Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[NH:12][C:13]3[C:18]([C:19]=2[CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Br:23][C:24]1[CH:33]=[CH:32][C:27]([CH:28]=[CH:29][CH2:30]Br)=[CH:26][CH:25]=1>CN(C)C=O.C(Cl)Cl>[Br:23][C:24]1[CH:33]=[CH:32][C:27]([CH:28]=[CH:29][CH2:30][NH:22][CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2[nH]c3ccccc3c2CCN)cc1OC
Reactant: BrCC=Cc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(-c2[nH]c3ccccc3c2CCNCC=Cc2ccc(Br)cc2)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[2-(3,4-dimethoxyphenyl)-1H-indol-3-yl]ethylamine (261 mg in a mixture of 3 mL N,N-dimethylformamide and 8 mL methylene chloride) at 0° C. was added a solution of 81 mg of 4-bromocinnamyl bromide in 2 mL methylene chloride and the mixture allowed to warm to room temperature. After 27 hours the reaction was quenched by the addition of water followed by extraction with ethyl acetate. The organic portion was dried over over sodium sulfate and purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (93 mg). m/e=491 (M)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.[F:24][C:25]1[N:30]=[C:29](F)[CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([S:20]([NH:23][C:27]2[CH:28]=[CH:29][N:30]=[C:25]([F:24])[N:26]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: Fc1ccnc(F)n1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(N)(=O)=O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccnc(F)n2)cc1F
Yield: 44.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 16d by using 3-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}benzenesulfonamide (0.10 g, 0.29 mmol) prepared in Example 16c, 2,4-difluoropyrimidine (0.10 g, 0.88 mmol), potassium carbonate (0.16 g, 1.18 mmol) and DMF (3.0 mL), to yield the title compound (56 mg, 63%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:37][CH2:38][CH:39]1[CH2:41][CH2:40]1>CC(O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[O:37][CH2:38][CH:39]1[CH2:41][CH2:40]1
Reactant: OCC1CC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: COc1nc(OCC2CC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
A 5-mL vial was sequentially charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.642 mmol), cesium carbonate (154 μl, 1.926 mmol), dimethyl sulfoxide (2.1 mL), and (hydroxymethyl)cyclopropane (130 μL, 1.605 mmol). The vial was sealed with a PTFE lined cap and heated to 90° C. After 16 h, the brown reaction mixture was allowed to cool to RT, then diluted with IPA (3 mL) and filtered through a pad of celite. The pad was rinsed with IPA (2×5 mL) and the filtrate was concentrated under reduced pressure to furnish a brown oil, which was dissolved in DMSO (2 mL) filtered through a 0.2 micron filter and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-(5-chloro-6-(cyclopropylmethoxy)-2-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (180 mg, 0.358 mmol, 55.7% yield) as a tan amorphous solid. 1H NMR (500 MHz, DMSO-d6) δ=11.65 (br. s., 1H) 8.72 (s, 1 H) 8.36 (s, 1 H) 8.21 (d, J=9.67 Hz, 1 H) 8.04 (s, 1 H) 7.85 (dd, J=8.95, 1.75 Hz, 1 H) 7.00 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.67 Hz, 1 H) 6.45 (d, J=1.10 Hz, 1 H) 4.23-4.40 (m, 2 H) 3.78 (s, 3 H) 1.30-1.43 (m, 1 H) 0.62 (d, J=7.66 Hz, 2 H) 0.41 (br. s., 2 H). m/z (ESI) 503.3 (M+H)+.
Reaction SMILES: [OH:1][Ge:2][OH:3].[CH:4]1[CH:5]=[CH:6][C:7]2[C:8](=[C:10]3[N:42]=[C:41]4[N:43]=[C:34]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=54)[N:33]=[C:31]4[NH:32][C:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=54)=[N:23][C:21]4=[N:22][C:14]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=54)=[N:13][C:12]=2[NH:11]3)[CH:9]=1.[C:44]1([CH:50]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][SiH2:67]O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCOCC1>[C:48]1([CH:41]([C:40]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][O:66][SiH2:67][O:1][Ge:2][O:3][SiH2:67][O:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH:50]([C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:49]=1.[CH:5]1[CH:4]=[CH:9][C:8]2[C:7](=[C:12]3[N:13]=[C:14]4[N:22]=[C:21]([C:20]5[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=54)[N:23]=[C:24]4[NH:32][C:31]([C:30]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=54)=[N:33][C:34]4=[N:43][C:41]([C:40]5[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=54)=[N:42][C:10]=2[NH:11]3)[CH:6]=1
Reactant: O[Ge]O
Reactant: O[SiH2]OCCCCCCCCCCCCCCCC(c1ccccc1)c1ccccc1
Agent: c1ccc2c(c1)-c1nc-2nc2[nH]c(nc3nc(nc4[nH]c(n1)c1ccccc41)-c1ccccc1-3)c1ccccc21
Solvent: C1COCCO1
Product: c1ccc(C(CCCCCCCCCCCCCCCO[SiH2]O[Ge]O[SiH2]OCCCCCCCCCCCCCCCC(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
Variant b: 2 g (3.24 mmol) of dihydroxygermanium-phthalocyanine are boiled at reflux with 2 equivalents of diphenylhexadecyloxysilanol in 210 ml of dioxane for 39 hours. After 24 hours, 500 mg of dihydroxygermanium-phthalocyanine are added. The reaction mixture is allowed to cool and the residue is chromatographed on basic aluminium oxide (Alox B) using pure hexane and hexane/ethyl acetate (4:1) in succession as eluants. The product-containing fractions are combined and concentrated. The residue is recrystallised from pentane at -20° C., yielding blue crystals of bis(diphenylhexadecyloxy-siloxy)-germanium-phthalocyanine.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[Na]>C(O)C>[CH2:11]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCBr
Reactant: NC(=O)c1ccccc1O
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCOc1ccccc1C(N)=O
Reaction time: 2.25 h

