Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([NH2:13])[S:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[F:14].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[S:24]([NH:13][C:11]1[S:10][CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][C:3]([F:14])=[C:2]([CH3:1])[CH:7]=2)[N:12]=1)(=[O:26])=[O:25]
Reactant: Cc1cc(-c2csc(N)n2)ccc1F
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: Cc1cc(-c2csc(NS(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)n2)ccc1F

Procedure:
The title compound was prepared from 2-amino-4-(4′-fluoro-3′-methyl)phenylthiazole and 2,4,6-trichlorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (50.9 mg) with purity >90%: MS (pos) m/z 451.0, 453.0, 455.0; HRMS m/z 449.9218 (calc. of monoisotopic mass for C16H10Cl3FN2O2S2 gives 449.9233).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])[CH:14]=3)=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]=[C:37]=[O:38])[CH:31]=1>CN(C=O)C>[Cl:1][C:2]1[N:6]2[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([CH:14]=3)[C:20]([N:22]3[CH2:23][CH2:24][N:25]([C:37]([NH:36][C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=4)=[O:38])[CH2:26][CH2:27]3)=[O:21])=[CH:8][NH:9][C:10](=[O:11])[C:5]2=[CH:4][C:3]=1[Cl:28]
Reactant: O=C(c1cc(Cc2c[nH]c(=O)c3cc(Cl)c(Cl)n23)ccc1F)N1CCNCC1
Reactant: O=C=Nc1cccc(F)c1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(F)c1)N1CCN(C(=O)c2cc(Cc3c[nH]c(=O)c4cc(Cl)c(Cl)n34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Example 16, P1 in DMF (0.1 M) was added 1-fluoro-3-isocyanatobenzene (1 eq). The resulting mixture was stirred for 1 hour at RT. The product was isolated by purification at preparative-HPLC. 1H NMR (300 MHz, DMSO-d6) δ: 10.90 (1H, m), 8.80 (1H, s), 7.48-7.37 (1H, m), 7.35-7.20 (5H, m), 7.15 (1H, s), 6.80-6.69 (1H, m), 6.55 (1H, m), 4.38 (2H, m), 3.72-3.62 (2H, m), 3.59-3.50 (2H, m), 3.44-3.35 (2H, m), 3.27-3.16 (2H, m). MS (ES) C26H21Cl2F2N5O3 requires: 559/561, found: 560/562 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[O:13][C:12]3[C:21]([CH3:28])=[C:22]([CH3:27])[C:23]([NH2:26])=[C:24]([CH3:25])[C:11]2=3)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1.CO.C(OC(C)C)(C)C>>[F:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:26][C:23]2[C:22]([CH3:27])=[C:21]([CH3:28])[C:12]3[O:13][C:14]4([CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]4)[CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=4)[C:11]=3[C:24]=2[CH3:25])=[O:35])=[CH:32][CH:31]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Solvent: CC(C)OC(C)C
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Yield: 38 %

Procedure:
By using 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 38%. Melting point: 271-272° C. (Methanol-isopropyl ether)
Reaction SMILES: CCO.[Br:4][C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-])=O)[C:6]=1[S:17][C:18]#[N:19].Cl.N>[Fe].O>[Br:4][C:5]1[C:6]2[S:17][C:18]([NH2:19])=[N:14][C:7]=2[CH:8]=[C:9]([NH2:11])[CH:10]=1
Reactant: N#CSc1c(Br)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)c2sc(N)nc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.2 %

