Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18](I)=[CH:17][C:16]=1[O:24][CH3:25])[CH3:13].C(=O)=O.CC(C)=O.[B:33](OC(C)C)([O:38]C(C)C)[O:34]C(C)C>O1CCCC1>[CH2:12]([O:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([B:33]([OH:38])[OH:34])=[CH:17][C:16]=1[O:24][CH3:25])[CH3:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1c(OC)cc(I)cc1OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOc1c(OC)cc(B(O)O)cc1OC
Yield: 38.7 %

Procedure:
Under argon, a 1.60 M solution of n-butyllithium in hexane (2.5 mL, 4.1 mmol) was added to anhydrous tetrahydrofuran (7.0 mL) stirred in a dry ice-acetone bath, followed by dropwise addition of a solution of 4-ethoxy-1-iodo-3,5-dimethoxybenzene (570.0 mg, 1.85 mmol) in anhydrous tetrahydrofuran (1.5 mL). After the mixture was stirred for 20 minutes in the dry ice-acetone bath, triisopropyl borate (0.50 mL, 2.2 mmol) was added, and the mixture was additionally stirred for 20 minutes. The reaction mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure. To the residue, a 0.1 M aqueous sodium hydroxide (4.4 mL) solution was added. The aqueous solution was washed with chloroform, acidified by the addition of concentrated hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Chloroform-hexane was added to the residue and the resulting precipitate was collected by filtration to afford the title compound as a colorless amorphous powder (162.0 mg, yield: 39%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:25][CH2:24][N:23](C([O:28][C:29]([CH3:32])(C)C)=O)[CH2:22][CH2:21]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[F:33][C:34]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37]>ClCCl.N1C=CC=CC=1>[C:29]([OH:37])(=[O:28])[CH3:32].[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:45])[F:46])=[CH:42][C:34]=4[F:33])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O
Product: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (0.10 g, 0.228 mmol) in dichloromethane (2 mL) and pyridine (1 mL) was treated with 2-fluoro-4-trifluoromethylbenzoyl chloride (0.057 g, 0.251 mmol) then stirred for 1 hour. The solvents were evaporated then the residue was treated with trifluoroacetic acid (1 mL) in dichloromethane (2 mL). The mixture was stirred for 1 hour at ambient temperature then the solvents were evaporated under reduced pressure and the residue purified by RP preparative HPLC on a C18 column using acetonitrile-0.05 M ammonium acetate as a mobile phase. Lyophilization afforded the pure title compound: 1H NMR (DMSO-d6, 400 MHz) δ 9.90 (d, 1H), 8.31 (d, 1H), 8.24 (s, 1H), 7.99 (t, 1H), 7.89 (d, 1H), 7.75 (d, 1H), 7.33 (s, 1H), 7.30 (d, 1H), 4.78 (m, 1H), 3.94 (s, 3H), 3.10 (m, 2H), 2.69 (m, 2H), 2.08 (m, 2H), 1.85-2.0 (m, 5H); RP-HPLC (Hypersil HS C18 Hypersil HS C18, 5 μm, 100A, 250×4.6 mm; 5%-100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 17.33 min;
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6](C(OC)=O)[CH2:5][CH2:4]1.[CH3:13][Mg]Br.CC(=O)[O:18][CH2:19][CH3:20]>C1COCC1>[NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:19]([OH:18])([CH3:20])[CH3:13])[CH2:5][CH2:4]1
Reactant: CCOC(C)=O
Reactant: C[Mg]Br
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Solvent: C1CCOC1
Product: CC(C)(O)[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-methyl 4-(aminomethyl)cyclohexanecarboxylate (1 g, 5.8 mmol) in THF (50 mL) was added dropwise methylmagnesium bromide (7.7 mL, 23.2 mmol) at −78° C. The mixture was stirred at room temperature for 2 h. TLC (PE:EA=5:1) showed the reaction was complete. The mixture was quenched by the addition of NH4Cl (100 mL) and extracted with EtOAc (100 mL×3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo to give 2-(trans-4-(aminomethyl)cyclohexyl)propan-2-ol (0.42 g, 39.2%) as a yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.NO[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC1C=CC=CC=1CC(Cl)=O>>[C:13]1([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:1]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NOc1ccccc1
Reactant: c1ccc2c(c1)NCCO2
Agent: O=C(Cl)Cc1ccccc1Cl
Product: c1ccc(C2CNc3ccccc3O2)cc1