Procedure:
Salicylamide (27.4 g.) and decyl bromide (48.3 ml.) were added to a solution of sodium (4.6 g.) in ethanol (175 ml.) and the mixture was heated to reflux with stirring for 2.25 hours. Most of the ethanol was removed by evaporation in vacuo and the residue was poured into water (350 ml.). The oil which separated solidified, and was filtered off and triturated with 2N sodium hydroxide (150 ml.). The solid was filtered off, washed with water (100 ml.), dried over phosphoric oxide, and recrystallised from light petroleum (b.p. 40°-60° C.) to give 2-decyloxybenzamide (40.5 g.), m.p. 58°-59° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](O)[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]1(=[O:43])[NH:37][C:36](=[O:38])[C:35]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:37]2[C:36](=[O:38])[C:35]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:34]3[C:33]2=[O:43])[CH2:10][C@H:9]1[CH2:14][O:15][Si:16]([C:29]([CH3:30])([CH3:32])[CH3:31])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](N2C(=O)c3ccccc3C2=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a stirred solution of cis-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-hydroxypyrrolidine (1.82 mg, 4.0 mmol), phthalimide (647 mg, 4.4 mmol), and Ph3P (1.26 g, 4.8 mmol) in THF (20 ml) was added DIAD (889 mg, 4.4 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (5/1, v/v) as eluent to give N-[cis-1tert-butoxycarbonyl-(2S)-(tert-butyldiphenylsilyloxy)methyl-4-pyrrolidinyl]phthalimide (1.6 g, 69%) as an amorphous solid. 1H-NMR (CDCl3) δ 1.07 (s, 9H), 1.30 and 1.44 (each s, total 9H), 2.27–2.37 (m, 1H), 2.94–2.96 (m, 1H), 3.81–4.09 (m, 51H), 4.72 (m, 1H), 7.37–7.38 (m, 6H), 7.67–7.74 (m, 6H), 7.84–7.86 (m, 2H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].[CH2:9]1[CH2:15][S:12](=[O:14])(=[O:13])[O:11][CH2:10]1>C1COCC1>[OH:8][CH2:7][C@@H:2]([NH:1][CH2:10][CH2:9][CH2:15][S:12]([OH:14])(=[O:13])=[O:11])[CH:3]([CH3:4])[CH2:5][CH3:6]
Reactant: O=S1(=O)CCCO1
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: C1CCOC1
Product: CCC(C)[C@@H](CO)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of L-(+)-isoleucinol (2.0 g, 17.1 mmol) in THF (30 mL) was slowly added 1,3-propanesultone (1.94 g, 16.3 mmol). The solution was stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 70% water/EtOH (240 mL). Dowex Marathon C ion exchange resin (strongly acidic, 15 g) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (60 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (1.70 g, 44%). 1H NMR (D2O, 500 MHz) δ ppm 3.78 (d, 1H, J=13.1 Hz), 3.64 (m, 1H), 3.14 (m, 3H), 2.03 (m, 2H), 1.75 (m, 1H), 1.32 (m, 1H), 1.17 (m, 1H), 0.79 (m, 6H). 13C (D2O, 125 MHz) δ ppm 63.42, 57.38, 48.27, 44.77, 33.64, 25.91, 21.52, 13.31, 10.94. [α]D=+20.4° (c=0.00212 in water), ES-MS 240 (M+1).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1[NH:14][N:13]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O>[CH2:3]([C:10]1[NH:14][N:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCc1cc(C(=O)OCC)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCc1cc(C(=O)O)n[nH]1
Yield: 75.2 %

