Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Cl:21][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 5.00 g (19.8 mmol) of (4′-trifluoromethylbiphenyl-4-yl)methanol in 40 ml of chloroform is mixed with 2.89 ml (39.7 mmol) of thionyl chloride dissolved in 10 ml of chloroform, and the mixture is stirred at room temperature over 12 hours. After reaction is complete, the reaction mixture is concentrated to dryness, and the residue is taken up ethyl acetate and washed with saturated sodium carbonate solution. The organic phase is subsequently separated off, dried over sodium sulfate and concentrated after filtration. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 9:1). 5.26 g (19.4 mmol, 98% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7](O)=[O:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:57]1([CH2:60][N:61]2[C:69]3[N:68]=[C:67]([CH2:70][C:71]4[CH:76]=[CH:75][C:74]([NH:77][CH3:78])=[CH:73][CH:72]=4)[NH:66][C:65]=3[C:64](=[O:79])[N:63]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:62]2=[O:88])[CH2:59][CH2:58]1>ClCCl>[CH:57]1([CH2:60][N:61]2[C:69]3[N:68]=[C:67]([CH2:70][C:71]4[CH:72]=[CH:73][C:74]([N:77]([CH3:78])[C:7]([C:6]5[S:5][C:4]([NH:10][C:11]([C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=6)([C:12]6[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=6)[C:18]6[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=6)=[N:3][C:2]=5[CH3:1])=[O:8])=[CH:75][CH:76]=4)[NH:66][C:65]=3[C:64](=[O:79])[N:63]([CH2:80][C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][C:82]=3[F:87])[C:62]2=[O:88])[CH2:59][CH2:58]1
Reactant: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)O
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)sc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
A mixture of 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid (46 mg, 0.11 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with triphenylphosphine (36 mg, 0.14 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (18 mg, 0.14 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (100 mg, 0.23 mmol) and dichloromethane (2.5 mL). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was treated with another portion of triphenylphosphine (36 mg, 0.14 mmol) and N-chlorosuccinimide (18 mg, 0.14 mmol). The reaction was stirred at 25° C. for 1 h. At this time, the reaction was diluted with dichloromethane (100 mL) and then washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80:20 ethyl acetate/petroleum ether) afforded 4-methyl-2-(trityl-amino)-thiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (75.1 mg, 80.0%). The product was used without further purification or characterization.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])=[N:4][CH:5]=[C:6]([F:18])[C:7]=1[NH:8]CC1C=CC(OC)=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:8][C:7]1[C:6]([F:18])=[CH:5][N:4]=[C:3]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])[C:2]=1[F:1]
Reactant: CCCS(=O)(=O)Nc1ncc(F)c(NCc2ccc(OC)cc2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCS(=O)(=O)Nc1ncc(F)c(N)c1F

Procedure:
A solution of N-(3,5-Difluoro-4-(4-methoxybenzylamino)pyridin-2-yl)propane-1-sulfonamide (1.05 g) in DCM (50 ml) and TFA (20 ml) was stirred at rt for 16 h. The mixture was concentrated. The residue was taken up in aqueous sodium bicarbonate solution, and the mixture was extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (10-50% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z: 251.9 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:40]=[CH:39][C:18]3[N:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]([O:37]C)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Li+].[OH-]>CO.O>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[CH:40]=[CH:39][C:18]3[N:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[C:30]([C:35]([OH:37])=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=5)=[CH:25][CH:24]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: COC(=O)c1ncccc1-c1ccc(Cn2cnc3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1cccc([C@H](C)NC(=O)c2ccc3c(c2)ncn3Cc2ccc(-c3cccnc3C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 3-(4-((5-(1-(3-isopropylphenyl)ethylcarbamoyl)-1H-benzo[d]imidazol-1-yl)methyl)phenyl)picolinate (30 mg, 0.056 mmol) in methanol (5 mL) and water (1 mL) was added LiOH (11 mg, 0.28 mmol), then the mixture was stirred at RT for 2 hrs. The methanol was removed under the reduced pressure. The residue in water was adjusted to pH=7 with 3N HCl, 1.5 then the mixture was concentrated. The residue was purified with prep-TLC (DCM/Methanol=10/1, silica gel) to get the titled compound.