Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.S([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[N:22]=[C:23]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Reactant: O=Cc1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)nc(-c1ccccc1)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
In a small pressure bottle was placed 4-(2-amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester, benzaldehyde (92 μL, 0.90 mmol), sodium hydrogensulfite (147 mg, 1.48 mmol) in DMF (5 mL). The bottle was sealed and heated at 100° C. for two hours and then stirred at 25° C. overnight for 16 hours. The reaction mixture was then concentrated in vacuo and partitioned between ethyl acetate (15 mL) and brine/water (1:1, 15 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. Flash chromatography (Biotage 40S column, 40/60 ethyl acetate/hexanes) afforded 4-(5-methyl-2-phenyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (339 mg, quantitative) as a light purple foam.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][S-:15].[Na+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][S:15][CH3:14])[CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: C[S-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(Br)cc1CSC
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A mixture of methyl 4-bromo-2-(bromomethyl)benzoate (12 g) and sodium thiomethoxide (2.5 g) in toluene was stirred at 100° C. for 2 hours. The mixture was then cooled, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (anhydrous sodium sulphate) and evaporated to afford a brown oil which was purified by column chromatography on silica gel giving methyl 4-bromo-2-(methylsulphenylmethyl)benzoate (4.1 g) as white crystals, m.p. 79.3° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22]Br.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:22][CH2:21][CH2:20][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[CH2:13]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: BrCCCc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2CC12CCCc1ccccc1C2
Reaction time: 2 h
Yield: 21.6 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-1H-inden-1-one (1.2 g, 5.71 mmol) and 1-(bromomethyl)-2-(3-bromopropyl)benzene (1.66 g, 5.71 mmol) in THF (40 mL) was added NaH (457 mg, 60%, 11.42 mmol) at room temperature. The mixture was refluxes for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was dried and concentrated to give the residue, which was purified by column chromatography to give 6′-bromo-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-inden]-1′(3′H)-one (420 mg, 22%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][CH3:33])[CH2:15][CH2:14]3)[N:10]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc(C3CCNCC3)n(-c3ncccn3)n2)cc1
Reactant: COc1ccccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of INTERMEDIATE 9 HCl salt (15.0 mg, 0.035 mmol) and triethylamine (22.9 mg, 0.23 mmol) in DMF (0.25 ml) was added (2-methoxyphenyl)acetic acid (7.8 mg, 0.045 mmol), followed by addition of HATU (17.2 mg, 0.045 mmol). After stirring at ambient temperature for 1.5 hour, the reaction mixture was quenched with 2 mL of a mixture of 1,4-dioxane and water (1:1). The mixture was purified by RP-HPLC (10 to 100% ACN/Water, both containing 0.1% TEA) to give the title compound as a white powder after lyophilization. LC-MS (m/z): 473.11 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[N:16]1[C:20](=[O:21])[C:19]2[CH2:22][CH2:23][CH2:24][CH2:25][C:18]=2[C:17]1=[O:26].[CH2:27]([NH2:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH:12]([CH3:15])[CH2:11]2)=[CH:4][C:3]=1[NH:16][C:17](=[O:26])[C:18]1[CH2:25][CH2:24][CH2:23][CH2:22][C:19]=1[C:20]([NH:33][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:21]
Reactant: CCCCCCN
Reactant: CC1CCC(Oc2cc(N3C(=O)C4=C(CCCC4)C3=O)c(F)cc2Cl)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)C1=C(C(=O)Nc2cc(OC3CCC(C)C3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
N-{2-Fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-3,4,5,6-tetrahydrophthalimide (1.26 g, 3.33 mmol), hexylamine (0.410 g, 4.05 mmol), triethylamine (0.380 g, 3.76 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-{2-fluoro-4-chloro-5-(3-methylcyclopentyl)oxyphenyl}-N'-hexyl-3,4,5,6-tetrahydrophthalamide as white crystals (1.29 g, 80.8% yield).