Procedure:
Into 81 ml of a 5% methanolic solution of sodium hydroxide, 20.0 g (0.084 mol) of ethyl 5-n-heptylpyrazole-3-carboxylate obtained in Example 1 was dissolved, and the solution was heated for 5 hours under a reflux condenser. After cooling the reaction mixture water was added, then methanol was distilled off under a reduced pressure, and the residue was acidified (pH of about 2) with concentrated hydrochloric acid. The deposited white precipitate was collected by filtration and recrystallized from a mixture of distilled water and methanol to obtain the object, 5-n-heptylpyrazole-3-carboxylic acid, as colourless needle-like crystals melting at 169°-171° C. in an amount of 13.3 g corresponding to the yield of 75.2%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1)([O-])=O>C(OC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][CH:33]=1)[CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:30])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(OCc2cccc([N+](=O)[O-])c2)c1)c1ccccc1C
Agent: [Pd]
Solvent: COC(C)=O
Product: COC(=O)CCC(C(=O)c1cccc(OCc2cccc(N)c2)c1)c1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.1 %

Procedure:
A solution of methyl (RS)-5-[3-(3-nitro-benzyloxy)phenyl]-5-oxo-4-(2-methylphenyl)pentanoate (1.2 g) in methyl acetate (30 mL) is treated with palladium on carbon catalyst (5%; 200 mg) and shaken under hydrogen at atmospheric pressure and room temperature for 3 hours. The mixture is filtered and evaporated giving methyl (RS)-5-[3-(3-aminobenzyloxy)- phenyl]-5-oxo-4-(2-methylphenyl)pentanoate (1.3 g) in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>COCCOC>[CH3:8][S:7][C:4]1[N:3]=[C:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])[S:6][N:5]=1
Reactant: CSc1nsc(Cl)n1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1nsc(-c2ccccc2F)n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To 4 ml of 1,2-dimethoxyethane were added 284 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole, 262 mg of 2-fluorophenylboronic acid, 98 mg of tetrakistriphenylphosphine palladium and 4 ml of a 2 M aqueous sodium carbonate solution, and the mixture was stirred at 80° C. for 12 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into an aqueous saturated sodium chloride solution, and the mixture was extracted with t-butyl methyl ether. The residue obtained by concentration of the organic layer was subjected to silica gel column chromatography to obtain 330 mg of 3-methylthio-5-(2-fluorophenyl)-1,2,4-thiadiazole.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:19]([OH:21])=[O:20])=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][CH:4]=1.[IH:22]>>[IH:22].[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:19]([OH:21])=[O:20])=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)cc(-c3ccccc3)nc2c1
Agent: I
Product: O=C(O)c1cc(-c2ccccc2)nc2cc(O)ccc12
Reaction time: 5 h