Procedure:
To a stirred mixture of EtOH (8.37 L) and water (8.37 L) at rt was added (2-bromo-4,6-dinitro-phenyl)thiocyanate (549 g, 1.81 mol) followed by addition of Fe powder (2.02 kg, 36.11 mol) and drop wise addition of HCl (12N, 527 mL) over 30 min. The resulting reaction mixture was stirred at rt for 20 min then heated to 80° C. for 45 min. After completion of the reaction (by TLC) the reaction mixture was cooled to rt and basified to pH 8-10 by addition of aqueous ammonia solution. The resulting solution was passed through celite bed, washed with EtOAc and the combined filtrate evaporated under reduced pressure. To the resulting residue was added water (8 L) then extracted with EtOAc (2×4 L). The combined organics were washed with brine, dried (anhydrous Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (412 g, 93%). 1H NMR (DMSO-d6): δ 5.16 (br s, 2H), 6.50 (d, J=2.0 Hz, 1H), 6.53 (d, J=1.60 Hz, 1H) and 7.44 (br s, 2H). LCMS: 243.86 [M+H]+.
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][C:16]([CH3:18])=[CH2:17])=[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]([CH3:18])[CH3:17])=[O:25])=[N:4][C:3]=1[C:19](=[O:23])[C:20]([CH3:22])=[CH2:21]
Reactant: C=C(C)Sc1nc(C(=O)C(=C)C)c(Cl)n1-c1ccc(CC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
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-(propen-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: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:30]([C:23]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:22]=2[O:21][CH3:20])(=[O:32])=[O:31])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Product: COc1ccc(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,4-dimethoxybenzene-1-sulfonyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH:9]=1)(C)(C)C.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([NH:15][C:16]2[N:17]=[CH:18][C:19]3[N:24]=[C:23]([NH:25][C:26](=[O:28])[CH3:27])[S:22][C:20]=3[N:21]=2)[CH:9]=1
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)OC(C)(C)C)ccc3C)nc2s1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Yield: 82.6 %

Procedure:
A solution of tert-butyl(3-{[2-(acetylamino)[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino}-4-methylphenyl)carbamate (1.27 g, 3.06 mmol) and anisole (2 mL) in trifluoroacetic acid (20 mL) was stirred at 0° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the obtained residue, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture (1:1, 50 mL, 2×10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (795 mg, 83%) as a pale-green solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][C:43]([CH2:55][OH:56])([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)[CH2:42]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:54][C:50]1[CH:49]=[C:48]([CH:53]=[CH:52][CH:51]=1)[O:47][C:43]1([CH2:55][OH:56])[CH2:44][CH2:45][CH2:46][CH:41]([NH:40][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:42]1
Reactant: NC1CCCC(CO)(Oc2cccc(F)c2)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(CO)(Oc5cccc(F)c5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.2 mmol, 100 mg), HCl salt of (3-amino-1-(3-fluorophenoxy)cyclohexyl)methanol (0.2 mmol, 55 mg), HATU (0.2 mmol, 76 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(3-fluorophenoxy)-3-(hydroxymethyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([CH3:12])[CH:3]=1.N([O-])=O.[Na+].[BrH:17]>O.[Cu]Br>[Br:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(N)ccc1OC(F)F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Br)ccc1OC(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a stirred solution of 4-amino-1-difluoromethoxy-2-methyl-benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0° C. was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0° C. Copper (I) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60° C. for 30 minutes. The resulting solution was extracted with EtOAc (3×50 mL) and the combined organic layers washed with H2O (1× 20 mL), dried over Na2SO4 and concentrated to provide 2.5 g (37%) of 4-bromo-1-(difluoromethoxy)-2-methylbenzene.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[OH-:20].[K+]>C(O)(C)(C)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:19]=[CH:18][C:15]([C:16]([NH2:17])=[O:20])=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Yield: 5.8 %

Procedure:
Combine 4-(1-Oxo-indan-5-yloxy)-benzonitrile (1.64 g, 6.58 mmol), tert-butyl alcohol (50 ml), and grounded KOH (1.85 g, 32.89 mmol) at room temperature under nitrogen atmosphere. Stir the reaction for 24 hours then concentrate under reduced pressure. Add Ethyl acetate to the reaction mixture and wash with brine. Dry the organic layer over Na2SO4. A yellow-mange solid precipitates out to afford 101.0 mg, 0.38 mmol (5.7% yield) of the title compound: No Characterization—Characterized by sequential reaction.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20](O)=[CH:19][C:18]=1[CH3:25].C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:20]1[CH:21]=[C:22]([CH3:23])[C:17]([Br:16])=[C:18]([CH3:25])[CH:19]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(O)cc(C)c1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoromethanesulfonic anhydride (2.0 mL) was added dropwise to a solution of 4-bromo-3,5-dimethylphenol (CAS No. 7463-51-6) (2.0 g) and TEA (1.94 mL) in DCM (20 mL) under ice-cooling over three minutes. The reaction mixture was stirred at room temperature for 30 minutes. Ice and ethyl acetate were added to the reaction mixture, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5%) to give the title compound (3.20 g).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13]C(=O)OC(C)(C)C)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3].O1CCOCC1>Cl.C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH2:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: [N-]=[N+]=NC[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 128.1 %