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:22][C:23]([O:25]C)=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.O.[OH-].[Li+]>O>[CH3:33][Si:2]([CH3:1])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][C:23]([OH:25])=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: COC(=O)CC(CC(=O)OC)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC(=O)O)CC(=O)O)c3)ncnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
Dimethyl 3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioate (43.0 g, 0.0908 mol) was dissolved in methanol (271.2 mL, 6.695 mol) and lithium hydroxide monohydrate (15 g, 0.36 mol) dissolved in water (125 mL) was added. The reaction was stirred at rt for 2 h. The methanol was removed in vacuo and a resulting aqueous layer was cooled in an ice bath. The solution was made acidic pH-4 with 1N HCl to give a white precipitate. The solid precipitate was collected, washed with water, dried to give 3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanedioic acid as a white crystalline powder (31.8 gm, 80%), LC/MS (M+H)+: 446, 1H NMR (DMSO-d6) δ 8.85s 1H), 8.75 (s, 1H), 8.42 (s, 1H), 7.85 (d, 1H), 7.17 (d, 1H), 5.71 (s, 2H), 5.18 (m, 1H), 3.65 (t, 2H), 3.05 (m, 4H), 0.92 (t, 2H), 0.1 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[N:12]=[C:13](Cl)[C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[S:17][C:15]=2[N:16]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[S:17][C:15]=2[N:16]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 4-fluorobenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27](C4C=CC(C(OC(C)(C)C)=O)=CC=4N)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[CH3:60])=[O:16])[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.O.[C:63]1([CH3:73])[CH:68]=[CH:67][C:66]([S:69]([OH:72])(=[O:71])=[O:70])=[CH:65][CH:64]=1.[C:74](#[N:76])[CH3:75]>>[C:63]1([CH3:73])[CH:64]=[CH:65][C:66]([S:69]([OH:72])(=[O:70])=[O:71])=[CH:67][CH:68]=1.[C:8]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:56])[C@@H:24]([NH:25][C:26](=[O:55])[C@H:27]([C:63]4[CH:64]=[CH:65][C:74]([NH2:76])=[CH:75][CH:68]=4)[NH:28][C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH2:37][CH3:38])[C:33](=[O:39])[C:32]4=[O:40])=[O:30])[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:57][O:58][C:59](=[O:61])[CH3:60])=[O:16])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(C(=O)OC(C)(C)C)cc2N)C(=O)C1=O
Reactant: CC#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCN1CCN(C(=O)N[C@H](C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(COC(C)=O)CS[C@H]23)c2ccc(N)cc2)C(=O)C1=O

Procedure:
In the manner described in Example 11, 3.883 g of 3-acetoxymethyl-7β-[(2S)-2-(4-BOC-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester are reacted with 1.75 g of p-toluenesulphonic acid monohydrate in 30 ml of acetonitrile and worked up. 3-Acetoxymethyl-7β-[(2S)-2-(4-aminophenyl)-2-(4-ethyl-2,3-dioxopiperazine-1-carboxamido)-acetamido]-3-cephem-4-carboxylic acid diphenylmethyl ester p-toluenesulphonate is obtained. [α]D20 =+32°±1° (0.90% in CH3OH).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[OH-].[Na+]>>[C:1]1([NH:11][C:12](=[O:14])[CH3:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC(=O)Nc1nccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1nccc2c1CCCC2
Yield: 59.1 %

Procedure:
Reaction of N-(isoquinol-1-yl)acetamide (159 mg, 0.854 mmol) using the general procedure for small scale hydrogenations (workup with NaOH in place of saturated NaHCO3) provided N-(5,6,7,8-tetrahydroisoquinolin-1-yl)acetamide (96 mg, 59%): 1H NMR δ 1.74–1.76 (m, 4H), 2.16–2.19 (m, 3H), 2.60–2.70 (m, 2H), 2.70–2.76 (m, 2H), 6.86 (d, 1H, J=5 Hz), 8.03 (d, 1H, J=5 Hz); 13C NMR δ 22.3, 22.8, 23.8, 25.1, 29.6, 122.9, 144.4 (2C), 149.5, 150.2, 170.6; MS m/z: 213 (M+Na+). N-(1,2,3,4-tetrahydroisoquinolin-1-yl)acetamide also was isolated (16 mg, 11%): 1H NMR δ 2.28 (m, 3H), 2.96–3.01 (m, 2H), 3.56–3.61 (m, 2H), 7.20 (d, 1H, J=8 Hz), 7.33–7.38 (m, 1H), 7.44–7.49 (m, 1H), 8.27 (d, 1H, J=8 Hz); 13C NMR δ 27.2, 28.7, 29.7, 39.3, 127.3, 127.5, 128.0, 132.6, 137.9, 162.8, 188.0; MS m/z: 191 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24](O)=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2].