Procedure:
1.5 g (5.4 mmol) of 7-methoxy-2-phenylquinoline-4-carboxylic acid were added portionwise to 50 ml of 57% aqueous HI. The reaction mixture was refluxed and vigourously stirred for 5 hours; then it was evaporated in-vacuo to dryness to yield 2.1 g of the title compound.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH3+:14])=[CH:8][CH:7]=1)=[O:5].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[CH2:19]([O:18][C:16]([NH:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]([O:3][CH3:2])=[O:5])=[CH:7][CH:8]=1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(CC[NH3+])cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
2-(4-(Methoxycarbonyl)phenyl)ethanaminium chloride (3 g, 13.9 mmol) was dissolved in the mixed solution of tetrahydrofuran (30 mL) and water (30 mL), and then benzyl chloroformate (2.37 g, 13.9 mmol) was dropped into it. To the mixture, sodium bicarbonate (2.9 g, 34.7 mmol) was added and the mixture was stirred at room temperature for 1.5 h. Then the mixture was poured into ethyl acetate (50 mL×3) and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate and condensed to get methyl 4-(2-(benzyloxycarbonylamino)ethyl)benzoate (3.3 g, yield 77%). LC-MS (ESI) m/z: 314 (M+1)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1)(O)=O>>[O:2]1[CH2:1][CH2:3][N:4]=[C:5]1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:13]=1
Reactant: O=C(O)CCCCc1cn(-c2cccnc2)c2ccccc12
Reactant: NCCO
Product: c1cncc(-n2cc(CCCCC3=NCCO3)c3ccccc32)c1

Procedure:
A solution of 6.1 g of ethanolamine and 2.94 g of 3-(4-carboxybutyl)-N-(3-pyridyl)indole are heated at 170° for 3 hours. Excess ethanolamine is removed by distillation under reduced pressure to yield 3-[4-(4,5-dihydrooxazol-2-yl)butyl]-N-(3-pyridyl)indole.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:67])[C:58]2[CH:63]=[C:62]([O:64][CH3:65])[CH:61]=[CH:60][C:59]=2[Br:66])[CH2:53][CH2:52]1)=[O:50].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[Br:66][C:59]1[CH:60]=[CH:61][C:62]([O:64][CH3:65])=[CH:63][C:58]=1[C:57]([N:54]1[CH2:53][CH2:52][N:51]([C:49](=[O:50])[CH2:48][NH:47][C:21](=[O:23])[C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:25][CH:24]=2)[CH2:56][CH2:55]1)=[O:67]
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Reactant: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CN)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(C(=O)N2CCN(C(=O)CNC(=O)c3ccc(Nc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
DIPEA (133 mg, 0.18 mL, 1.0 mmol) was added drop wise to 4-(-phenyl-amino)-benzoic acid (75 mg, 0.35 mmol) in DMF (5 mL). EDCI (167 mg, 0.87 mmol) and HOBT (56 mg, 0.42 mmol) were added consecutively and, after 10 minutes, 2-amino-1-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-ethanone in its TFA salt form (164 mg, 0.42 mmol) was added. The resulting mixture was stirred at room temperature overnight. Cold water was then added and filtered the solid to afford 130 mg (67% yield) of N-{2-[4-(2-bromo-5-methoxy-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenylamino-benzamide. LC-MS purity: 96.77%. 1H-NMR (DMSO-d6): δ 8.6 (s, 1H), 8.3 (t, 1H), 7.8 (d, 2H), 7.6 (d, 1H), 7.3 (d, 2H), 7.1 (d, 2H), 7.0 (m, 3H) 4.2 (dd, 2H), 3.8 (s, 3H), 3.6 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH:5]2O.O.[NH2:14]N>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][N:14]=[CH:5]2
Reactant: NN
Reactant: O=C1NC(O)c2cc(Br)ccc21
Solvent: O
Product: O=c1[nH]ncc2cc(Br)ccc12
Temperature: 95 °C