Procedure:
A solution of tert-butyl (S)-3-azido-1-phenylpropan-2-ylcarbamate (1.0045 g, 3.6 mmol) was dissolved in 4 M HCl in dioxane (20 mL, 80 mmol) and stirred at rt for 2 h. The solvent was stripped. The residue was taken up in CH2Cl2 (50 mL) and 1 N aq NaOH (10 mL), extracted with CH2Cl2 (3×10 mL), washed with brine (3×5 mL), dried (Na2SO4), decanted, and stripped to afford (S)-1-azido-3-phenylpropan-2-amine (812.9 mg, quant, 80% purity) as a clear oil. MS ESI +ve m/z 177 (M+1).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2]1.[NH2:7][C@H:8]1[C:21]2[C:12](=[CH:13][C:14]3[C:15]([CH3:23])=[CH:16][C:17]([Cl:22])=[N:18][C:19]=3[CH:20]=2)[O:11][C:10]([CH3:25])([CH3:24])[C@@H:9]1[OH:26].Cl([O-])(=O)(=O)=O.[Li+].C(OCC)(=O)C>O1CCOCC1>[Cl:22][C:17]1[CH:16]=[C:15]([CH3:23])[C:14]2[CH:13]=[C:12]3[O:11][C:10]([CH3:24])([CH3:25])[C@H:9]([OH:26])[C@@H:8]([NH:7][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH3:6])[C:21]3=[CH:20][C:19]=2[N:18]=1
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Reactant: CCCC1CO1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC(O)CN[C@H]1c2cc3nc(Cl)cc(C)c3cc2OC(C)(C)[C@@H]1O
Temperature: 70 °C
Reaction time: 25 h
Yield: 59 %

Procedure:
Under nitrogen stream, 1,2-epoxypentane (71 μL, 0.682 mmol) was added to a solution of (3R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (100 mg, 0.343 mmol) and lithium perchlorate (36 mg, 0.343 mmol) in dioxane (0.50 mL) at room temperature, and the resulting mixture was stirred at 70° C. for 25 hours. Upon the completion of the reaction, ethyl acetate was added thereto, the resulting reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/1) to obtain the aimed product (yield: 59%).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[CH2:15](O)[CH3:16]>>[Br:1][C:2]1[S:3][C:4]([Br:10])=[CH:5][C:6]=1[C:7]([O:9][CH2:15][CH3:16])=[O:8]
Reactant: CCO
Reactant: O=C(O)c1cc(Br)sc1Br
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Br)sc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 2,5-dibromothiophene-3-carboxylic acid (33.5 g) synthesized above in ethanol (300 mL) was added dropwise thionyl chloride (4.23 mL), and the mixture was stirred at room temperature overnight and then stirred with heating under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1, volume ratio) to give the title compound (33.4 g, 92%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl[CH2:42][C:43]1[N:44]([CH2:48][CH2:49][CH3:50])[CH:45]=[CH:46][N:47]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:42][C:43]5[N:44]([CH2:48][CH2:49][CH3:50])[CH:45]=[CH:46][N:47]=5)=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:39]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCn1ccnc1CCl
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(O)cc2)CCN3CC(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(OCc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-(4-hydroxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.5 g), 2-chloromethyl-1-propylimidazole hydrochloride (0.22 g) and potassium carbonate (0.4 g), N,N-dimethylformamide (15 ml) was added, and the mixture was stirred overnight under nitrogen atmosphere at room temperature. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(1-propylimidazole-2-yl) methoxy]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 25) (0.51 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15]>O.C(O)(C)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[Cl:15]
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1Cl
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(-c2ccc(=O)[nH]n2)cc1Cl