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]([C:29](=[O:41])[NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][CH:34]=2)([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][CH2:31][NH:30][C:29]([C:18]2([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[O:41])=[CH:34][CH:35]=1)[CH3:40]
Reactant: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(CCNC(=O)C2(Cc3ccccc3F)CCNCC2)cc1
Yield: 79.7 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution 4-[2-(4-ethyl-phenyl)-ethylcarbamoyl]-4-(2-fluoro-benzyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 0.64 mmol) in dichloromethane (50 mL). After 1 h the reaction mixture was concentrated under reduced pressure, the crude product taken up in 1M sodium hydroxide (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected, concentrated under reduced pressure and crude product purified by column chromatography to give 0.188 g (80 %) of 4-(2-fluoro-benzyl)-piperidine-4-carboxylic acid [2-(4-ethyl-phenyl)-ethyl]-amide LRMS m/z 369.1 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1)[C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:43][C:42]2[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=2)[CH:36]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: Cl
Product: COc1ccc(N(Cc2cnn(Cc3ccc(C(F)(F)F)cc3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-[(pyrazol-4-yl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.936 g) and 4-(trifluoromethyl)benzyl chloride (0.592 mL) as starting materials, 5-benzyloxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.25 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, 5-hydroxy-N-(6-methoxypyridin-3-yl)-N-{[1-(4-trifluoromethylbenzyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.53 g) was obtained. melting point: 199-200° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.ClC(OC(Cl)C)=O>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@H:9]([CH:14]2[CH2:15][NH:16][CH2:17]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(F)[C@H](c1cc(F)cc(F)c1)C1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sample of 2.25 g (5.5 mmol) of 3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]-1-(diphenylmethyl)azetidine(Step 2 of Preparation 14) was dissolved in 15 mL of THF and 1.1 mL (10 mmole) of 1-chloroethyl chloroformate was added. The solution was stirred at room temperature. After 2 h, the solution was concentrated under reduced pressure and the residue was dried under high vacuum for 1 h. The residue was dissolved in 20 mL of CH3OH and heated to reflux for 6 h. The solution was concentrated and the residue was partitioned between 100 mL ether and 50 mL of 1:1 saturated Na2CO3 solution-1M NaOH. The aqueous layer was washed with 3 portions of 100 mL ether, and the combined organic extracts were washed with NaHCO3, then brine, then concentrated. The oily residue was applied to a silica gel column packed in 20% ethyl acetate-hexane and the column was washed with 5 column volumes of 20% ethyl acetate-hexane, then with CH2Cl2, with 10% CH3OH in CH2Cl2 and finally with 80:20:2 CH2Cl2—CH3OH-ammonium hydroxide. Homogenous fractions were concentrated to afford the title compound, which was not further purified but was used directly in the next step; Mass Spectrum: m/e=244 (M+1).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:26]=[CH:25][C:9]2[N:10]([CH2:13][C:14]3[CH:24]=[CH:23][C:17]4[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=4[CH:15]=3)[CH:11]=[N:12][C:8]=2[CH:7]=1.[C:27]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH3:27][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:26]=[CH:25][C:9]3[N:10]([CH2:13][C:14]4[CH:24]=[CH:23][C:17]5[N:18]=[C:19]([S:21][CH3:22])[S:20][C:16]=5[CH:15]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: CSc1nc2ccc(Cn3cnc4cc(-c5nn[nH]n5)ccc43)cc2s1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Cn3cnc4cc(-c5nnn(C)n5)ccc43)cc2s1