Procedure:
By a procedure similar to that described for the synthesis of 3,4-dihydro-2H-1,4-benzoxazine (Example 142), O-aminophenol and 2-chlorophenylacetyl chloride produces 3,4-dihydro-2-phenyl-2H-1,4-benzoxazine, m.p. 113°-116° which, according to the reaction scheme of Example 110 is converted to the title compound, m.p. 311°-313° .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:9]1\[C:10](=[O:29])[NH:11][C:12]2[C:17]\1=[C:16]([C:18]#[C:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:15]([N+:26]([O-])=O)=[CH:14][CH:13]=2.[NH4+].[Cl-].CN(C=O)C>O.CO.[Zn]>[NH2:26][C:15]1[C:16]([C:18]#[C:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:29])/[C:9]/2=[CH:8]\[C:4]1[NH:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#Cc3cccnc3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#Cc3cccnc3)c21
Temperature: 90 °C

Procedure:
Using Method L above, (Z)-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one (0.1 g, 0.26 mmol) (from Example 68 above) was reduced with Zn (0.15 g, 2.33 mmol) and NH4Cl (30.6 mg, 0.57 mmol) in 10% water in methanol (10 mL) with a trace of DMF and heating at 90° C. for 5 h, to yield (Z)-5-amino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-4-[(3-pyridinyl)ethynyl]-2H-indol-2-one. (Yield 28 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][C:23]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25][NH2:26]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:23]=2[O:22][CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COc1cccc(CN)c1OC
Product: COc1cccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)c1OC

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (160 mg, 0.43 mmol) and 2,3-dimethoxy benzylamine (87 mg, 0.52 mmol). The title compound was obtained as a solid (80 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.25 (1H, m), 8.98 (2H, m), 8.51 (1H, s), 6.99 (2H, m), 6.82 (1H, m), 4.38 (2H, m), 3.78 (3H, s), 3.71 (3H, s). MS m/z: 498.29, 500.27 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH2:10].[Br:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16]>>[BrH:11].[CH3:16][O:15][CH2:14][CH2:13][CH2:12][N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][C:2]1=[NH:10]
Reactant: Nc1nc2ccccc2s1
Reactant: COCCCBr
Product: Br
Product: COCCCn1c(=N)sc2ccccc21
Yield: 84.9 %

