N:9][C:8]([C:11]([F:12])([F:13])[F:14])=[N:7][CH:6]=1
Reactant: [OH-]
Reactant: C=Cc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.6 %

Procedure:
To the solution of 5-(2-fluoro-4-vinylphenoxy)-2-(trifluoromethyl)pyrimidine (540 mg, 1.900 mmol) in dry THF (8 mL), was added 9-BBN (5.70 mL, 2.85 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (1 mL), followed by aq. NaOH (2.5 mL, 7.50 mmol), and 30% H2O2 (2.585 g, 22.80 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (756 mg, 2.501 mmol, 132% yield) as a white oil. LCMS: rt=3.63 min, [M+H+]=285
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[NH2:7][C:8]1[N:13]=[C:12]([N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=[C:10]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33](OC)=[O:34])=[N:31][CH:32]=3)[O:24][N:23]=2)[N:9]=1>C1(C)C=CC=CC=1>[NH2:7][C:8]1[N:13]=[C:12]([N:14]([CH3:21])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:11]=[C:10]([C:22]2[N:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:34])=[N:31][CH:32]=3)[O:24][N:23]=2)[N:9]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)NCC(F)(F)F)nc3)n2)n1
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of 2,2,2-trifluoro-ethylamine (39 mg, 395 μmol) in anhydrous toluene (3 mL) was added bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (DABAL-Me3) (101 mg, 395 μmol). The resulting solution was stirred at 40 C for 1 h. Methyl 5-(3-{4-amino-6-[methyl(phenyl)amino]-1,3,5-triazin-2-yl}-1,2,4-oxadiazol-5-yl)pyridine-2-carboxylate (prepared in an analogous manner to Example 279, 80 mg, 197 μmol) was then added to the solution and the reaction mixture was stirred for a further 16 h at 80 C. The reaction mixture was quenched with 1M HCl (1 mL), evaporated to dryness and re-dissolved in DCM. The organic solution was washed with water (3×25 mL), dried over magnesium sulfate, evaporated and purified by silica chromatography (50:50 EtOAc:heptane) to afford the title compound as a white solid (40 mg, 43%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24]([NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:25])=[N:12][C:13]([CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:36]1[CH:53]=[CH:52][C:39]([CH2:40][C:41]2[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=2[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=1>>[CH2:2]([O:9][C:10]1[C:11]([C:24](=[O:25])[NH:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[N:12][C:13]([CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([C:36]3[CH:53]=[CH:52][C:39]([CH2:40][C:41]4[CH:51]=[CH:50][CH:49]=[CH:48][C:42]=4[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:38][CH:37]=3)[CH2:22][CH2:23]2)=[N:14][C:15]=1[CH3:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccccc1Cc1ccc(Br)cc1
Reactant: Cc1nc(CC2CCNCC2)nc(C(=O)NCC(=O)OC(C)(C)C)c1OCc1ccccc1
Agent: Cl
Product: CCOC(=O)c1ccccc1Cc1ccc(N2CCC(Cc3nc(C)c(OCc4ccccc4)c(C(=O)NCC(=O)OC(C)(C)C)n3)CC2)cc1
Yield: 72 %

Procedure:
In accordance with Example 1-(9), but using tert-butyl ({[5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidin-4-yl]carbonyl}amino)acetate hydrochloride instead of tert-butyl 5-(benzyloxy)-6-methyl-2-(piperidin-4-ylmethyl)pyrimidine-4-carboxylate hydrochloride, and ethyl 2-(4-bromobenzyl)benzoate instead of [(4′-bromobiphenyl-4-yl)methoxy](tert-butyl)dimethylsilane, the title compound (yield 72%) was afforded as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH3:9])=[C:4]([CH:19]=[O:20])[CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:21])=[O:15])[CH2:7][CH2:8][CH3:9])=[C:4]([CH:19]=[O:20])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCCN(CCCCC(=O)O)c1ccc(Br)cc1C=O
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCCCC(=O)OC)c1ccc(Br)cc1C=O
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a suspension of 5-(4-bromo-2-formyl-N-propylanilino)pentanoic acid (8.00 g) and potassium carbonate (3.88 g) in DMF (25 ml) was added dropwise a solution of iodomethane (4.66 g) in DMF (5 ml) under a nitrogen atmosphere. The mixture was stirred overnight under a nitrogen atmosphere. Then, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain brown oil of methyl 5-(4-bromo-2-formyl-N-propylanilino)pentanoate (7.89 g).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C(S(O[CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)(=O)=O)=CC=CC=1>>[CH:32]1([CH2:31][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Cc1ccccc1S(=O)(=O)OCC1CCCC1
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CCCC2)c(=O)[nH]c1=O
Yield: 56.4 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclopentyl)-methyl toluenesulfonate were reacted by the same method with example 20 to obtain the titled compound. (80 mg)
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]6[N:24]([CH2:29][CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:16][CH:15]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1nc(C)cc1C(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCN(C)CC4)cc2)C(=O)N3)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-amide (as prepared in Example 7, 70 mg, 0.168 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (35.4 mg, 0.184 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 46% (45 mg, 0.076 mmol) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH:52]1([CH2:59][CH2:60][NH2:61])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=[CH:53]1>ClCCl.CN(C)C=O>[CH:52]1([CH2:59][CH2:60][NH:61][C:15](=[O:17])[C@H:14]([CH3:18])[C@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[O:19][CH3:20])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=[CH:53]1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: NCCC1C=CC=CC=C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)NCCC1C=CC=CC=C1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.33 h
Yield: 58.8 %