[N:35]1(C(N2C=CN=C2)=O)C=CN=[CH:36]1.CN>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]([NH:35][CH3:36])=[O:25])=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)O)ccn34)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(C(=O)NC)ccn34)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To 3-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-ylcarbamoyl) imidazo[1,2-a]pyridine-7-carboxylic acid (26 mg, 0.057 mmol; prepared as in Example 28, step A) in DMF (2 mL) was added di(1H-imidazol-1-yl)methanone (14 mg, 0.086 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. Methanamine (286 μL, 0.57 mmol) was added to the reaction mixture. The reaction vial was sealed and the mixture was heated at 70° C. for 2 hours. The mixture was cooled to ambient temperature. The DMF was removed under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH 10:1) to provide the final product (13 mg). MS (ES+APCI) m/z=468 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:13]([O:15][CH3:16])=[O:14])=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=1)[CH2:2][CH3:3].[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:12][O:11][C:9]([C:7]1[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Br:17])=[CH:19][CH:20]=2)[C:6]=1[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: CCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(Br)cc1
Yield: 88.3 %

Procedure:
A solution of 40.0 g (0.177 mole) of 2-propyl-4,5-bis(methoxycarbonyl)-imidazole and 44.6 g (0.178 mole) of 4-bromobenzyl bromide in 350 mL of DMF was stirred in the presence of 37.5 g (0.271 mole) of K2CO3 overnight at room temperature. The reaction mixture was then poured into 1200 mL of water and extracted with 3×300 mL of ether. The combined ether extracts were washed with 8×1000 mL of water and once with brine, then dried over MgSO4. The solvent was removed under reduced pressure to yield 61.8 g (88%) of the title compound as a solid. 1H NMR (300 MHz, CDCl3): δ 0.94 (t, J=7.6 Hz, 3H); 1.73 (m, 2H); 2.63 (t, J=7.9 Hz, 2H); 3.81 (s, 3H); 3.93 (s, 3H); 5.37 (s, 2H); 6.86 (d, J=8.8 Hz, 2H); 7.45 (d, J=8.8 Hz, 2H). MS [DCI (NH3)]: m/z 395/397 (M+H, 1 Br).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: NCCCOc1ccc(F)cc1
Reactant: CCOC(=O)C(CC)Oc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C(CC)Oc1cccc(CNCCCOc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(3-formylphenoxy)butyrate (5.0 g, 21.2 mmol) was dissolved in 1,2-dichloroethane (20 mL). Subsequently, 3-(4-fluorophenoxy)propylamine (4.65 g, 27.5 mmol) was added thereto, and the resultant mixture was stirred for 20 minutes. Subsequently, sodium triacetoxyborohydride (95%, 7.1 g, 31.8 mmol) and small amount of acetic acid were added thereto, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The reaction mixture was extracted with chloroform, and the organic layer was washed with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (6.7 g, 81%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:40][C:41]([NH2:43])=[O:42]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:17](=[O:32])[N:18]([CH2:40][C:41]([NH2:43])=[O:42])[N:19]=[C:20]4[CH2:21][C@@H:22]4[CH2:26][CH2:25][N:24]([C:27]([CH:29]5[CH2:30][CH2:31]5)=[O:28])[CH2:23]4)=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Reactant: NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.117 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (50 mg, 0.362 mmol, 3.1 eq) and 2-chloroacetamide (16 mg, 0.175 mmol, 1.5 eq). The vial was capped and purged with nitrogen gas, and the reaction mixture was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had gone to completion. The reaction mixture was cooled to room temperature and poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 20-50% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (25 mg, 44%). MS(ES)+ m/e 486.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2nccc(Oc3ccccc3OC)c2cc1OC
Temperature: 150 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (102 mg) and commercially available 2-methoxyphenol (0.5 ml) were mixed and stirred at 150° C. for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting first with hexane/ethyl acetate and then with chloroform/methanol to obtain 76 mg of the title compound (yield: 54%).