Procedure:
Benzothiazol-2-ylamine (1.0 g, 6.6 mmol) and 1-bromo-3-methoxy-propane (1.2 g, 7.9 mmol) were processed as described in Example 2A. Recrystallization from ethyl acetate afforded 1.7 g (89%) of the title compound. 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.90-2.02 (m, 2H), 3.18 (s, 3H), 3.39 (t, J=5.9 Hz, 2H), 4.31 (t, J=7.1 Hz, 2H), 7.37-7.48 (m, 1H), 7.53-7.69 (m, 2H), 8.00 (dd, J=8.0, 0.8 Hz, 1H), 10.08 (s, 1H); MS (DCI/NH3) m/z 233 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].O>O1CCCC1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[S:24]([N:8]1[CH:9]=[C:10]([CH:12]=[O:13])[N:11]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: O=Cc1c[nH]c(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cn(S(=O)(=O)c2c(F)cccc2F)c(-c2ccccc2)n1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 2-phenyl-1H-imidazole-4-carbaldehyde (1.00 g) in tetrahydrofuran (70 mL) was added sodium hydride (60% in oil, 348 mg) at room temperature, and the mixture was stirred for 30 min. 2,6-Difluorobenzenesulfonyl chloride (1.36 g) was added to the reaction mixture, and the mixture was stirred for 1.5 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from diethyl ether to give the title compound as colorless crystals (yield 1.36 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[Br:17]Br.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:17][C:16]1[C:3]2[C:4](=[N:5][N:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[Cl:1])[NH:14][N:15]=1
Reactant: BrBr
Reactant: Clc1c(-c2ccccc2)nnc2[nH]ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Clc1c(-c2ccccc2)nnc2[nH]nc(Br)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
A mixture of 4-chloro-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (155 mg, 0.67 mmol), bromine (51 μL, 1 mmol) and triethylamine (98 μL, 0.7 mmol) in chloroform (4 mL) was stirred at room temperature for 1 h. Additional bromine (25 μL) and chloroform (4 mL) were added and the reaction mixture was stirred at room temperature for 4 h. Further bromine (25 μL) and triethylamine (98 μL) were added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with CH2Cl2 and a sodium bicarbonate solution. The aqueous phase was extracted with CH2Cl2 and the combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, ethyl acetate/isohexane 0:1 to 1:1), to provide Compound Ibb as a solid (97 mg).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29]>>[Br-:20].[C:28]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([OH:30])=[O:29]
Reactant: O=C(O)CCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O)CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 88.5 %

Procedure:
Triphenylphosphine (26.3 g) and 8-bromooctanoic acid (21.3 g) were reacted as in Example 82. The crude salt was crystallized from a mixture of ethanol (100 mL), chloroform (200 mL) and ether (500 mL) to give 41 g of (7-carboxyheptyl) triphenylphosphonium bromide, mp 121°-123° C. Anal. Calculated for C26H30BrO2P: C, 64.33; H, 6.23; Br, 16.46. Found: C, 63.97; H, 6.23; Br, 16.07.
Reaction SMILES: [O:1]=[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])[CH2:3][C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[O:5]=[C:4]([NH:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])[C:3](=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]([NH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20])=[O:1]
Reactant: O=Cc1ccccc1
Reactant: O=C(CC(=O)Nc1ccccc1C(=O)O)Nc1ccccc1C(=O)O
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1C(=O)O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)O
Yield: 54.6 %