Procedure:
To a solution of #11 (3.57 g, 12.4 mmol, 1 eq.) in dichloromethane (100 mL, 0.1 M) and N,N-dimethylformamide (4 mL) was added HATU (5.36 g, 13.7 mmol, 1.1 eq.). After 20 minutes, triethylamine (5.20 mL, 37.3 mmol, 3 eq.) was added, followed by #62 (1.68 g, 12.4 mmol, 1 eq.), and the mixture was stirred for 18 hours. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate and washed with water (50 mL). The aqueous layer was back-extracted with ethyl acetate (3 times) and the combined organic layers were dried, filtered, and concentrated in vacuo to provide a brown oil, which was purified by silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) to provide #63 (2.95 g, 59% yield) as a viscous oil. LC-MS: m/z 405.4 [M+H+], 427.4 [M+Na+], retention time=0.75 minutes; 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 6.63-6.68 (m, 2H), 6.16-6.23 (m, 2H), 5.19 (br dd, J=9.0, 5.8 Hz, 2H), 3.51-3.63 and 3.71-3.90 (2 br multiplets, total 3H), 3.42 (s, 3H), 3.18-3.29 and 3.34-3.47 (2 br multiplets, total 3H), 2.27-2.45 (br m, 1H), 1.6-2.00 (m, 7H), 1.47 and 1.50 (2 br s, total 9H), 1.16-1.29 (br m, 3H).
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.[OH:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[OH-].[Na+]>O>[CH3:1][O:8][C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COS(=O)(=O)OC
Reactant: Oc1cc2ccccc2cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Dimethylsulfate (32 ml) was added to the solution of 2,3-dihydroxynaphthalene (32 g) and sodium hydroxide (10 M, 32 ml) in water (300 ml). After being stirred for six hours at room temperature, the side product 2,3-dimethoxynaphthalene was filtered off (yield 16.6 g). The water phase was acidified, stirred on ice bath, filtered, washed with water and recrystallized from ethanol-water (3:2). Yield: 13.5 g, melting point 108-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([O:10]C)=O.[OH-].[Na+].Cl.[Cl-].[NH4+].C([N:19](CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O.CO>[NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:19])=[O:10]
Reactant: COC(=O)c1sc(Br)cc1N
Reactant: CCN(CC)CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1sc(Br)cc1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
A mixture of methyl 3-amino-5-bromothiophene-2-carboxylate (5.67 g, 24.0 mmol) was mixed with sodium hydroxide (2.94 g, 73.6 mmol), MeOH (100 mL) and water (25 mL) was stirred at 70° C. overnight. After cooling to 0° C., 6 M HCl (8.17 mL, 49.0 mmol) was added. This mixture was concentrated under reduced pressure to give a yellow solid. Co-evaporation was carried out with toluene and the resulting solid was dried under reduced pressure well. This residue was mixed with ammonium chloride (26.3 g, 491 mmol), triethylamine (49.7 g, 491 mmol) and DMF (230 mL). After stirred at room temperature for 5 min, 1-hydroxybenzotriazole (19.9 g, 144 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.2 g, 147 mmol) were added. The stirring was continued for 2 days. The reaction mixture was poured into saturated aqueous NaHCO3 (700 mL) and extracted with EtOAc (700 mL), and the extract was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residual brown oil was purified by column chromatography (Purif, silica gel, hexane to EtOAc) to afford the title compound (4.05 g, 75%) as yellow solid:
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[C:9]([NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[CH2:17][CH2:16]2)(=[O:11])[CH3:10]>>[CH3:3][N:4](/[CH:6]=[C:17]1/[C:18](=[O:22])[C:19]2[C:15]([CH2:16]/1)=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH3:10])=[CH:21][CH:20]=2)[CH3:5]
Reactant: CC(=O)Nc1ccc2c(c1)CCC2=O
Reactant: COC(OC)N(C)C
Product: CC(=O)Nc1ccc2c(c1)C/C(=C\N(C)C)C2=O
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
Dimethylformamide dimethylacetal was added to 5-acetamido-1-indanone (2.5 g, 13.2 mmol), which was stirred at 100° C. for 3.5 hours, and cooled to room temperature. The precipitated crude products were collected, which was washed with ethyl acetate to give the titled compound (2.73 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]2[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]2)[S:9][CH:10]=1)=[O:5])[CH3:2].[Si:17](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:17]([O:16][C@@H:13]1[CH2:14][CH2:15][N:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)[CH2:12]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1csc(N2CC[C@@H](O)C2)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1csc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reaction time: 0.17 h
Yield: 98.1 %