Temperature: 60 °C
Reaction time: 4 h
Yield: 38.5 %

Procedure:
To a stirred mixture of 6-((5-(2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (796 mg, 2.1 mmol), Cs2CO3 (673 mg, 2.1 mmol), and DMF (10 mL) was added iodomethane (129 μL, 2.1 mmol). The mixture was heated at 60° C. for 6 h. Additional iodomethane (30 μL, 0.5 mmol) was added and the mixture was stirred at 60° C. for an additional 4 h. The mixture was cooled to rt and partitioned between EtOAc (200 mL) and 0.5 M aq Na2CO3 (100 mL). The organic layer was separated and washed with brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography, eluting with 2% MeOH in CH2Cl2, to afford 6-((5-(2-methyl-2H-tetrazol-5-yl)-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (318 mg, 39%) as a white solid. The regiochemistry of the alkylation was determined by 2-dimensional nuclear Overhauser effect (NOE) experiment. 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.93 (dd, J=1.0, 8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.46 (dd, J=1.2, 8.4 Hz, 1H), 5.66 (s, 2H), 4.41 (s, 3H), 2.76 (s, 3H); LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH3:17])[CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][CH:2]1[CH:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5][N:4]([CH2:14][CH2:15][NH:16][CH3:17])[CH2:3]1
Reactant: CCOC(=O)CC1CCN(CCN(C)C(=O)OC(C)(C)C)CC1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1CCN(CCNC)CC1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of ethyl 3-fluoro-1-[2-(N-tert-butoxycarbonyl-N-methylamino)ethyl]4-piperidinylacetate (236 mg, 0.68 mmol) in CH2Cl2 (10 mL) was added TFA (5 mL) at 0° C. After being stirred at room temperature for 4 hr, the reaction mixture was concentrated. The residue was taken up with sat. NaHCO3 solution and extracted with CHCl3. The extracts were dried over MgSO4 and concentrated to afford ethyl 3-fluoro-1-[2-(N-methylamino)ethyl]4-piperidinylacetate (117 mg, 70%) as a reddish oil. 1H-NMR (CDCl3)δ 1.26 (t, J=7.1 Hz, 3H), 1.58 (m, 1H), 1.70 (m, 1H), 1.99 (m, 1H), 2.14 (m, 1H), 2.27–2.33 (m, 1H), 2.47 (s, 3H), 2.48–2.56 (m, 4H), 2.72 (t, J=6.3 Hz, 2H), 2.90 (m, 1H), 3.16 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 4.67 (d, J=48.3 Hz, 1H); ESI-MS m/z 247 (M++1)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([OH:16])=O.C(Cl)(=O)C([Cl:20])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][C:14]([Cl:20])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.5 %

Procedure:
To a solution of 137g (20.0 g, 91 mmol) in DCM (250 mL) were added oxalyl chloride (13.8 g, 109 mmol) and DMF (0.1 mL). See FIG. 2. The mixture was stirred at RT for 4 h. Upon reaction completion, the mixture was concentrated to give 3-(1,3-dioxoisoindolin-2-yl)propanoyl chloride 137h (20.0 g, 92%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13](Cl)=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH3:33])[CH2:28]2)[C:20]=1[C:21]#[N:22]>>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([C:13]([NH:18][C:19]3[CH:26]=[CH:25][CH:24]=[C:23]([N:27]4[CH2:32][CH2:31][O:30][CH:29]([CH3:33])[CH2:28]4)[C:20]=3[C:21]#[N:22])=[O:14])=[N:11][N:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nnnc2C(=O)Cl)cc1
Reactant: CC1CN(c2cccc(N)c2C#N)CCO1
Product: COc1ccc(Cn2nnnc2C(=O)Nc2cccc(N3CCOC(C)C3)c2C#N)cc1

Procedure:
In a manner similar to Example I, 1-(4-methoxybenzyl)-1H-tetrazole-5-carbonyl chloride is condensed with 2-amino-6-(2-methyl-4-morpholinyl)benzonitrile to give 1-(4-methoxybenzyl)-N-[2-cyano-3-(2-methyl-4-morpholinyl)phenyl]-1H-tetrazole-5-carboxamide.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:29]=[CH:28][C:19]4[C:20]([C:24]([O:26]C)=[O:25])=[C:21]([CH3:23])[O:22][C:18]=4[CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[CH3:23][C:21]1[O:22][C:18]2[CH:17]=[C:16]([O:15][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)=[CH:6][CH:7]=4)[N:12]=[CH:11][CH:10]=3)[CH:29]=[CH:28][C:19]=2[C:20]=1[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(OCCBr)ccc34)ccc12
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: Cc1oc2cc(Oc3ccnc4cc(OCCN5CCCC5)ccc34)ccc2c1C(=O)O
Yield: 14.1 %

Procedure:
To a solution of methyl 6-[(7-hydroxyquinolin-4-yl)oxy]-2-methyl-1-benzofuran-3-carboxylate 121-D (2.4 g, 7.2 mmol) in DMF (20 ml) was added K2CO3 (5 g, 35.8 mmol) and dibromoethane (2.7 g, 14.3 mmol). The reaction mixture was stirred at room temperature overnight. Column chromatography gave methyl 6-{[7-(2-bromoethoxy)quinolin-4-yl]oxy}-2-methyl-1-benzofuran-3-carboxylate 121-E (1.5 g). A solution of compound 121-E (750 mg) and pyrrolidine (351 mg) in DMF (3 ml) was heated to 60° C. for 45 min. The reaction mixture was extracted with EtOAc. Methyl 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxylate 121-F (110 mg) was purified by silica gel chromatography using 5-10% MeOH/CH2Cl2. Compound 121-F (110 mg) was treated with 20% NaOH (1 ml) in MeOH (1 ml) overnight. The reaction mixture was acidified with AcOH and extracted with EtOAc. The residue was purified by silica gel chromatography using 0-10% MeOH in CH2Cl2 to give 2-methyl-6-{[7-(2-pyrrolidin-1-ylethoxy)quinolin-4-yl]oxy}-1-benzofuran-3-carboxylic acid 121-G (100 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([O:13]C)=O.C(O)C.O.[NH2:19][NH2:20]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:19][NH2:20])=[O:13]
Reactant: COC(=O)c1ccc2ccccc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2ccccc2c1
Yield: 88 %

Procedure:
First, 5.0 g of methyl 2-naphthoate and 20 mL of ethanol were put in a four-neck flask, and stirred. Then, 5 mL of hydrazine monohydrate (NH2NH2.H2O) was added to this mixture, and heated and stirred at 80° C. for 5 hours to be reacted. After the reaction, the solution was added to 100 mL of water, whereby a solid was precipitated. The resulting suspension was subjected to suction filtration to give a solid. This solid was recrystallized from a mixed solvent of chloroform and hexane, so that 4.4 g of 2-naphthohydrazide was prepared as a white solid with a yield of 88%. The synthetic scheme of Step 1 is shown by (a-12).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:27])=[O:26])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](OC)=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:24][S:25]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[CH:35][CH:34]=[CH:33]2)(=[O:26])=[O:27])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:20])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2cccc3cccnc23)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
65 mg (0.12 mmol) of (2S)-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-2-(quinoline-8-sulfonylamino)-propionic acid tert-butyl ester was dissolved in 1 ml of dimethylformamide and 59 mg (0.6 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 72 mg. MS (ES+): m/e=609.3 (M+H+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[C:25]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[NH:26][C:27]3=[O:30])=[CH:22][CH:21]=2)[C:16]1=[O:41].[Cl-].[NH4+]>ClCCl>[O:41]=[C:16]1[CH:15]([CH2:14][O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18][N:17]1[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1C(CO)CCN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
Methanesulfonyl chloride (0.023 ml, 0.299 mmol) and triethylamine (0.03 ml, 0.299 mmol) were added at −20° C. to a dichloromethane solution (2 ml) that contained the 7-(3-hydroxymethyl-2-oxopyrrolidin-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (80 mg, 199 mmol) obtained in Example 1-46. The obtained mixture was stirred at −20° C. for 2 hours. Thereafter, a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1->20:1), so as to obtain methanesulfonic acid 2-oxo-1-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-pyrrolidin-3-ylmethyl ester (38 mg, 40%) in the form of a colorless oil substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:27][O:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([N:29]3[C@H:28]([CH2:30][O:31][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:27][O:26][C:25]3=[O:24])=[CH:17][C:16]=2[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3COC(=O)c3ccccc3)cc2F)CC1
Yield: 49.9 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester (3.49 g) described in Preparation Example 154 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.99 g), the title compound (2.37 g) was obtained.