Procedure:
2,2'-[(1,3-Dioxo-1,3-propanediyl)diimino]bisbenzoic acid (1.0 g) and benzaldehyde (0.46 g, 1.5 mol equivalent) were heated under reflux in dry pyridine (8 1) for 16 hours. After removing pyridine, the mixture was treated with water, made alkaline with 10% aqueous ammonia under ice cooling, and the aqueous layer was washed with ether. The aqueous layer was made acidic (pH=2) with 1N HCl, and the precipitated crystals were collected by filtration. After washing with water, the resulting solid was purified by dissolving in tetrahydrofuran, adsorbing on the silica gel column and separating the desired compound using a developing solvent [ethyl acetate:benzene=1:1 (containing 1% acetic acid)]. After removing the initially eluted impurities, the solvent was removed from the effluent out liquid containing the desired compound. The residue was crystallized by adding water, collected on a filter, washed with water, and dried to give the title compound (0.686 g, yield, 51%), which was recrystallized from the mixed solvent of CH3OH--H2O system to obtain pale yellow crystals of monohydrate (Crystal a, 0.507 g) (Drying: 1 mm Hg, 100° C., 15 hours), m.p., 195°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9]CC1C=CC(OC)=CC=1.C1(S)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccccc5OC)c4c3)cc2OC)cc1
Agent: O=C([O-])O
Agent: Sc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)ccc1O
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a 50 ml round bottomed flask were added 5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (48 mg, 0.10 mmol), methylene chloride (2.5 ml) and 396 mg (0.28 mmol) PS-thiophenol (1.41 mmol·g−1; Argonaut Technologies). Trifluoroacetic acid (500 μl) was added and the suspension was shaken in a orbital shaker for 1 hour. The yellow reaction mixture was filtered, and the resin was washed three times with dichloromethane and ether, then twice with dichloromethane. The combined filtrate was concentrated to obtain a yellow residue, which was distributed between ethyl acetate and saturated aqueous solution of sodium bicarbonate. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate and hexanes gave 31 mg (86%) of 2-methoxy-4-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-phenol as a light yellow powder. 1H-NMR (d6-DMSO) δ=11.87 (br.s, 1H), 9.04 (br.s, 1H), 8.48 (d, 1H), 8.07 (d, 1H), 7.68 (dd, 1H), 7.57 (dd, 1H), 7.27 (t, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 7.08 (dd, 1H), 7.02 (t, 1H), 6.85 (d, 1H), 3.85 (s, 3H), 3.82 (s, 3H); MS m/z: 347 [MH]+.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC1(c2ccc(/C=C/C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
In a mixed solvent of THF (250 ml) and water (125 ml), (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (9.80 g) was dissolved, and the resulting mixture was cooled to 0° C. Barium hydroxide octahydrate (3.14 g) was added thereto and the resulting mixture was stirred at 0° C. for 8 hours. The reaction solution was concentrated to remove THF, and water (150 ml) was added thereto, followed by washing the resulting mixture with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: chloroform/methanol=10/1). The obtained crudely purified product was further purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate 1/1→ethyl acetate) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (6.15 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].[Br:13]Br.O>CC(O)=O>[Br:13][C:7]1[C:8]([OH:11])=[CH:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([OH:12])[CH:1]=2
Reactant: BrBr
Reactant: Oc1ccc2ccc(O)cc2c1
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc2cc(Br)c(O)cc2c1
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
To a solution of naphthalene-2,7-diol (5.00 g, 31.3 mmol) in AcOH (25 mL) was added Br2 (3.3 mL, 62.6 mmol) in AcOH (25 mL) dropwise over 15 minutes at 10-15° C., then mixture was stirred at 10-15° C. for 1 hour. Sn powder (7.75 g, 64.6 mmol) and H2O (20 mL) was added and the mixture was heated to 80° C. for 1 hour. The mixture was diluted with ice-water (50 mL), the extracted with EtOAc (30 mL×3), organic was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (PE/EtOAc=15/1) and further prep-HPLC (0.1% TFA as additive) gave the product (2.0 g, yield 27%) as a solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].[CH:22](N(CC)C(C)C)(C)C>CS(C)=O>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[CH2:21][CH3:22])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CN(CC2CC2)CCN1
Solvent: CS(C)=O
Product: CCc1cc([N+](=O)[O-])ccc1N1CCN(CC2CC2)CC1