Procedure:
3 In a mixture of water and isopropanol (20 : 5) was suspended 0.34 g. of 6-(4-amino-3-chlorophenyl)-4,5-dihydro-3(2H)pyridazinone. The resulting suspension was then treated in the manner as in Example 7 - 3 to give 0.18 g. of the desired product of m.p. 280° - 282° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:59])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:56]=[CH:55][C:34]([C:35]([O:37][CH:38]([O:40][C:41](=[O:54])[NH:42][CH2:43][C:44]([O:46]CC3C=CC=CC=3)=[O:45])[CH3:39])=[O:36])=[CH:33][C:32]=2[O:57][CH3:58])=[O:29])[CH:5]=[CH:6][CH:7]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[C:3]([F:59])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:56]=[CH:55][C:34]([C:35]([O:37][CH:38]([O:40][C:41]([NH:42][CH2:43][C:44]([OH:46])=[O:45])=[O:54])[CH3:39])=[O:36])=[CH:33][C:32]=2[O:57][CH3:58])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)OC(C)OC(=O)NCC(=O)OCc2ccccc2)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OC(C)OC(=O)NCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Yield: 64.4 %

Procedure:
To a solution of 1-(2-(benzyloxy)-2-oxoethylcarbamoyloxy)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate (Example 23, 35.8 mg, 0.042 mmol) in ethyl acetate (8 mL) was added 10% palladium on carbon (12 mg). The content was stirred at room temperature under 1 atm of hydrogen for 2 h. Palladium on carbon solids were filtered off and washed with ethyl acetate. The solution was concentrated to give 2-((1-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)ethoxy)carbonylamino)acetic acid as a white solid (20.6 mg, 61%)). MS (ES+) m/z calcd. for C36H37Cl2F2N4O8 [(M+H)+]: 761, found: 761.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([OH:11])(=[O:10])[C:8]#[CH:9].[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15]Br>CC(C)=O>[C:7]([O:11][CH2:15][CH:14]=[C:13]([CH3:17])[CH3:12])(=[O:10])[C:8]#[CH:9]
Reactant: C#CC(=O)O
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CC(=O)OCC=C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
41.5 g (0.3 mol) of potassium carbonate were added at 0° to a solution of 18.4 ml (0.3 mol) of propiolic acid in 300 ml of acetone. The mixture was stirred at room temperature for 4 hours, then 34.7 ml (0.3 mol) of 3,3-dimethylallyl bromide were added and the mixture was subsequently boiled at reflux for a further 20 hours. The cooled reaction mixture was concentrated on a rotary evaporator. The residue was poured onto ice/water and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. Distillation of the residue in a water-jet vacuum yielded 3-methyl-2-butenyl propiolate of boiling point 77°-78°/15 mmHg.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13]C)=[O:12])=[O:4].[OH-].[Na+]>CO.O>[C:3]([CH2:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([OH:13])=[O:12])([OH:4])=[O:2]
Reactant: COC(=O)Cc1sccc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1sccc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
13.0 g of the compound obtained in Example 1 was dissolved in 260 mL of methanol, and a solution obtained by dissolving 4.84 g of sodium hydroxide in 26 mL of water was added thereto. The resulting solution was refluxed for 4 hours, cooled to room temperature, concentrated under reduced pressure to remove methanol. The resulting aqueous solution was washed with 10 ml of diethyl ether and acidified to pH 2 to 3 using concentrated HCl. The solids thus solidified were filtered, washed with a small amount of cold water and dried at 40° C. to obtain 9.60 g (yield of 85%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10]O)=[C:7]([CH3:12])[C:6]=2[CH:13]=1.P(Br)(Br)[Br:15].CN(C=O)C>CCOCC>[Br:15][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][C:6]=2[C:7]=1[CH3:12]
Reactant: BrP(Br)Br
Reactant: Cc1c(CO)oc2ccc(Cl)cc12
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(CBr)oc2ccc(Cl)cc12
Reaction time: 3 h

Procedure:
A solution of 5-chloro-3-methyl benzofuran 2-methanol (18.3 mmol, 3.6 g) in ether (200 mL) was cooled to 0° C. To this was added drop-wise phosphorus tribromide (29.3 mmol, 7.9 g) and then DMF (2 mL). After allowing the reaction mixture to come to room temperature over three hours, the reaction was quenched with ice water (100 mL). The ether layer was collected, dried, filtered and the filtrate was evaporated to a yellow solid: 2-bromomethyl-5-chloro-3-methyl benzofuran (88%, 4.2 g); mp 81° C.-82° C.