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[C:8](O)=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:14])=O>>[CH2:1]([O:6][CH:7]([CH3:11])[C:8]([Cl:14])=[O:9])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCOC(C)C(=O)O
Product: CCCCCOC(C)C(=O)Cl

Procedure:
10 ml of thionyl chloride was added to 2.0 g of α-pentyloxypropionic acid and the mixture was refluxed under heat for 2 hours. Excess of thionyl chloride was distilled off to obtain α-pentyloxypropionic acid chloride. 20 ml of dry pyridine was added thereto, and 7.0 g of 5-decyl-2-(4-hydroxyphenyl)pyrimidine dissolved in 50 ml of dry benzene was further added dropwise. After the addition, the mixture was refluxed under heat, charged into ice water and extracted with benzene. The extract was purified with a silica gel column chromatography to obtain 5-decyl-2-(4'-α-pentyloxypropanoyloxyphenyl)pyrimidine.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([Cl:25])=[CH:20][CH:21]=2)[N:16]=1.C(#N)C>O>[Cl:25][C:19]1[N:18]=[C:17]2[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=3)=[N:16]2)=[CH:21][CH:20]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Yield: 77.9 %

Procedure:
The procedure is analogous to that described in Example 1, but starting with 4-trifluoromethylbenzoic acid (10 g), N,N'-carbonyldiimidazole (8.4 g) and 2-amino-7-chloro-1,8-naphthyridine (5.9 g). The product obtained by precipitation in water (11.5 g; m.p. 236° C.) is dissolved in boiling acetonitrile (250 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (2×20 cc) and dried at 45° C. under reduced pressure (0.07 kPa). N-(7-Chloro-1,8-naphthyridin-2-yl)-4-trifluoromethylbenzamide (9 g), m.p. 236° C., is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][Si](C(C)(C)C)(C)C)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:23])([F:22])[F:21])=[N:7]2.Cl.O>CO>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:20]([F:21])([F:22])[F:23])=[N:7]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Agent: Cl
Solvent: CO
Solvent: O
Product: Oc1ccc(Br)c2ccc(C(F)(F)F)nc12
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of 5-bromo-8-(tert-butyldimethylsilanyloxy)-2-trifluoromethylquinoline (21 g) in methanol (150 ml) was treated with 37% hydrochloric acid solution (5 ml) and water (5 ml). The mixture was stirred for 12 h at room temperature and at 45° C. for 2 h. The methanol was removed in vacuo and the residue partitioned between 10% sodium hydroxide solution (100 ml) and dichloromethane (50 ml). The aqueous layer was neutralised with 37% hydrochloric acid solution to pH7.2 and extracted with dichloromethane (4×50 ml). The combined organic extracts were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give the product (12 g) as a cream solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC=CC=1>CN(C)C=O>[CH3:20][NH:21][C:22]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:23]
Reactant: CNC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
Sodium hydride (430 mg, 10.75 mmol) was suspended in N,N-dimethylformamide (25 ml) under nitrogen atmosphere, and 4-(1H-5-indolyloxy)-2-pyridinamine (2.253 g, 10.00 mmol, CAS No. 417722-11-3) described in WO 02/32872 was gradually added while stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice water bath, and then phenyl N-methylcarbamate (1.587 g, 10.50 mmol) was added. The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and was dried over anhydrous sodium sulfate. The solvent was removed by distilled off. The crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (2.163 g, 7.66 mmol, 76.6%) as pale brown crystals.