Procedure:
In the same manner as in Production Example 5-1, but using 4-(cyclopropylmethyl)piperazine in place of N-ethylpiperazine used in Production Example 5-1, using 2-fluoro-5-nitrotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, 280 mg of the entitled compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[C:17]([CH3:18])=[CH:16][S:15][CH:14]=1)=S.NC1C=C(F)C=CC=1NC(NC1C(C)=CSC=1)=S.[OH-].[Na+].C1(C)C=CC(S([Cl:48])(=O)=O)=CC=1>C1COCC1.O>[ClH:48].[F:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:10]([NH:12][C:13]3[C:17]([CH3:18])=[CH:16][S:15][CH:14]=3)=[N:9][C:3]=2[CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cscc1NC(=S)Nc1cc(F)ccc1N
Agent: Cc1cscc1NC(=S)Nc1ccc(F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cscc1Nc1nc2cc(F)ccc2[nH]1
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The mixture of 1-(2-amino-5-fluorophenyl)-3-(4-methylthiophen-3-yl)thiourea and 1-(2-amino-4-fluorophenyl)-3-(4-methylthiophen-3-yl)thiourea (1.75 g) was dissolved in THF (50 ml) and admixed with a solution of sodium hydroxide (0.622 g) and water (15 ml). Within 5 min, a solution of p-toluenesulfonyl chloride (1.304 g) and THF (10 ml) was added dropwise. On completion of addition, the mixture was stirred at room temperature for a half hour. The reaction mixture was poured onto water, and the aqueous phase was extracted three times. The combined ether phases were dried with magnesium sulfate, filtered and concentrated. The crude product was dissolved in ethyl acetate and adjusted to pH 2 using ethereal HCl. It was precipitated by adding ether. After drying, 750 mg of the desired product were obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=O.[N:17]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]([NH2:29])=[S:28])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44](Cl)=[O:45]>O1CCOCC1>[CH3:10][C:9]1[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[CH:6][C:5]=1[C:3]1[N:29]=[C:27]([N:26]([CH2:25][CH2:24][CH2:23][N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:44]([C:40]2[S:39][CH:43]=[CH:42][CH:41]=2)=[O:45])[S:28][CH:2]=1
Reactant: O=C(Cl)c1cccs1
Reactant: NC(=S)NCCCN1CCOCC1
Reactant: Cc1c(C(=O)CBr)cnn1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(-c2csc(N(CCCN3CCOCC3)C(=O)c3cccs3)n2)cnn1-c1ccccc1
Temperature: 80 °C
Yield: 65.2 %

Procedure:
A mixture of 2-bromo-1-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-1-ethanone (167 mg, 0.6 mmol) and (3-morpholin-4-yl-propyl)-thiourea (122 mg, 0.6 mmol) in dry dioxane (5 ml) was heated at 80° C. for 2 h, cooled to room temperature, and concentrated in vacuo. The resulting residue was suspended in dichloromethane (5 mL) followed by the addition of N,N-diisopropylethylamine (209 μL, 1.2 mmol) and thiophene-2-carbonyl chloride (96 μL, 0.9 mmol). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (2.5 mL) and subjected to HPLC purification (Method Y). The resulting free amine was dissolved in MeOH (1 mL) and 1M HCl/ether (50 mL) was added. The precipitate was filtered and dried in vacuo to provide the title compound (193 mg) as an yellow solid as the hydrochloride salt. LC/MS (ESI) m/z 494.3 [M+H]. HPLC retention time (Method B)=2.72 min.
Reaction SMILES: [CH2:1]=O.[C:3]1([C@H:9]([N:11]2[C@@H:18]3[C@@H:14]([CH2:15][NH:16][CH2:17]3)[CH2:13][CH2:12]2)[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)=O>[CH3:1][N:16]1[CH2:17][C@@H:18]2[N:11]([C@@H:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH3:10])[CH2:12][CH2:13][C@@H:14]2[CH2:15]1
Reactant: C[C@H](c1ccccc1)N1CC[C@@H]2CNC[C@@H]21
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: C[C@H](c1ccccc1)N1CC[C@@H]2CN(C)C[C@@H]21
Temperature: 75 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
37% aqueous formaldehyde (1.6 L) was added to a solution of (3aR,6aR)-1-[(1R)-1-phenylethyl]-3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[3,2-c]pyrrole (Intermediate 39, 108 g, 0.5 mol) in HCOOH (800 mL) at r.t., then the mixture was stirred at 70-80° C. for 2 h. The mixture was then cooled to 0° C. and basified with solid NaOH to pH-13. This mixture was then extracted with CH2Cl2 (2×2 L). The combined organic solutions were concentrated in vacuo. Purification by FCC, eluting with 2:1 to 1:10 hexanes/EtOAc, gave the title compound (80 g, 70%) as red oil; 1H NMR: (CDCl3) 1.36 (3H, d), 1.65 (1H, m), 1.85 (1H, m), 2.22 (3H, m), 2.32 (3H, s), 2.54 (1H, m), 2.68 (2H, m), 2.83 (1H, m), 3.10 (1H, m), 3.40 (1H, m), 7.21-7.33 (5H, m).