Procedure:
To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95° C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:5][CH2:4]1.[O:23]1[C:28]2=[CH:29][N:30]=[C:31]([CH:33]=O)[CH:32]=[C:27]2[CH2:26][CH2:25][CH2:24]1.C([BH3-])#N.[Na+].C[O-].[Na+].CO>CO.C(OCC)(=O)C.C(O)(=O)C>[ClH:1].[O:23]1[C:28]2=[CH:29][N:30]=[C:31]([CH2:33][NH:2][CH:3]3[CH2:4][CH2:5][N:6]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[N:16][CH:17]=[C:18]([F:21])[CH:19]=5)[CH:14]=[CH:13][C:12]4=[O:22])[CH2:7][CH2:8]3)[CH:32]=[C:27]2[CH2:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCC2
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: C[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCCC3)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 75.8 %

Procedure:
To a suspension of 0.10 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride and 61 mg of 3,4-dihydro-2H-pyrano(2,3-c)pyridine-6-carbaldehyde in 2.5 mL of methanol, 62 mg of sodium cyanoborohydride, 0.14 g of a 28% sodium methoxide/methanol solution and 86 μL of acetic acid were added, and the mixture was stirred at room temperature for 1 hour 50 minutes. Thereto were added ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution, and a 2 mol/L aqueous sodium hydroxide solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate twice. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=10:1. The resultant residue was dissolved in 1 mL of methanol and 1 mL of and ethyl acetate, and thereto was added 0.5 mL of a 4 mol/L hydrogen chloride/ethyl acetate solution at room temperature. The solvent was distilled off under reduced pressure, diethyl ether was added the resultant residue, and the solid was filtered off to obtain 0.11 g of 1-(2-(4-((3,4-dihydro-2H-pyrano(2,3-c)pyridin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one hydrochloride as a light yellow solid.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:22]([NH:24][C@H:25]([C:33]([NH:35][O:36][P:37]([CH3:40])(=[O:39])[OH:38])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[CH3:21])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:22]([NH:24][C@H:25]([C:33]([NH:35][O:36][P:37]([CH3:40])(=[O:38])[OH:39])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[CH3:21]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NOP(C)(=O)O
Solvent: NCc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)NOP(C)(=O)O

Procedure:
In a manner analogous to that given in Example 7 (b), from the benzylamine salt of [(N-benzyloxycarbonyl-L-alanyl-L-phenylalanyl)amino]-methylphosphonic acid there was obtained (L-alanyl-L-phenylalanylamino)-methylphosphonic acid of melting point 278°-280° C (decomposition); [α]D20 = +8.6° (c = 0.54% in 1-N sodium hydroxide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]2[S:31][C:30]([O:32][CH3:33])=[N:29][CH:4]2[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][NH:38][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]3[S:31][C:30]([O:32][CH3:33])=[N:29][CH:4]3[CH:5]=2)=[O:28])[CH2:36][CH2:35]1
Reactant: COC1=NC2C=c3c(nc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)oc3=O)=C(Cl)C2S1
Reactant: NCC1CC1
Product: COC1=NC2C=C(C(=O)NCC3CC3)C(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)=C(Cl)C2S1

Procedure:
See step f) of example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-2-methoxy-3a,9a-dihydro-7-oxa-3-thia-1,5-diaza-cyclopenta[b]naphthalen-8-one as starting material and cyclopropanemethylamine. After overnight reaction and chromatography column purification, the expected product is obtained within 34%; LC/MS: 585/587 (M+1)+; m.p.: 199-201° C.