Procedure:
To a solution of (3R)-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)-3-hydroxypyrrolidine (3.0 g, 12.4 mmol) (obtained as described in Reference Example 18(2)) in dimethylformamide (90 ml) were added t-butyldiphenylsilyl chloride (6.45 ml, 24.8 mmol) and imidazole (1.69 g, 24.8 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol (2.59 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→1:1) as the eluant to afford (3R)-3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)pyrrolidine (5.85 g, yield 90%) as a pale brown solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[Cl:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=3)[CH2:34][CH2:33]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1ccc(F)cc1

Procedure:
162 mg (85%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(3,4-dichlorophenyl)piperazine (84 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]CC)=[O:23])[C:13](=[O:15])[CH3:14].C(OC(CCCCC)CCCN(CCCCCCC(OCC)=O)C(=O)C)(=O)C>>[OH:7][CH:8]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[C:13](=[O:15])[CH3:14]
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC1CCCCO1
Agent: CCCCCC(CCCN(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O
Product: CCCCCC(O)CCCN(CCCCCCC(=O)O)C(C)=O

Procedure:
The preparation of this compound is carried out essentially by the method described for Example 1, Step B except that the ethyl 7-{N-[4-(2-tetrahydropyranyloxy)-nonyl]acetamido}heptanoate of Example 1, Step B is replaced by an equimolar quantity of ethyl 7-[N-(4-acetoxynonyl)-acetamido]heptanoate; and omitting the acid treatment, there is obtained the subject compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[C:6]=4[N:7]=[C:8](OS(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[C:10](=[O:15])[C:11]=2[CH:12]=[CH:13][N:14]=1.[NH2:34][CH2:35][CH2:36][N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]([CH2:43][CH2:44][NH2:45])[CH3:42]>>[Cl:1][C:2]1[C:3]2[C:4]3[C:5]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[C:6]=4[N:7]=[C:8]([NH:45][CH2:44][CH2:43][N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH2:36][CH2:35][NH:34][C:8]4[C:9]5[C:10](=[O:15])[C:11]6[CH:12]=[CH:13][N:14]=[C:2]([Cl:1])[C:3]=6[C:4]=5[C:5]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[C:6]=5[N:7]=4)[CH3:46])[CH3:42])[C:9]=3[C:10](=[O:15])[C:11]=2[CH:12]=[CH:13][N:14]=1
Reactant: COc1ccc2c3c(c(OS(=O)(=O)c4ccc(C)cc4)nc2c1C)C(=O)c1ccnc(Cl)c1-3
Reactant: CN(CCN)CCCN(C)CCN
Product: COc1ccc2c3c(c(NCCN(C)CCCN(C)CCNc4nc5c(C)c(OC)ccc5c5c4C(=O)c4ccnc(Cl)c4-5)nc2c1C)C(=O)c1ccnc(Cl)c1-3

Procedure:
In a similar manner to Example 4, this compound was obtained starting from toluene-4-sulfonic acid 11-chloro-3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 5) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.